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In crystallography, a crystallographic point group is a three-dimensional point group whose symmetry operations are compatible with a three-dimensional crystallographic lattice. According to the crystallographic restriction it may only contain one-, two-, three-, four- and sixfold rotations or rotoinversions. This reduces the number of crystallographic point groups to 32 (from an infinity of general point groups). These 32 groups are the same as the 32 types of morphological (external) crystalline symmetries derived in 1830 by Johann Friedrich Christian Hessel from a consideration of observed crystal forms. In 1867 Axel Gadolin, who was unaware of the previous work of Hessel, found the crystallographic point groups independently using stereographic projection to represent the symmetry elements of the 32 groups.: 379
In the classification of crystals, to each space group is associated a crystallographic point group by "forgetting" the translational components of the symmetry operations, that is, by turning screw rotations into rotations, glide reflections into reflections and moving all symmetry elements into the origin. Each crystallographic point group defines the (geometric) crystal class of the crystal.
The point group of a crystal determines, among other things, the directional variation of physical properties that arise from its structure, including optical properties such as birefringency, or electro-optical features such as the Pockels effect.
== Notation ==
The point groups are named according to their component symmetries. There are several standard notations used by crystallographers, mineralogists, and physicists.
For the correspondence of the two systems below, see crystal system.
=== Schoenflies notation ===
In Schoenflies notation, point groups are denoted by a letter symbol with a subscript. The symbols used in crystallography mean the following:
Cn (for cyclic) indicates that the group has an n-fold rotation axis. Cnh is Cn with the addition of a mirror (reflection) plane perpendicular to the axis of rotation. Cnv is Cn with the addition of n mirror planes parallel to the axis of rotation.
S2n (for Spiegel, German for mirror) denotes a group with only a 2n-fold rotation-reflection axis.
Dn (for dihedral, or two-sided) indicates that the group has an n-fold rotation axis plus n twofold axes perpendicular to that axis. Dnh has, in addition, a mirror plane perpendicular to the n-fold axis. Dnd has, in addition to the elements of Dn, mirror planes parallel to the n-fold axis.
The letter T (for tetrahedron) indicates that the group has the symmetry of a tetrahedron. Td includes improper rotation operations, T excludes improper rotation operations, and Th is T with the addition of an inversion.
The letter O (for octahedron) indicates that the group has the symmetry of an octahedron, with (Oh) or without (O) improper operations (those that change handedness).
Due to the crystallographic restriction theorem, n = 1, 2, 3, 4, or 6 in 2- or 3-dimensional space.
D4d and D6d are actually forbidden because they contain improper rotations with n=8 and 12 respectively. The 27 point groups in the table plus T, Td, Th, O and Oh constitute 32 crystallographic point groups.
=== Hermann–Mauguin notation ===
An abbreviated form of the Hermann–Mauguin notation commonly used for space groups also serves to describe crystallographic point groups. Group names are
=== The correspondence between different notations ===
== Isomorphisms ==
Many of the crystallographic point groups share the same internal structure. For example, the point groups 1, 2, and m contain different geometric symmetry operations, (inversion, rotation, and reflection, respectively) but all share the structure of the cyclic group C2. All isomorphic groups are of the same order, but not all groups of the same order are isomorphic. The point groups which are isomorphic are shown in the following table:
This table makes use of cyclic groups (C1, C2, C3, C4, C6), dihedral groups (D2, D3, D4, D6), one of the alternating groups (A4), and one of the symmetric groups (S4). Here the symbol " × " indicates a direct product.
== Deriving the crystallographic point group (crystal class) from the space group ==
Leave out the Bravais lattice type.
Convert all symmetry elements with translational components into their respective symmetry elements without translation symmetry. (Glide planes are converted into simple mirror planes; screw axes are converted into simple axes of rotation.)
Axes of rotation, rotoinversion axes, and mirror planes remain unchanged.
== See also ==
Molecular symmetry
Point group
Space group
Point groups in three dimensions
Crystal system
== References ==
== External links ==
Point-group symbols in International Tables for Crystallography (2006). Vol. A, ch. 12.1, pp. 818-820
Names and symbols of the 32 crystal classes in International Tables for Crystallography (2006). Vol. A, ch. 10.1, p. 794
Pictorial overview of the 32 groups | Wikipedia/Crystallographic_point_groups |
Radiography is an imaging technique using X-rays, gamma rays, or similar ionizing radiation and non-ionizing radiation to view the internal form of an object. Applications of radiography include medical ("diagnostic" radiography and "therapeutic radiography") and industrial radiography. Similar techniques are used in airport security, (where "body scanners" generally use backscatter X-ray). To create an image in conventional radiography, a beam of X-rays is produced by an X-ray generator and it is projected towards the object. A certain amount of the X-rays or other radiation are absorbed by the object, dependent on the object's density and structural composition. The X-rays that pass through the object are captured behind the object by a detector (either photographic film or a digital detector). The generation of flat two-dimensional images by this technique is called projectional radiography. In computed tomography (CT scanning), an X-ray source and its associated detectors rotate around the subject, which itself moves through the conical X-ray beam produced. Any given point within the subject is crossed from many directions by many different beams at different times. Information regarding the attenuation of these beams is collated and subjected to computation to generate two-dimensional images on three planes (axial, coronal, and sagittal) which can be further processed to produce a three-dimensional image.
== History ==
Radiography's origins and fluoroscopy's origins can both be traced to 8 November 1895, when German physics professor Wilhelm Conrad Röntgen discovered the X-ray and noted that, while it could pass through human tissue, it could not pass through bone or metal. Röntgen referred to the radiation as "X", to indicate that it was an unknown type of radiation. He received the first Nobel Prize in Physics for his discovery.
There are conflicting accounts of his discovery because Röntgen had his lab notes burned after his death, but this is a likely reconstruction by his biographers: Röntgen was investigating cathode rays using a fluorescent screen painted with barium platinocyanide and a Crookes tube which he had wrapped in black cardboard to shield its fluorescent glow. He noticed a faint green glow from the screen, about 1 metre away. Röntgen realized some invisible rays coming from the tube were passing through the cardboard to make the screen glow: they were passing through an opaque object to affect the film behind it.
Röntgen discovered X-rays' medical use when he made a picture of his wife's hand on a photographic plate formed due to X-rays. The photograph of his wife's hand was the first ever photograph of a human body part using X-rays. When she saw the picture, she said, "I have seen my death."
The first use of X-rays under clinical conditions was by John Hall-Edwards in Birmingham, England, on 11 January 1896, when he radiographed a needle stuck in the hand of an associate. On 14 February 1896, Hall-Edwards also became the first to use X-rays in a surgical operation.
The United States saw its first medical X-ray obtained using a discharge tube of Ivan Pulyui's design. In January 1896, on reading of Röntgen's discovery, Frank Austin of Dartmouth College tested all of the discharge tubes in the physics laboratory and found that only the Pulyui tube produced X-rays. This was a result of Pulyui's inclusion of an oblique "target" of mica, used for holding samples of fluorescent material, within the tube. On 3 February 1896 Gilman Frost, professor of medicine at the college, and his brother Edwin Frost, professor of physics, exposed the wrist of Eddie McCarthy, whom Gilman had treated some weeks earlier for a fracture, to the X-rays and collected the resulting image of the broken bone on gelatin photographic plates obtained from Howard Langill, a local photographer also interested in Röntgen's work.
X-rays were put to diagnostic use very early; for example, Alan Archibald Campbell-Swinton opened a radiographic laboratory in the United Kingdom in 1896, before the dangers of ionizing radiation were discovered. Indeed, Marie Curie pushed for radiography to be used to treat wounded soldiers in World War I. Initially, many kinds of staff conducted radiography in hospitals, including physicists, photographers, physicians, nurses, and engineers. The medical speciality of radiology grew up over many years around the new technology. When new diagnostic tests were developed, it was natural for the radiographers to be trained in and to adopt this new technology. Radiographers now perform fluoroscopy, computed tomography, mammography, ultrasound, nuclear medicine and magnetic resonance imaging as well. Although a nonspecialist dictionary might define radiography quite narrowly as "taking X-ray images", this has long been only part of the work of "X-ray departments", radiographers, and radiologists. Initially, radiographs were known as roentgenograms, while skiagrapher (from the Ancient Greek words for "shadow" and "writer") was used until about 1918 to mean radiographer. The Japanese term for the radiograph, rentogen (レントゲン), shares its etymology with the original English term.
== Medical uses ==
Since the body is made up of various substances with differing densities, ionising and non-ionising radiation can be used to reveal the internal structure of the body on an image receptor by highlighting these differences using attenuation, or in the case of ionising radiation, the absorption of X-ray photons by the denser substances (like calcium-rich bones). The discipline involving the study of anatomy through the use of radiographic images is known as radiographic anatomy. Medical radiography acquisition is generally carried out by radiographers, while image analysis is generally done by radiologists. Some radiographers also specialise in image interpretation. Medical radiography includes a range of modalities producing many different types of image, each of which has a different clinical application.
=== Projectional radiography ===
The creation of images by exposing an object to X-rays or other high-energy forms of electromagnetic radiation and capturing the resulting remnant beam (or "shadow") as a latent image is known as "projection radiography". The "shadow" may be converted to light using a fluorescent screen, which is then captured on photographic film, it may be captured by a phosphor screen to be "read" later by a laser (CR), or it may directly activate a matrix of solid-state detectors (DR—similar to a very large version of a CCD in a digital camera). Bone and some organs (such as lungs) especially lend themselves to projection radiography. It is a relatively low-cost investigation with a high diagnostic yield. The difference between soft and hard body parts stems mostly from the fact that carbon has a very low X-ray cross section compared to calcium.
=== Computed tomography ===
Computed tomography or CT scan (previously known as CAT scan, the "A" standing for "axial") uses ionizing radiation (x-ray radiation) in conjunction with a computer to create images of both soft and hard tissues. These images look as though the patient was sliced like bread (thus, "tomography" – "tomo" means "slice"). Though CT uses a higher amount of ionizing x-radiation than diagnostic x-rays (both utilising X-ray radiation), with advances in technology, levels of CT radiation dose and scan times have reduced. CT exams are generally short, most lasting only as long as a breath-hold, Contrast agents are also often used, depending on the tissues needing to be seen. Radiographers perform these examinations, sometimes in conjunction with a radiologist (for instance, when a radiologist performs a CT-guided biopsy).
=== Dual energy X-ray absorptiometry ===
DEXA, or bone densitometry, is used primarily for osteoporosis tests. It is not projection radiography, as the X-rays are emitted in two narrow beams that are scanned across the patient, 90 degrees from each other. Usually the hip (head of the femur), lower back (lumbar spine), or heel (calcaneum) are imaged, and the bone density (amount of calcium) is determined and given a number (a T-score). It is not used for bone imaging, as the image quality is not good enough to make an accurate diagnostic image for fractures, inflammation, etc. It can also be used to measure total body fat, though this is not common. The radiation dose received from DEXA scans is very low, much lower than projection radiography examinations.
=== Fluoroscopy ===
Fluoroscopy is a term invented by Thomas Edison during his early X-ray studies. The name refers to the fluorescence he saw while looking at a glowing plate bombarded with X-rays.
The technique provides moving projection radiographs. Fluoroscopy is mainly performed to view movement (of tissue or a contrast agent), or to guide a medical intervention, such as angioplasty, pacemaker insertion, or joint repair/replacement. The last can often be carried out in the operating theatre, using a portable fluoroscopy machine called a C-arm. It can move around the surgery table and make digital images for the surgeon. Biplanar Fluoroscopy works the same as single plane fluoroscopy except displaying two planes at the same time. The ability to work in two planes is important for orthopedic and spinal surgery and can reduce operating times by eliminating re-positioning.
Angiography is the use of fluoroscopy to view the cardiovascular system. An iodine-based contrast is injected into the bloodstream and watched as it travels around. Since liquid blood and the vessels are not very dense, a contrast with high density (like the large iodine atoms) is used to view the vessels under X-ray. Angiography is used to find aneurysms, leaks, blockages (thromboses), new vessel growth, and placement of catheters and stents. Balloon angioplasty is often done with angiography.
=== Contrast radiography ===
Contrast radiography uses a radiocontrast agent, a type of contrast medium, to make the structures of interest stand out visually from their background. Contrast agents are required in conventional angiography, and can be used in both projectional radiography and computed tomography (called contrast CT).
=== Other medical imaging ===
Although not technically radiographic techniques due to not using X-rays, imaging modalities such as PET and MRI are sometimes grouped in radiography because the radiology department of hospitals handle all forms of imaging. Treatment using radiation is known as radiotherapy.
== Industrial radiography ==
Industrial radiography is a method of non-destructive testing where many types of manufactured components can be examined to verify the internal structure and integrity of the specimen. Industrial Radiography can be performed utilizing either X-rays or gamma rays. Both are forms of electromagnetic radiation. The difference between various forms of electromagnetic energy is related to the wavelength. X and gamma rays have the shortest wavelength and this property leads to the ability to penetrate, travel through, and exit various materials such as carbon steel and other metals. Specific methods include industrial computed tomography.
== Image quality ==
Image quality will depend on resolution and density.
Resolution is the ability of an image to show closely spaced structure in the object as separate entities in the image while density is the blackening power of the image.
Sharpness of a radiographic image is strongly determined by the size of the X-ray source. This is determined by the area of the electron beam hitting the anode.
A large photon source results in more blurring in the final image and is worsened by an increase in image formation distance. This blurring can be measured as a contribution to the modulation transfer function of the imaging system.
== Radiation dose ==
The dosage of radiation applied in radiography varies by procedure. For example, the effective dosage of a chest x-ray is 0.1 mSv, while an abdominal CT is 10 mSv. The American Association of Physicists in Medicine (AAPM) have stated that the "risks of medical imaging at patient doses below 50 mSv for single procedures or 100 mSv for multiple procedures over short time periods are too low to be detectable and may be nonexistent." Other scientific bodies sharing this conclusion include the International Organization of Medical Physicists, the UN Scientific Committee on the Effects of Atomic Radiation, and the International Commission on Radiological Protection. Nonetheless, radiological organizations, including the Radiological Society of North America (RSNA) and the American College of Radiology (ACR), as well as multiple government agencies, indicate safety standards to ensure that radiation dosage is as low as possible.
=== Shielding ===
Lead is the most common shield against X-rays because of its highdensity (11,340 kg/m3), stopping power, ease of installation and low cost. The maximum range of a high-energy photon such as an X-ray in matter is infinite; at every point in the matter traversed by the photon, there is a probability of interaction. Thus there is a very small probability of no interaction over very large distances. The shielding of photon beam is therefore exponential (with an attenuation length being close to the radiation length of the material); doubling the thickness of shielding will square the shielding effect.
Starting in the 1950s, personal lead shielding began to be used on directly on patients during all X-rays over the abdomen to intending to protect the gonads (reproductive organs) or a fetus if the patient was pregnant. Dental X-rays would also typically additionally use lead shielding to protect the thyroid. However, a consensus was reached between 2019 and 2021 that lead shielding for routine diagnostic X-rays is not necessary and may in some cases be harmful. Personal shielding for medical professionals and other people in the room is still recommended.
Rooms where X-rays are performed are lined with lead. The table in this section shows the recommended thickness of lead shielding for a room where X-rays are performed as function of X-ray energy, from the Recommendations by the Second International Congress of Radiology.
=== Campaigns ===
In response to increased concern by the public over radiation doses and the ongoing progress of best practices, The Alliance for Radiation Safety in Pediatric Imaging was formed within the Society for Pediatric Radiology. In concert with the American Society of Radiologic Technologists, the American College of Radiology, and the American Association of Physicists in Medicine, the Society for Pediatric Radiology developed and launched the Image Gently campaign which is designed to maintain high quality imaging studies while using the lowest doses and best radiation safety practices available on pediatric patients. This initiative has been endorsed and applied by a growing list of various professional medical organizations around the world and has received support and assistance from companies that manufacture equipment used in radiology.
Following upon the success of the Image Gently campaign, the American College of Radiology, the Radiological Society of North America, the American Association of Physicists in Medicine, and the American Society of Radiologic Technologists have launched a similar campaign to address this issue in the adult population called Image Wisely. The World Health Organization and International Atomic Energy Agency (IAEA) of the United Nations have also been working in this area and have ongoing projects designed to broaden best practices and lower patient radiation dose.
=== Provider payment ===
Contrary to advice that emphasises only conducting radiographs when in the patient's interest, recent evidence suggests that they are used more frequently when dentists are paid under fee-for-service.
== Equipment ==
=== Sources ===
In medicine and dentistry, projectional radiography and computed tomography images generally use X-rays created by X-ray generators, which generate X-rays from X-ray tubes. The resultant images from the radiograph (X-ray generator/machine) or CT scanner are correctly referred to as "radiograms"/"roentgenograms" and "tomograms" respectively.
A number of other sources of X-ray photons are possible, and may be used in industrial radiography or research; these include betatrons, linear accelerators (linacs), and synchrotrons. For gamma rays, radioactive sources such as 192Ir, 60Co, or 137Cs are used.
=== Grid ===
An anti-scatter grid may be placed between the patient and the detector to reduce the quantity of scattered x-rays that reach the detector. This improves the contrast resolution of the image, but also increases radiation exposure for the patient.
=== Detectors ===
Detectors can be divided into two major categories: imaging detectors (such as photographic plates and X-ray film (photographic film), now mostly replaced by various digitizing devices like image plates or flat panel detectors) and dose measurement devices (such as ionization chambers, Geiger counters, and dosimeters used to measure the local radiation exposure, dose, and/or dose rate, for example, for verifying that radiation protection equipment and procedures are effective on an ongoing basis).
=== Side markers ===
A radiopaque anatomical side marker is added to each image. For example, if the patient has their right hand x-rayed, the radiographer includes a radiopaque "R" marker within the field of the x-ray beam as an indicator of which hand has been imaged. If a physical marker is not included, the radiographer may add the correct side marker later as part of digital post-processing.
=== Image intensifiers and array detectors ===
As an alternative to X-ray detectors, image intensifiers are analog devices that readily convert the acquired X-ray image into one visible on a video screen. This device is made of a vacuum tube with a wide input surface coated on the inside with caesium iodide (CsI). When hit by X-rays, phosphor material causes the photocathode adjacent to it to emit electrons. These electrons are then focused using electron lenses inside the intensifier to an output screen coated with phosphorescent materials. The image from the output can then be recorded via a camera and displayed.
Digital devices known as array detectors are becoming more common in fluoroscopy. These devices are made of discrete pixelated detectors known as thin-film transistors (TFT) which can either work indirectly by using photo detectors that detect light emitted from a scintillator material such as CsI, or directly by capturing the electrons produced when the X-rays hit the detector. Direct detectors do not tend to experience the blurring or spreading effect caused by phosphorescent scintillators or by film screens since the detectors are activated directly by X-ray photons.
== Dual-energy ==
Dual-energy radiography is where images are acquired using two separate tube voltages. This is the standard method for bone densitometry. It is also used in CT pulmonary angiography to decrease the required dose of iodinated contrast.
== See also ==
Autoradiograph – Radiograph made by recording radiation emitted by samples on photographic plates
Background radiation – Measure of ionizing radiation in the environment
Computer-aided diagnosis – Type of diagnosis assisted by computers
GXMO
Imaging science – Representation or reproduction of an object's formPages displaying short descriptions of redirect targets
List of civilian radiation accidents
Medical imaging in pregnancy – Types of pregnancy imaging techniques
Radiation – Waves or particles moving through space
Digital radiography – Form of radiography
Radiation contamination – Undesirable radioactive elements on surfaces or in gases, liquids, or solids is a problemPages displaying short descriptions of redirect targets
Radiographer – Healthcare professional
Thermography – Infrared imaging used to reveal temperature
== References ==
== Further reading ==
== External links ==
MedPix Medical Image Database
Video on X-ray inspection and industrial computed tomography, Karlsruhe University of Applied Sciences
NIST's XAAMDI: X-Ray Attenuation and Absorption for Materials of Dosimetric Interest Database
NIST's XCOM: Photon Cross Sections Database
NIST's FAST: Attenuation and Scattering Tables
A lost industrial radiography source event
RadiologyInfo - The radiology information resource for patients: Radiography (X-rays) | Wikipedia/X-ray_radiography |
Serial femtosecond crystallography (SFX) is a form of X-ray crystallography developed for use at X-ray free-electron lasers (XFELs). Single pulses at free-electron lasers are bright enough to generate resolvable Bragg diffraction from sub-micron crystals. However, these pulses also destroy the crystals, meaning that a full data set involves collecting diffraction from many crystals. This method of data collection is referred to as serial, referencing a row of crystals streaming across the X-ray beam, one at a time. It can be performed at room temperature, allowing for the study of biochemical dynamics. It can be used to visualize samples prone to radiation damage, such as metalloproteins, and to observe transient structures, such as reaction intermediates, which would not be captured using conventional X-ray crystallography.
== History ==
While the idea of serial crystallography had been proposed earlier, it was first demonstrated with XFELs by Chapman et al. at the Linac Coherent Light Source (LCLS) in 2011. This method has since been extended to solve unknown structures, perform time-resolved experiments, and later even brought back to synchrotron X-ray sources.
== Methods ==
In comparison to conventional crystallography, where a single (relatively large) crystal is rotated in order to collect a 3D data set, some additional methods have to be developed to measure in the serial mode. First, a method is required to efficiently stream crystals across the beam focus. The other major difference is in the data analysis pipeline. Here, each crystal is in a random, unknown orientation which must be computationally determined before the diffraction patterns from all the crystals can be merged into a set of 3D hkℓ intensities.
=== Sample Delivery ===
The first sample delivery system used for this technique was the Gas Dynamic Virtual Nozzle (GDVN) which generates a liquid jet in vacuum (accelerated by a concentric helium gas stream) containing crystals. Since then, many other methods have been successfully demonstrated at both XFELs and synchrotron sources. A summary of these methods along with their key relative features is given below:
Gas Dynamic Virtual Nozzle (GDVN) - low background scattering, but high sample consumption. Only method available for high repetition rate sources.
Lipidic Cubic Phase (LCP) injector - Low sample consumption, with relatively high background. Specially suited for membrane proteins
Other viscous delivery media - Similar to LCP, low sample consumption with high background
Fixed target scanning systems (wide variety of systems have been used with different features, with standard crystal loops, or silicon chips) - Low sample consumption, background depends on system, mechanically complex
Tape drive (crystals auto-pipetted onto a Kapton tape and brought to X-ray focus) - Similar to fixed target systems, except with fewer moving parts
=== Data Analysis ===
In order to recover a 3D structure from the individual diffraction patterns, they must be oriented, scaled and merged to generate a list of hkℓ intensities. These intensities can then be passed to standard crystallographic phasing and refinement programs. The first experiments only oriented the patterns and obtained accurate intensity values by averaging over a large number of crystals (> 100,000). Later versions correct for variations in individual pattern properties such as overall intensity variations and B-factor variations as well as refining the orientations to fix the "partialities" of the individual Bragg reflections.
== References ==
== External links ==
CrystFEL
cctbx.xfel
NXDS
The revolution of XFEL | Wikipedia/Serial_femtosecond_crystallography |
Orientations of Proteins in Membranes (OPM) database provides spatial positions of membrane protein structures with respect to the lipid bilayer. Positions of the proteins are calculated using an implicit solvation model of the lipid bilayer. The results of calculations were verified against experimental studies of spatial arrangement of transmembrane and peripheral proteins in membranes.
Proteins structures are taken from the Protein Data Bank. OPM also provides structural classification of membrane-associated proteins into families and superfamilies, membrane topology, quaternary structure of proteins in membrane-bound state, and the type of a destination membrane for each protein. The coordinate files with calculated membrane boundaries are downloadable. The site allows visualization of protein structures with membrane boundary planes through Jmol.
The database was widely used in experimental and theoretical studies of membrane-associated proteins. However, structures of many membrane-associated proteins are not included in the database if their spatial arrangement in membrane can not be computationally predicted from the three-dimensional structure. This is the case when all membrane-anchoring parts of the proteins (amphiphilic alpha helices, exposed nonpolar residues, or lipidated amino acid residues) are missing in the experimental structures. The database also does not include lower resolution structures with only main chain atoms provided by the Protein Data Bank. The calculated spatial arrangements of the lower resolution protein structures in the lipid bilayer can be found in other resources, such as PDBTM.
== References == | Wikipedia/Orientations_of_Proteins_in_Membranes_database |
Le Bail analysis is a whole diffraction pattern profile fitting technique used to characterize the properties of crystalline materials, such as structure. It was invented by Armel Le Bail around 1988.
== Background ==
The Le Bail method extracts intensities (Ihkl) from powder diffraction data. This is done in order to find intensities that are suitable to determine the atomic structure of a crystalline material and to refine the unit cell and has the added advantage of checking phase-purity. Generally, the intensities of powder diffraction data are complicated by overlapping diffraction peaks with similar d-spacings. For the Le Bail method, the unit cell and the approximate space group of the sample must be predetermined because they are included as a part of the fitting technique. The algorithm involves refining the unit cell, the profile parameters, and the peak intensities to match the measured powder diffraction pattern. It is not necessary to know the structural factor and associated structural parameters, since they are not considered in this type of analysis. Le Bail can be used to find phase transitions in high pressure and temperature experiments. It generally provides a quick method to refine the unit cell, which allows better experimental planning. Le Bail analysis provides a more reliable estimate for the intensities of allowed reflections for different crystal symmetries.
Crystallographic structural determination can be accomplished in multiple ways. Le Bail technique is relevant for diffraction studies that involve using a radiation source, which may be neutron or synchrotron, to collect a high resolution, high quality powder diffraction profile. Initially, peak positions are found in the data. Next, the pattern is indexed in order to determine the unit cell or lattice parameters. Then, space group determination follows based on symmetry and the presence or absence of certain reflections. Then, either Le Bail or Pawley technique may be used to extract intensities and refine the unit cell.
== Refinement ==
Le Bail analysis fits parameters using a steepest descent minimization process. Specifically, the method is least squares analysis, which is an iterative process that is discussed later in this article. The parameters being fitted include the unit-cell parameters, the instrumental zero error, peak width parameters, and peak shape parameters. First, the Le Bail method defines an arbitrary starting value for the intensities (Iobs). This value is ordinarily set to one, but other values may be used. While peak positions are constrained by the unit cell parameters, intensities are unconstrained. The equation to calculate intensities is:
I
o
b
s
(
1
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=
∑
y
i
(
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b
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)
y
i
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1
)
y
i
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{\displaystyle I_{obs}(1)={\frac {\sum y_{i}(obs)y_{i}(1)}{y_{i}(calc)}}}
In the equation, Iobs is the intensity observed at a particular step and yi(obs) is the observed profile point. yi(calc) is the A single intensity value may contain more than one peak. Other peaks may be calculated similarly. The final intensity for a peak is calculated as y(calc) = yi(1) + yi(2). The summation is carried out over all contributing profile points for a particular 2-theta bin. The summation process is known as profile intensity partitioning, and it works over any number of peaks. Le Bail technique works especially well with overlapping intensities since in this method the intensity is allotted based on the multiplicity of the intensities that contribute to a particular peak.
The somewhat arbitrary choice of starting values produces a bias in the calculated values. The refinement process continues by setting the new calculated structure factor to the observed structure factor value. The process is then repeated with the new structure factor estimate. At this point, the unit cell, background, peak widths, peak shape, and resolution function are refined, and the parameters are improved. The structure factor is then reset to the new structure factor value, and the process begins again. Structural refinement can continue with whole profile fitting techniques or further treatment of peak overlap. Probabilistic approaches may also be used to treat peak overlap.
== Advantages ==
Some authors suggest the Le Bail technique exploits prior information more efficiently than Pawley method. This was an important consideration at the time of development when computing power was limited. Le Bail is also easily integrated into Rietveld analysis software, and is a part of a number of programs. Both methods improve subsequent structural refinements.
== Available software ==
Le Bail analysis is commonly a part of Rietveld analysis software, such as GSAS/EXPGUI. It is also used in ARITVE, BGMN, EXPO, EXTRACT, FullProf, GENEFP, Jana2006, Overlap, Powder Cell, Rietan, TOPAS and Highscore.
== References ==
== Sources ==
Dinnebier, R. (2008), Dinnebier, R E; Billinge, S J L (eds.), Powder Diffraction: Theory and Practice (1st ed.), RSC, p. 200, doi:10.1039/9781847558237, ISBN 978-0-85404-231-9
LeBail, A (2005). "Whole Powder Pattern Decomposition Methods and Applications: A Retrospection". Powder Diffraction. 20 (4): 316–326. Bibcode:2005PDiff..20..316L. doi:10.1154/1.2135315.
Department of Chemistry, University College, London, Powder Diffraction on the Web, retrieved 5 Sep 2017{{citation}}: CS1 maint: multiple names: authors list (link) | Wikipedia/Le_Bail_method |
In crystallography, the R-factor (sometimes called residual factor or reliability factor or the R-value or RWork) is a measure of the disagreement between the crystallographic model and the experimental X-ray diffraction data - lower the R value lower is the disagreement or better is the agreement. In other words, it is a measure of how well the refined structure predicts the observed data. The value is also sometimes called the discrepancy index, as it mathematically describes the difference between the experimental observations and the ideal calculated values. It is defined by the following equation:
R
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|
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{\displaystyle R={\frac {\sum {||F_{\text{obs}}|-|F_{\text{calc}}||}}{\sum {|F_{\text{obs}}|}}},}
where F is the so-called structure factor and the sum extends over all the reflections of X-rays measured and their calculated counterparts respectively. The structure factor is closely related to the intensity of the reflection it describes:
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{\displaystyle I_{hkl}\propto |F(hkl)|^{2}}
.
The minimum possible value is zero, indicating perfect agreement between experimental observations and the structure factors predicted from the model. There is no theoretical maximum, but in practice, values are considerably less than one even for poor models, provided the model includes a suitable scale factor. Random experimental errors in the data contribute to
R
{\displaystyle R}
even for a perfect model, and these have more leverage when the data are weak or few, such as for a low-resolution data set. Model inadequacies such as incorrect or missing parts and unmodeled disorder are the other main contributors to
R
{\displaystyle R}
, making it useful to assess the progress and final result of a crystallographic model refinement. For large molecules, the R-factor usually ranges between 0.6 (when computed for a random model and against an experimental data set) and 0.2 (for example for a well refined macro-molecular model at a resolution of 2.5 Ångström). Small molecules (up to ca. 1000 atoms) usually form better-ordered crystals than large molecules, and thus it is possible to attain lower R-factors. In the Cambridge Structural Database of small-molecule structures, more than 95% of the 500,000+ crystals have an R-factor lower than 0.15, and 9.5% have an R-factor lower than 0.03.
Crystallographers also use the Free R-Factor (
R
F
r
e
e
{\displaystyle R_{Free}}
) to assess possible overmodeling of the data.
R
F
r
e
e
{\displaystyle R_{Free}}
is computed according to the same formula given above, but on a small, random sample of data that are set aside for the purpose and never included in the refinement.
R
F
r
e
e
{\displaystyle R_{Free}}
will always be greater than
R
{\displaystyle R}
because the model is not fitted to the reflections that contribute to
R
F
r
e
e
{\displaystyle R_{Free}}
, but the two statistics should be similar because a correct model should predict all the data with uniform accuracy. If the two statistics differ significantly then that indicates the model has been over-parameterized, so that to some extent it predicts not the ideal error-free data for the correct model, but rather the error-afflicted data actually observed.
The quantities
R
sym
{\displaystyle R_{\text{sym}}}
and
R
merge
{\displaystyle R_{\text{merge}}}
are similarly used to describe the internal agreement of measurements in a crystallographic data set.
== References ==
== See also ==
Patterson function | Wikipedia/R-factor_(crystallography) |
The Bavarian Academy of Sciences and Humanities (German: Bayerische Akademie der Wissenschaften) is an independent public institution, located in Munich. It appoints scholars whose research has contributed considerably to the increase of knowledge within their subject. The general goal of the academy is the promotion of interdisciplinary encounters and contacts and the cooperation of representatives of different subjects.
== History ==
On 12 October 1758 the lawyer Johann Georg von Lori (1723–1787), Privy Counsellor at the College of Coinage and Mining in Munich, founded the Bayerische Gelehrte Gesellschaft (Learned Society of Bavaria).
This led to the foundation by Maximilian III Joseph, Elector of Bavaria, of the Bavarian Academy of Sciences and Humanities on 28 March 1759.
Count Sigmund von Haimhausen was the first president.
The Academy's foundation charter specifically mentions the Parnassus Boicus, an earlier learned society.
Originally, the Academy consisted of two divisions, the Class for History (Historische Klasse) and the Class for Philosophy (Philosophische Klasse); natural sciences, including mathematics and physics, were thought of as part of the Class for Philosophy. Today, the Academy is still divided into two classes, but the classes are now the Class for Philosophy and History (which also includes the humanities and social sciences) and the Class for Mathematics and the Natural Sciences.
== Members ==
In each class, the number of ordinary members is limited to 45, and the number of corresponding members is limited to 80. However, ordinary members at or over the age of 70 are not counted towards this limit; the number of ordinary members is, therefore, usually around 120.
During the course of its history, the academy has had numerous famous members including Johann Wolfgang von Goethe, the Grimm brothers, Theodor Mommsen, Anthimos Gazis, Alexander and Wilhelm von Humboldt, Kurt Sethe, Max Planck, Otto Hahn, Albert Einstein, Max Weber, Werner Heisenberg and Adolf Butenandt.
The first women were admitted as full members of the academy in 1995, and including the geneticist Regine Kafmann and the Indo-European linguist Johanna Narten.
== Presidents ==
First president was the chairman of the Mint and Mining Commission, Sigmund, Count of Haimhausen. Further presidents included Friedrich Heinrich Jacobi, Anton Clemens von Toerring-Seefeld, Friedrich Wilhelm von Schelling, Justus von Liebig, Ignaz von Döllinger, Max von Pettenkofer and Walther Meißner.
At present, the presidency is held by Thomas Höllmann.
== Commissions of the Academy ==
For the pursuit of long-term projects, the Academy forms Commissions. At present, 37 Commissions employ more than 450 persons.
== See also ==
Ludwig Maximilian University of Munich
Technical University of Munich
List of universities in Germany
Bavaria
German Academy of Sciences Leopoldina
== References ==
Citations
Further reading
== External links ==
Homepage of the Bavarian Academy of Sciences and Humanities
Sitzungsberichte der mathematisch-physikalischen Klasse (Proceedings of the Mathematical-Physical Class, in German) 1860–2004 at ZOBODAT
"Union der deutschen Akademien der Wissenschaften". Bayerische Akademie der Wissenschaften (in German). Retrieved 8 July 2021.
"Bayerische Akademie der Wissenschaften". TUM (in German). Archived from the original on 29 May 2022. Retrieved 8 July 2021.
"Bayerische Akademie der Wissenschaften, München". Friedrich-Alexander-Universität Erlangen-Nürnberg (in German). Retrieved 8 July 2021. | Wikipedia/Bavarian_Academy_of_Sciences_and_Humanities |
The Structural Classification of Proteins (SCOP) database is a largely manual classification of protein structural domains based on similarities of their structures and amino acid sequences. A motivation for this classification is to determine the evolutionary relationship between proteins. Proteins with the same shapes but having little sequence or functional similarity are placed in different superfamilies, and are assumed to have only a very distant common ancestor. Proteins having the same shape and some similarity of sequence and/or function are placed in "families", and are assumed to have a closer common ancestor.
Similar to CATH and Pfam databases, SCOP provides a classification of individual structural domains of proteins, rather than a classification of the entire proteins which may include a significant number of different domains.
The SCOP database is freely accessible on the internet. SCOP was created in 1994 in the Centre for Protein Engineering and the Laboratory of Molecular Biology. It was maintained by Alexey G. Murzin and his colleagues in the Centre for Protein Engineering until its closure in 2010 and subsequently at the Laboratory of Molecular Biology in Cambridge, England.
The work on SCOP 1.75 has been discontinued in 2014. Since then SCOPe team from UC Berkeley has been responsible for updating the database in a compatible manner, with a combination of automated and manual methods. As of April 2019, the latest release is SCOPe 2.07 (March 2018).
The new Structural Classification of Proteins version 2 (SCOP2) database was released at the beginning of 2020. The new update featured an improved database schema, a new API and modernised web interface. This was the most significant update by the Cambridge group since SCOP 1.75 and builds on the advances in schema from the SCOP 2 prototype.
== Hierarchical organisation ==
The source of protein structures is the Protein Data Bank. The unit of classification of structure in SCOP is the protein domain. What the SCOP authors mean by "domain" is suggested by their statement that small proteins and most medium-sized ones have just one domain, and by the observation that human hemoglobin, which has an α2β2 structure, is assigned two SCOP domains, one for the α and one for the β subunit.
The shapes of domains are called "folds" in SCOP. Domains belonging to the same fold have the same major secondary structures in the same arrangement with the same topological connections. 1195 folds are given in SCOP version 1.75. Short descriptions of each fold are given. For example, the "globin-like" fold is described as core: 6 helices; folded leaf, partly opened. The fold to which a domain belongs is determined by inspection, rather than by software.
The levels of SCOP version 1.75 are as follows.
Class: Types of folds, e.g., beta sheets.
Fold: The different shapes of domains within a class.
Superfamily: The domains in a fold are grouped into superfamilies, which have at least a distant common ancestor.
Family: The domains in a superfamily are grouped into families, which have a more recent common ancestor.
Protein domain: The domains in families are grouped into protein domains, which are essentially the same protein.
Species: The domains in "protein domains" are grouped according to species.
Domain: part of a protein. For simple proteins, it can be the entire protein.
=== Classes ===
The broadest groups on SCOP version 1.75 are the protein fold classes. These classes group structures with similar secondary structure composition, but different overall tertiary structures and evolutionarily origins. This is the top level "root" of the SCOP hierarchical classification.
All alpha proteins [46456] (284): Domains consisting of α-helices
All beta proteins [48724] (174): Domains consisting of β-sheets
Alpha and beta proteins (a/b) [51349] (147): Mainly parallel beta sheets (beta-alpha-beta units)
Alpha and beta proteins (a+b) [53931] (376): Mainly antiparallel beta sheets (segregated alpha and beta regions)
Multi-domain proteins (alpha and beta) [56572] (66): Folds consisting of two or more domains belonging to different classes
membrane and cell surface proteins and peptides [56835] (58): Does not include proteins in the immune system
Small proteins [56992] (90): Usually dominated by metal ligand, cofactor, and/or disulfide bridges
coiled-coil proteins [57942] (7): Not a true class
Low resolution protein structures [58117] (26): Peptides and fragments. Not a true class
Peptides [58231] (121): peptides and fragments. Not a true class.
Designed proteins [58788] (44): Experimental structures of proteins with essentially non-natural sequences. Not a true class
The number in brackets, called a "sunid", is a SCOP unique integer identifier for each node in the SCOP hierarchy. The number in parentheses indicates how many elements are in each category. For example, there are 284 folds in the "All alpha proteins" class. Each member of the hierarchy is a link to the next level of the hierarchy.
=== Folds ===
Each class contains a number of distinct folds. This classification level indicates similar tertiary structure, but not necessarily evolutionary relatedness. For example, the "All-α proteins" class contains >280 distinct folds, including: Globin-like (core: 6 helices; folded leaf, partly opened), long alpha-hairpin (2 helices; antiparallel hairpin, left-handed twist) and Type I dockerin domains (tandem repeat of two calcium-binding loop-helix motifs, distinct from the EF-hand).
=== Superfamilies ===
Domains within a fold are further classified into superfamilies. This is a largest grouping of proteins for which structural similarity is sufficient to indicate evolutionary relatedness and therefore share a common ancestor. However, this ancestor is presumed to be distant, because the different members of a superfamily have low sequence identities. For example, the two superfamilies of the "Globin-like" fold are: the Globin superfamily and alpha-helical ferredoxin superfamily (contains two Fe4-S4 clusters).
=== Families ===
Protein families are more closely related than superfamilies. Domains are placed in the same family if that have either:
>30% sequence identity
some sequence identity (e.g., 15%) and perform the same function
The similarity in sequence and structure is evidence that these proteins have a closer evolutionary relationship than do proteins in the same superfamily. Sequence tools, such as BLAST, are used to assist in placing domains into superfamilies and families. For example, the four families in the "globin-like" superfamily of the "globin-like" fold are truncated hemoglobin (lack the first helix), nerve tissue mini-hemoglobin (lack the first helix but otherwise is more similar to conventional globins than the truncated ones), globins (Heme-binding protein), and phycocyanin-like phycobilisome proteins (oligomers of two different types of globin-like subunits containing two extra helices at the N-terminus binds a bilin chromophore). Families in SCOP are each assigned a concise classification string, sccs, where the letter identifies the class to which the domain belongs; the following integers identify the fold, superfamily, and family, respectively (e.g., a.1.1.2 for the "Globin" family).
=== PDB entry domains ===
A "TaxId" is the taxonomy ID number and links to the NCBI taxonomy browser, which provides more information about the species to which the protein belongs. Clicking on a species or isoform brings up a list of domains. For example, the "Hemoglobin, alpha-chain from Human (Homo sapiens)" protein has >190 solved protein structures, such as 2dn3 (complexed with cmo), and 2dn1 (complexed with hem, mbn, oxy). Clicking on the PDB numbers is supposed to display the structure of the molecule, but the links are currently broken (links work in pre-SCOP).
== Example ==
Most pages in SCOP contain a search box. Entering "trypsin +human" retrieves several proteins, including the protein trypsinogen from humans. Selecting that entry displays a page that includes the "lineage", which is at the top of most SCOP pages.
Human trypsonogen lineage
Root: scop
Class: All beta proteins [48724]
Fold: Trypsin-like serine proteases [50493]
barrel, closed; n=6, S=8; greek-key
duplication: consists of two domains of the same fold
Superfamily: Trypsin-like serine proteases [50494]
Family: Eukaryotic proteases [50514]
Protein: Trypsin(ogen) [50515]
Species: Human (Homo sapiens) [TaxId: 9606] [50519]
Searching for "Subtilisin" returns the protein, "Subtilisin from Bacillus subtilis, carlsberg", with the following lineage.
Subtilisin from Bacillus subtilis, carlsberg lineage
Root: scop
Class: Alpha and beta proteins (a/b) [51349]
Mainly parallel beta sheets (beta-alpha-beta units)
Fold: Subtilisin-like [52742]
3 layers: a/b/a, parallel beta-sheet of 7 strands, order 2314567; left-handed crossover connection between strands 2 & 3
Superfamily: Subtilisin-like [52743]
Family: Subtilases [52744]
Protein: Subtilisin [52745]
Species: Bacillus subtilis, carlsberg [TaxId: 1423] [52746]
Although both of these proteins are proteases, they do not even belong to the same fold, which is consistent with them being an example of convergent evolution.
== Comparison to other classification systems ==
SCOP classification is more dependent on manual decisions than the semi-automatic classification by CATH, its chief rival. Human expertise is used to decide whether certain proteins are evolutionary related and therefore should be assigned to the same superfamily, or their similarity is a result of structural constraints and therefore they belong to the same fold. Another database, FSSP, is purely automatically generated (including regular automatic updates) but offers no classification, allowing the user to draw their own conclusion as to the significance of structural relationships based on the pairwise comparisons of individual protein structures.
=== SCOP successors ===
By 2009, the original SCOP database manually classified 38,000 PDB entries into a strictly hierarchical structure. With the accelerating pace of protein structure publications, the limited automation of classification could not keep up, leading to a non-comprehensive dataset. The Structural Classification of Proteins extended (SCOPe) database was released in 2012 with far greater automation of the same hierarchical system and is full backwards compatible with SCOP version 1.75. In 2014, manual curation was reintroduced into SCOPe to maintain accurate structure assignment. As of February 2015, SCOPe 2.05 classified 71,000 of the 110,000 total PDB entries.
SCOP2 prototype was a beta version of Structural classification of proteins and classification system that aimed to more the evolutionary complexity inherent in protein structure evolution.
It is therefore not a simple hierarchy, but a directed acyclic graph network connecting protein superfamilies representing structural and evolutionary relationships such as circular permutations, domain fusion and domain decay. Consequently, domains are not separated by strict fixed boundaries, but rather are defined by their relationships to the most similar other structures. The prototype was used for the development of the SCOP version 2 database. The SCOP version 2, release January 2020, contains 5134 families and 2485 superfamilies compared to 3902 families and 1962 superfamilies in SCOP 1.75. The classification levels organise more than 41 000 non-redundant domains that represent more than 504 000 protein structures.
The Evolutionary Classification of Protein Domains (ECOD) database released in 2014 is a similar to SCOPe expansion of SCOP version 1.75. Unlike the compatible SCOPe, it renames the class-fold-superfamily-family hierarchy into an architecture-X-homology-topology-family (A-XHTF) grouping, with the last level mostly defined by Pfam and supplemented by HHsearch clustering for uncategorized sequences. ECOD has the best PDB coverage of all three successors: it covers every PDB structure, and is updated biweekly. The direct mapping to Pfam has proven useful to Pfam curators who use the homology-level category to supplement their "clan" grouping.
== See also ==
Structural alignment
CATH
FSSP
SUPERFAMILY
Pfam
== References ==
== External links ==
Structural Classification of Proteins (SCOP 2) - Manual classification of representative domains, regularly updated by the SCOP authors
Structural Classification of Proteins (SCOP 1.75) - Legacy SCOP 1.75 site, no longer updated
Structural Classification of Proteins extended (SCOPe) - The more automated successor of SCOP version 1.75
Evolutionary Classification of Protein Domains (ECOD) - Evolutionary classification based on SCOP version 1.75 and Pfam
Structural Classification of Proteins 2 (SCOP2 prototype) - Legacy site of the SCOP 2 prototype, no longer updated
SUPERFAMILY - Library of HMMs representing SCOP superfamilies and database of (superfamily and family) annotations for all completely sequenced organisms
Protein Structure Classification - a book chapter that discusses different protein classifications in detail. | Wikipedia/Structural_Classification_of_Proteins |
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. They are coupled with G proteins. They pass through the cell membrane seven times in the form of six loops (three extracellular loops interacting with ligand molecules, three intracellular loops interacting with G proteins, an N-terminal extracellular region and a C-terminal intracellular region) of amino acid residues, which is why they are sometimes referred to as seven-transmembrane receptors. Ligands can bind either to the extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (rhodopsin-like family). They are all activated by agonists, although a spontaneous auto-activation of an empty receptor has also been observed.
G protein-coupled receptors are found only in eukaryotes, including yeast, and choanoflagellates. The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters. They vary in size from small molecules to peptides, to large proteins. G protein-coupled receptors are involved in many diseases.
There are two principal signal transduction pathways involving the G protein-coupled receptors:
the cAMP signal pathway and
the phosphatidylinositol signal pathway.
When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor (GEF). The GPCR can then activate an associated G protein by exchanging the GDP bound to the G protein for a GTP. The G protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type (Gαs, Gαi/o, Gαq/11, Gα12/13).: 1160
GPCRs are an important drug target, and approximately 34% of all Food and Drug Administration (FDA) approved drugs target 108 members of this family. The global sales volume for these drugs is estimated to be 180 billion US dollars as of 2018. It is estimated that GPCRs are targets for about 50% of drugs currently on the market, mainly due to their involvement in signaling pathways related to many diseases i.e. mental, metabolic including endocrinological disorders, immunological including viral infections, cardiovascular, inflammatory, senses disorders, and cancer. The long ago discovered association between GPCRs and many endogenous and exogenous substances, resulting in e.g. analgesia, is another dynamically developing field of the pharmaceutical research.
== History and significance ==
With the determination of the first structure of the complex between a G-protein coupled receptor (GPCR) and a G-protein trimer (Gαβγ) in 2011 a new chapter of GPCR research was opened for structural investigations of global switches with more than one protein being investigated. The previous breakthroughs involved determination of the crystal structure of the first GPCR, rhodopsin, in 2000 and the crystal structure of the first GPCR with a diffusible ligand (β2AR) in 2007. The way in which the seven transmembrane helices of a GPCR are arranged into a bundle was suspected based on the low-resolution model of frog rhodopsin from cryogenic electron microscopy studies of the two-dimensional crystals. The crystal structure of rhodopsin, that came up three years later, was not a surprise apart from the presence of an additional cytoplasmic helix H8 and a precise location of a loop covering retinal binding site. However, it provided a scaffold which was hoped to be a universal template for homology modeling and drug design for other GPCRs – a notion that proved to be too optimistic.
Results 7 years later were surprising because the crystallization of β2-adrenergic receptor (β2AR) with a diffusible ligand revealed quite a different shape of the receptor extracellular side than that of rhodopsin. This area is important because it is responsible for the ligand binding and is targeted by many drugs. Moreover, the ligand binding site was much more spacious than in the rhodopsin structure and was open to the exterior. In the other receptors crystallized shortly afterwards the binding side was even more easily accessible to the ligand. New structures complemented with biochemical investigations uncovered mechanisms of action of molecular switches which modulate the structure of the receptor leading to activation states for agonists or to complete or partial inactivation states for inverse agonists.
The 2012 Nobel Prize in Chemistry was awarded to Brian Kobilka and Robert Lefkowitz for their work that was "crucial for understanding how G protein-coupled receptors function". There have been at least seven other Nobel Prizes awarded for some aspect of G protein–mediated signaling. As of 2012, two of the top ten global best-selling drugs (Advair Diskus and Abilify) act by targeting G protein-coupled receptors.
== Classification ==
The exact size of the GPCR superfamily is unknown, but at least 831 different human genes (or about 4% of the entire protein-coding genome) have been predicted to code for them from genome sequence analysis. Although numerous classification schemes have been proposed, the superfamily was classically divided into three main classes (A, B, and C) with no detectable shared sequence homology between classes.
The largest class by far is class A, which accounts for nearly 85% of the GPCR genes. Of class A GPCRs, over half of these are predicted to encode olfactory receptors, while the remaining receptors are liganded by known endogenous compounds or are classified as orphan receptors. Despite the lack of sequence homology between classes, all GPCRs have a common structure and mechanism of signal transduction. The very large rhodopsin A group has been further subdivided into 19 subgroups (A1-A19).
According to the classical A-F system, GPCRs can be grouped into six classes based on sequence homology and functional similarity:
Class A (or 1) (Rhodopsin-like)
Class B (or 2) (Secretin receptor family)
Class C (or 3) (Metabotropic glutamate/pheromone)
Class D (or 4) (Fungal mating pheromone receptors)
Class E (or 5) (Cyclic AMP receptors)
Class F (or 6) (Frizzled/Smoothened)
More recently, an alternative classification system called GRAFS (Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, Secretin) has been proposed for vertebrate GPCRs. They correspond to classical classes C, A, B2, F, and B.
An early study based on available DNA sequence suggested that the human genome encodes roughly 750 G protein-coupled receptors, about 350 of which detect hormones, growth factors, and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome have unknown functions.
Some web-servers and bioinformatics prediction methods have been used for predicting the classification of GPCRs according to their amino acid sequence alone, by means of the pseudo amino acid composition approach.
== Physiological roles ==
GPCRs are involved in a wide variety of physiological processes. Some examples of their physiological roles include:
The visual sense: The opsins use a photoisomerization reaction to translate electromagnetic radiation into cellular signals. Rhodopsin, for example, uses the conversion of 11-cis-retinal to all-trans-retinal for this purpose.
The gustatory sense (taste): GPCRs in taste cells mediate release of gustducin in response to bitter-, umami- and sweet-tasting substances.
The sense of smell: Receptors of the olfactory epithelium bind odorants (olfactory receptors) and pheromones (vomeronasal receptors)
Behavioral and mood regulation: Receptors in the mammalian brain bind several different neurotransmitters, including serotonin, dopamine, histamine, GABA, and glutamate
Regulation of immune system activity and inflammation: chemokine receptors bind ligands that mediate intercellular communication between cells of the immune system; receptors such as histamine receptors bind inflammatory mediators and engage target cell types in the inflammatory response. GPCRs are also involved in immune-modulation, e. g. regulating interleukin induction or suppressing TLR-induced immune responses from T cells.
Autonomic nervous system transmission: Both the sympathetic and parasympathetic nervous systems are regulated by GPCR pathways, responsible for control of many automatic functions of the body such as blood pressure, heart rate, and digestive processes
Cell density sensing: A novel GPCR role in regulating cell density sensing.
Homeostasis modulation (e.g., water balance).
Involved in growth and metastasis of some types of tumors.
Used in the endocrine system for peptide and amino-acid derivative hormones that bind to GCPRs on the cell membrane of a target cell. This activates cAMP, which in turn activates several kinases, allowing for a cellular response, such as transcription.
== Receptor structure ==
GPCRs are integral membrane proteins that possess seven membrane-spanning domains or transmembrane helices. The extracellular parts of the receptor can be glycosylated. These extracellular loops also contain two highly conserved cysteine residues that form disulfide bonds to stabilize the receptor structure. Some seven-transmembrane helix proteins (channelrhodopsin) that resemble GPCRs may contain ion channels, within their protein.
In 2000, the first crystal structure of a mammalian GPCR, that of bovine rhodopsin (1F88), was solved. In 2007, the first structure of a human GPCR was solved This human β2-adrenergic receptor GPCR structure proved highly similar to the bovine rhodopsin. The structures of activated or agonist-bound GPCRs have also been determined. These structures indicate how ligand binding at the extracellular side of a receptor leads to conformational changes in the cytoplasmic side of the receptor. The biggest change is an outward movement of the cytoplasmic part of the 5th and 6th transmembrane helix (TM5 and TM6). The structure of activated beta-2 adrenergic receptor in complex with Gs confirmed that the Gα binds to a cavity created by this movement.
GPCRs exhibit a similar structure to some other proteins with seven transmembrane domains, such as microbial rhodopsins and adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2). However, these 7TMH (7-transmembrane helices) receptors and channels do not associate with G proteins. In addition, ADIPOR1 and ADIPOR2 are oriented oppositely to GPCRs in the membrane (i.e. GPCRs usually have an extracellular N-terminus, cytoplasmic C-terminus, whereas ADIPORs are inverted).
== Structure–function relationships ==
In terms of structure, GPCRs are characterized by an extracellular N-terminus, followed by seven transmembrane (7-TM) α-helices (TM-1 to TM-7) connected by three intracellular (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3), and finally an intracellular C-terminus. The GPCR arranges itself into a tertiary structure resembling a barrel, with the seven transmembrane helices forming a cavity within the plasma membrane that serves a ligand-binding domain that is often covered by EL-2. Ligands may also bind elsewhere, however, as is the case for bulkier ligands (e.g., proteins or large peptides), which instead interact with the extracellular loops, or, as illustrated by the class C metabotropic glutamate receptors (mGluRs), the N-terminal tail. The class C GPCRs are distinguished by their large N-terminal tail, which also contains a ligand-binding domain. Upon glutamate-binding to an mGluR, the N-terminal tail undergoes a conformational change that leads to its interaction with the residues of the extracellular loops and TM domains. The eventual effect of all three types of agonist-induced activation is a change in the relative orientations of the TM helices (likened to a twisting motion) leading to a wider intracellular surface and "revelation" of residues of the intracellular helices and TM domains crucial to signal transduction function (i.e., G-protein coupling). Inverse agonists and antagonists may also bind to a number of different sites, but the eventual effect must be prevention of this TM helix reorientation.
The structure of the N- and C-terminal tails of GPCRs may also serve important functions beyond ligand-binding. For example, The C-terminus of M3 muscarinic receptors is sufficient, and the six-amino-acid polybasic (KKKRRK) domain in the C-terminus is necessary for its preassembly with Gq proteins. In particular, the C-terminus often contains serine (Ser) or threonine (Thr) residues that, when phosphorylated, increase the affinity of the intracellular surface for the binding of scaffolding proteins called β-arrestins (β-arr). Once bound, β-arrestins both sterically prevent G-protein coupling and may recruit other proteins, leading to the creation of signaling complexes involved in extracellular-signal regulated kinase (ERK) pathway activation or receptor endocytosis (internalization). As the phosphorylation of these Ser and Thr residues often occurs as a result of GPCR activation, the β-arr-mediated G-protein-decoupling and internalization of GPCRs are important mechanisms of desensitization. In addition, internalized "mega-complexes" consisting of a single GPCR, β-arr(in the tail conformation), and heterotrimeric G protein exist and may account for protein signaling from endosomes.
A final common structural theme among GPCRs is palmitoylation of one or more sites of the C-terminal tail or the intracellular loops. Palmitoylation is the covalent modification of cysteine (Cys) residues via addition of hydrophobic acyl groups, and has the effect of targeting the receptor to cholesterol- and sphingolipid-rich microdomains of the plasma membrane called lipid rafts. As many of the downstream transducer and effector molecules of GPCRs (including those involved in negative feedback pathways) are also targeted to lipid rafts, this has the effect of facilitating rapid receptor signaling.
GPCRs respond to extracellular signals mediated by a huge diversity of agonists, ranging from proteins to biogenic amines to protons, but all transduce this signal via a mechanism of G-protein coupling. This is made possible by a guanine-nucleotide exchange factor (GEF) domain primarily formed by a combination of IL-2 and IL-3 along with adjacent residues of the associated TM helices.
== Mechanism ==
The G protein-coupled receptor is activated by an external signal in the form of a ligand or other signal mediator. This creates a conformational change in the receptor, causing activation of a G protein. Further effect depends on the type of G protein. G proteins are subsequently inactivated by GTPase activating proteins, known as RGS proteins.
=== Ligand binding ===
GPCRs include one or more receptors for the following ligands:
sensory signal mediators (e.g., light and olfactory stimulatory molecules);
adenosine, bombesin, bradykinin, endothelin, γ-aminobutyric acid (GABA), hepatocyte growth factor (HGF), melanocortins, neuropeptide Y, opioid peptides, opsins, somatostatin, GH, tachykinins, members of the vasoactive intestinal peptide family, and vasopressin;
biogenic amines (e.g., dopamine, epinephrine, norepinephrine, histamine, serotonin, and melatonin);
glutamate (metabotropic effect);
glucagon;
acetylcholine (muscarinic effect);
chemokines;
lipid mediators of inflammation (e.g., prostaglandins, prostanoids, platelet-activating factor, and leukotrienes);
peptide hormones (e.g., calcitonin, C5a anaphylatoxin, follicle-stimulating hormone [FSH], gonadotropin-releasing hormone [GnRH], neurokinin, thyrotropin-releasing hormone [TRH], and oxytocin);
and endocannabinoids.
GPCRs that act as receptors for stimuli that have not yet been identified are known as orphan receptors.
However, in contrast to other types of receptors that have been studied, wherein ligands bind externally to the membrane, the ligands of GPCRs typically bind within the transmembrane domain. However, protease-activated receptors are activated by cleavage of part of their extracellular domain.
=== Conformational change ===
The transduction of the signal through the membrane by the receptor is not completely understood. It is known that in the inactive state, the GPCR is bound to a heterotrimeric G protein complex. Binding of an agonist to the GPCR results in a conformational change in the receptor that is transmitted to the bound Gα subunit of the heterotrimeric G protein via protein domain dynamics. The activated Gα subunit exchanges GTP in place of GDP which in turn triggers the dissociation of Gα subunit from the Gβγ dimer and from the receptor. The dissociated Gα and Gβγ subunits interact with other intracellular proteins to continue the signal transduction cascade while the freed GPCR is able to rebind to another heterotrimeric G protein to form a new complex that is ready to initiate another round of signal transduction.
It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive biophysical states. The binding of ligands to the receptor may shift the equilibrium toward the active receptor states. Three types of ligands exist: Agonists are ligands that shift the equilibrium in favour of active states; inverse agonists are ligands that shift the equilibrium in favour of inactive states; and neutral antagonists are ligands that do not affect the equilibrium. It is not yet known how exactly the active and inactive states differ from each other.
=== G-protein activation/deactivation cycle ===
When the receptor is inactive, the GEF domain may be bound to an also inactive α-subunit of a heterotrimeric G-protein. These "G-proteins" are a trimer of α, β, and γ subunits (known as Gα, Gβ, and Gγ, respectively) that is rendered inactive when reversibly bound to Guanosine diphosphate (GDP) (or, alternatively, no guanine nucleotide) but active when bound to guanosine triphosphate (GTP). Upon receptor activation, the GEF domain, in turn, allosterically activates the G-protein by facilitating the exchange of a molecule of GDP for GTP at the G-protein's α-subunit. The cell maintains a 10:1 ratio of cytosolic GTP:GDP so exchange for GTP is ensured. At this point, the subunits of the G-protein dissociate from the receptor, as well as each other, to yield a Gα-GTP monomer and a tightly interacting Gβγ dimer, which are now free to modulate the activity of other intracellular proteins. The extent to which they may diffuse, however, is limited due to the palmitoylation of Gα and the presence of an isoprenoid moiety that has been covalently added to the C-termini of Gγ.
Because Gα also has slow GTP→GDP hydrolysis capability, the inactive form of the α-subunit (Gα-GDP) is eventually regenerated, thus allowing reassociation with a Gβγ dimer to form the "resting" G-protein, which can again bind to a GPCR and await activation. The rate of GTP hydrolysis is often accelerated due to the actions of another family of allosteric modulating proteins called regulators of G-protein signaling, or RGS proteins, which are a type of GTPase-activating protein, or GAP. In fact, many of the primary effector proteins (e.g., adenylate cyclases) that become activated/inactivated upon interaction with Gα-GTP also have GAP activity. Thus, even at this early stage in the process, GPCR-initiated signaling has the capacity for self-termination.
=== Crosstalk ===
GPCRs downstream signals have been shown to possibly interact with integrin signals, such as FAK. Integrin signaling will phosphorylate FAK, which can then decrease GPCR Gαs activity.
== Signaling ==
If a receptor in an active state encounters a G protein, it may activate it. Some evidence suggests that receptors and G proteins are actually pre-coupled. For example, binding of G proteins to receptors affects the receptor's affinity for ligands. Activated G proteins are bound to GTP.
Further signal transduction depends on the type of G protein. The enzyme adenylate cyclase is an example of a cellular protein that can be regulated by a G protein, in this case the G protein Gs. Adenylate cyclase activity is activated when it binds to a subunit of the activated G protein. Activation of adenylate cyclase ends when the G protein returns to the GDP-bound state.
Adenylate cyclases (of which 9 membrane-bound and one cytosolic forms are known in humans) may also be activated or inhibited in other ways (e.g., Ca2+/calmodulin binding), which can modify the activity of these enzymes in an additive or synergistic fashion along with the G proteins.
The signaling pathways activated through a GPCR are limited by the primary sequence and tertiary structure of the GPCR itself but ultimately determined by the particular conformation stabilized by a particular ligand, as well as the availability of transducer molecules. Currently, GPCRs are considered to utilize two primary types of transducers: G-proteins and β-arrestins. Because β-arr's have high affinity only to the phosphorylated form of most GPCRs (see above or below), the majority of signaling is ultimately dependent upon G-protein activation. However, the possibility for interaction does allow for G-protein-independent signaling to occur.
=== G-protein-dependent signaling ===
There are three main G-protein-mediated signaling pathways, mediated by four sub-classes of G-proteins distinguished from each other by sequence homology (Gαs, Gαi/o, Gαq/11, and Gα12/13). Each sub-class of G-protein consists of multiple proteins, each the product of multiple genes or splice variations that may imbue them with differences ranging from subtle to distinct with regard to signaling properties, but in general they appear reasonably grouped into four classes. Because the signal transducing properties of the various possible βγ combinations do not appear to radically differ from one another, these classes are defined according to the isoform of their α-subunit.: 1163
While most GPCRs are capable of activating more than one Gα-subtype, they also show a preference for one subtype over another. When the subtype activated depends on the ligand that is bound to the GPCR, this is called functional selectivity (also known as agonist-directed trafficking, or conformation-specific agonism). However, the binding of any single particular agonist may also initiate activation of multiple different G-proteins, as it may be capable of stabilizing more than one conformation of the GPCR's GEF domain, even over the course of a single interaction. In addition, a conformation that preferably activates one isoform of Gα may activate another if the preferred is less available. Furthermore, feedback pathways may result in receptor modifications (e.g., phosphorylation) that alter the G-protein preference. Regardless of these various nuances, the GPCR's preferred coupling partner is usually defined according to the G-protein most obviously activated by the endogenous ligand under most physiological or experimental conditions.
==== Gα signaling ====
The effector of both the Gαs and Gαi/o pathways is the cyclic-adenosine monophosphate (cAMP)-generating enzyme adenylate cyclase, or AC. While there are ten different AC gene products in mammals, each with subtle differences in tissue distribution or function, all catalyze the conversion of cytosolic adenosine triphosphate (ATP) to cAMP, and all are directly stimulated by G-proteins of the Gαs class. In contrast, however, interaction with Gα subunits of the Gαi/o type inhibits AC from generating cAMP. Thus, a GPCR coupled to Gαs counteracts the actions of a GPCR coupled to Gαi/o, and vice versa. The level of cytosolic cAMP may then determine the activity of various ion channels as well as members of the ser/thr-specific protein kinase A (PKA) family. Thus cAMP is considered a second messenger and PKA a secondary effector.
The effector of the Gαq/11 pathway is phospholipase C-β (PLCβ), which catalyzes the cleavage of membrane-bound phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers inositol (1,4,5) trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on IP3 receptors found in the membrane of the endoplasmic reticulum (ER) to elicit Ca2+ release from the ER, while DAG diffuses along the plasma membrane where it may activate any membrane localized forms of a second ser/thr kinase called protein kinase C (PKC). Since many isoforms of PKC are also activated by increases in intracellular Ca2+, both these pathways can also converge on each other to signal through the same secondary effector. Elevated intracellular Ca2+ also binds and allosterically activates proteins called calmodulins, which in turn tosolic small GTPase, Rho. Once bound to GTP, Rho can then go on to activate various proteins responsible for cytoskeleton regulation such as Rho-kinase (ROCK). Most GPCRs that couple to Gα12/13 also couple to other sub-classes, often Gαq/11.
==== Gβγ signaling ====
The above descriptions ignore the effects of Gβγ–signalling, which can also be important, in particular in the case of activated Gαi/o-coupled GPCRs. The primary effectors of Gβγ are various ion channels, such as G-protein-regulated inwardly rectifying K+ channels (GIRKs), P/Q- and N-type voltage-gated Ca2+ channels, as well as some isoforms of AC and PLC, along with some phosphoinositide-3-kinase (PI3K) isoforms.
=== G-protein-independent signaling ===
Although they are classically thought of working only together, GPCRs may signal through G-protein-independent mechanisms, and heterotrimeric G-proteins may play functional roles independent of GPCRs. GPCRs may signal independently through many proteins already mentioned for their roles in G-protein-dependent signaling such as β-arrs, GRKs, and Srcs. Such signaling has been shown to be physiologically relevant, for example, β-arrestin signaling mediated by the chemokine receptor CXCR3 was necessary for full efficacy chemotaxis of activated T cells. In addition, further scaffolding proteins involved in subcellular localization of GPCRs (e.g., PDZ-domain-containing proteins) may also act as signal transducers. Most often the effector is a member of the MAPK family.
==== Examples ====
In the late 1990s, evidence began accumulating to suggest that some GPCRs are able to signal without G proteins. The ERK2 mitogen-activated protein kinase, a key signal transduction mediator downstream of receptor activation in many pathways, has been shown to be activated in response to cAMP-mediated receptor activation in the slime mold D. discoideum despite the absence of the associated G protein α- and β-subunits.
In mammalian cells, the much-studied β2-adrenoceptor has been demonstrated to activate the ERK2 pathway after arrestin-mediated uncoupling of G-protein-mediated signaling. Therefore, it seems likely that some mechanisms previously believed related purely to receptor desensitisation are actually examples of receptors switching their signaling pathway, rather than simply being switched off.
In kidney cells, the bradykinin receptor B2 has been shown to interact directly with a protein tyrosine phosphatase. The presence of a tyrosine-phosphorylated ITIM (immunoreceptor tyrosine-based inhibitory motif) sequence in the B2 receptor is necessary to mediate this interaction and subsequently the antiproliferative effect of bradykinin.
==== GPCR-independent signaling by heterotrimeric G-proteins ====
Although it is a relatively immature area of research, it appears that heterotrimeric G-proteins may also take part in non-GPCR signaling. There is evidence for roles as signal transducers in nearly all other types of receptor-mediated signaling, including integrins, receptor tyrosine kinases (RTKs), cytokine receptors (JAK/STATs), as well as modulation of various other "accessory" proteins such as GEFs, guanine-nucleotide dissociation inhibitors (GDIs) and protein phosphatases. There may even be specific proteins of these classes whose primary function is as part of GPCR-independent pathways, termed activators of G-protein signalling (AGS). Both the ubiquity of these interactions and the importance of Gα vs. Gβγ subunits to these processes are still unclear.
== Details of cAMP and PIP2 pathways ==
There are two principal signal transduction pathways involving the G protein-linked receptors: the cAMP signal pathway and the phosphatidylinositol signal pathway.
=== cAMP signal pathway ===
The cAMP signal transduction contains five main characters: stimulative hormone receptor (Rs) or inhibitory hormone receptor (Ri); stimulative regulative G-protein (Gs) or inhibitory regulative G-protein (Gi); adenylyl cyclase; protein kinase A (PKA); and cAMP phosphodiesterase.
Stimulative hormone receptor (Rs) is a receptor that can bind with stimulative signal molecules, while inhibitory hormone receptor (Ri) is a receptor that can bind with inhibitory signal molecules.
Stimulative regulative G-protein is a G-protein linked to stimulative hormone receptor (Rs), and its α subunit upon activation could stimulate the activity of an enzyme or other intracellular metabolism. On the contrary, inhibitory regulative G-protein is linked to an inhibitory hormone receptor, and its α subunit upon activation could inhibit the activity of an enzyme or other intracellular metabolism.
Adenylyl cyclase is a 12-transmembrane glycoprotein that catalyzes the conversion of ATP to cAMP with the help of cofactor Mg2+ or Mn2+. The cAMP produced is a second messenger in cellular metabolism and is an allosteric activator of protein kinase A.
Protein kinase A is an important enzyme in cell metabolism due to its ability to regulate cell metabolism by phosphorylating specific committed enzymes in the metabolic pathway. It can also regulate specific gene expression, cellular secretion, and membrane permeability. The protein enzyme contains two catalytic subunits and two regulatory subunits. When there is no cAMP, the complex is inactive. When cAMP binds to the regulatory subunits, their conformation is altered, causing the dissociation of the regulatory subunits, which activates protein kinase A and allows further biological effects.
These signals then can be terminated by cAMP phosphodiesterase, which is an enzyme that degrades cAMP to 5'-AMP and inactivates protein kinase A.
=== Phosphatidylinositol signal pathway ===
In the phosphatidylinositol signal pathway, the extracellular signal molecule binds with the G-protein receptor (Gq) on the cell surface and activates phospholipase C, which is located on the plasma membrane. The lipase hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into two second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds with the IP3 receptor in the membrane of the smooth endoplasmic reticulum and mitochondria to open Ca2+ channels. DAG helps activate protein kinase C (PKC), which phosphorylates many other proteins, changing their catalytic activities, leading to cellular responses.
The effects of Ca2+ are also remarkable: it cooperates with DAG in activating PKC and can activate the CaM kinase pathway, in which calcium-modulated protein calmodulin (CaM) binds Ca2+, undergoes a change in conformation, and activates CaM kinase II, which has unique ability to increase its binding affinity to CaM by autophosphorylation, making CaM unavailable for the activation of other enzymes. The kinase then phosphorylates target enzymes, regulating their activities. The two signal pathways are connected together by Ca2+-CaM, which is also a regulatory subunit of adenylyl cyclase and phosphodiesterase in the cAMP signal pathway.
== Receptor regulation ==
GPCRs become desensitized when exposed to their ligand for a long period of time. There are two recognized forms of desensitization: 1) homologous desensitization, in which the activated GPCR is downregulated; and 2) heterologous desensitization, wherein the activated GPCR causes downregulation of a different GPCR. The key reaction of this downregulation is the phosphorylation of the intracellular (or cytoplasmic) receptor domain by protein kinases.
=== Phosphorylation by cAMP-dependent protein kinases ===
Cyclic AMP-dependent protein kinases (protein kinase A) are activated by the signal chain coming from the G protein (that was activated by the receptor) via adenylate cyclase and cyclic AMP (cAMP). In a feedback mechanism, these activated kinases phosphorylate the receptor. The longer the receptor remains active the more kinases are activated and the more receptors are phosphorylated. In β2-adrenoceptors, this phosphorylation results in the switching of the coupling from the Gs class of G-protein to the Gi class. cAMP-dependent PKA mediated phosphorylation can cause heterologous desensitisation in receptors other than those activated.
=== Phosphorylation by GRKs ===
The G protein-coupled receptor kinases (GRKs) are protein kinases that phosphorylate only active GPCRs. G-protein-coupled receptor kinases (GRKs) are key modulators of G-protein-coupled receptor (GPCR) signaling. They constitute a family of seven mammalian serine-threonine protein kinases that phosphorylate agonist-bound receptor. GRKs-mediated receptor phosphorylation rapidly initiates profound impairment of receptor signaling and desensitization. Activity of GRKs and subcellular targeting is tightly regulated by interaction with receptor domains, G protein subunits, lipids, anchoring proteins and calcium-sensitive proteins.
Phosphorylation of the receptor can have two consequences:
Translocation: The receptor is, along with the part of the membrane it is embedded in, brought to the inside of the cell, where it is dephosphorylated within the acidic vesicular environment and then brought back. This mechanism is used to regulate long-term exposure, for example, to a hormone, by allowing resensitisation to follow desensitisation. Alternatively, the receptor may undergo lysozomal degradation, or remain internalised, where it is thought to participate in the initiation of signalling events, the nature of which depending on the internalised vesicle's subcellular localisation.
Arrestin linking: The phosphorylated receptor can be linked to arrestin molecules that prevent it from binding (and activating) G proteins, in effect switching it off for a short period of time. This mechanism is used, for example, with rhodopsin in retina cells to compensate for exposure to bright light. In many cases, arrestin's binding to the receptor is a prerequisite for translocation. For example, beta-arrestin bound to β2-adrenoreceptors acts as an adaptor for binding with clathrin, and with the beta-subunit of AP2 (clathrin adaptor molecules); thus, the arrestin here acts as a scaffold assembling the components needed for clathrin-mediated endocytosis of β2-adrenoreceptors.
=== Mechanisms of GPCR signal termination ===
As mentioned above, G-proteins may terminate their own activation due to their intrinsic GTP→GDP hydrolysis capability. However, this reaction proceeds at a slow rate (≈0.02 times/sec) and, thus, it would take around 50 seconds for any single G-protein to deactivate if other factors did not come into play. Indeed, there are around 30 isoforms of RGS proteins that, when bound to Gα through their GAP domain, accelerate the hydrolysis rate to ≈30 times/sec. This 1500-fold increase in rate allows for the cell to respond to external signals with high speed, as well as spatial resolution due to limited amount of second messenger that can be generated and limited distance a G-protein can diffuse in 0.03 seconds. For the most part, the RGS proteins are promiscuous in their ability to deactivate G-proteins, while which RGS is involved in a given signaling pathway seems more determined by the tissue and GPCR involved than anything else. In addition, RGS proteins have the additional function of increasing the rate of GTP-GDP exchange at GPCRs, (i.e., as a sort of co-GEF) further contributing to the time resolution of GPCR signaling.
In addition, the GPCR may be desensitized itself. This can occur as:
a direct result of ligand occupation, wherein the change in conformation allows recruitment of GPCR-Regulating Kinases (GRKs), which go on to phosphorylate various serine/threonine residues of IL-3 and the C-terminal tail. Upon GRK phosphorylation, the GPCR's affinity for β-arrestin (β-arrestin-1/2 in most tissues) is increased, at which point β-arrestin may bind and act to both sterically hinder G-protein coupling as well as initiate the process of receptor internalization through clathrin-mediated endocytosis. Because only the liganded receptor is desensitized by this mechanism, it is called homologous desensitization
the affinity for β-arrestin may be increased in a ligand occupation and GRK-independent manner through phosphorylation of different ser/thr sites (but also of IL-3 and the C-terminal tail) by PKC and PKA. These phosphorylations are often sufficient to impair G-protein coupling on their own as well.
PKC/PKA may, instead, phosphorylate GRKs, which can also lead to GPCR phosphorylation and β-arrestin binding in an occupation-independent manner. These latter two mechanisms allow for desensitization of one GPCR due to the activities of others, or heterologous desensitization. GRKs may also have GAP domains and so may contribute to inactivation through non-kinase mechanisms as well. A combination of these mechanisms may also occur.
Once β-arrestin is bound to a GPCR, it undergoes a conformational change allowing it to serve as a scaffolding protein for an adaptor complex termed AP-2, which in turn recruits another protein called clathrin. If enough receptors in the local area recruit clathrin in this manner, they aggregate and the membrane buds inwardly as a result of interactions between the molecules of clathrin, in a process called opsonization. Once the pit has been pinched off the plasma membrane due to the actions of two other proteins called amphiphysin and dynamin, it is now an endocytic vesicle. At this point, the adapter molecules and clathrin have dissociated, and the receptor is either trafficked back to the plasma membrane or targeted to lysosomes for degradation.
At any point in this process, the β-arrestins may also recruit other proteins—such as the non-receptor tyrosine kinase (nRTK), c-SRC—which may activate ERK1/2, or other mitogen-activated protein kinase (MAPK) signaling through, for example, phosphorylation of the small GTPase, Ras, or recruit the proteins of the ERK cascade directly (i.e., Raf-1, MEK, ERK-1/2) at which point signaling is initiated due to their close proximity to one another. Another target of c-SRC are the dynamin molecules involved in endocytosis. Dynamins polymerize around the neck of an incoming vesicle, and their phosphorylation by c-SRC provides the energy necessary for the conformational change allowing the final "pinching off" from the membrane.
=== GPCR cellular regulation ===
Receptor desensitization is mediated through a combination phosphorylation, β-arr binding, and endocytosis as described above. Downregulation occurs when endocytosed receptor is embedded in an endosome that is trafficked to merge with an organelle called a lysosome. Because lysosomal membranes are rich in proton pumps, their interiors have low pH (≈4.8 vs. the pH≈7.2 cytosol), which acts to denature the GPCRs. In addition, lysosomes contain many degradative enzymes, including proteases, which can function only at such low pH, and so the peptide bonds joining the residues of the GPCR together may be cleaved. Whether or not a given receptor is trafficked to a lysosome, detained in endosomes, or trafficked back to the plasma membrane depends on a variety of factors, including receptor type and magnitude of the signal.
GPCR regulation is additionally mediated by gene transcription factors. These factors can increase or decrease gene transcription and thus increase or decrease the generation of new receptors (up- or down-regulation) that travel to the cell membrane.
== Receptor oligomerization ==
G-protein-coupled receptor oligomerisation is a widespread phenomenon. One of the best-studied examples is the metabotropic GABAB receptor. This so-called constitutive receptor is formed by heterodimerization of GABABR1 and GABABR2 subunits. Expression of the GABABR1 without the GABABR2 in heterologous systems leads to retention of the subunit in the endoplasmic reticulum. Expression of the GABABR2 subunit alone, meanwhile, leads to surface expression of the subunit, although with no functional activity (i.e., the receptor does not bind agonist and cannot initiate a response following exposure to agonist). Expression of the two subunits together leads to plasma membrane expression of functional receptor. It has been shown that GABABR2 binding to GABABR1 causes masking of a retention signal of functional receptors.
== Origin and diversification of the superfamily ==
Signal transduction mediated by the superfamily of GPCRs dates back to the origin of multicellularity. Mammalian-like GPCRs are found in fungi, and have been classified according to the GRAFS classification system based on GPCR fingerprints. Identification of the superfamily members across the eukaryotic domain, and comparison of the family-specific motifs, have shown that the superfamily of GPCRs have a common origin. Characteristic motifs indicate that three of the five GRAFS families, Rhodopsin, Adhesion, and Frizzled, evolved from the Dictyostelium discoideum cAMP receptors before the split of opisthokonts. Later, the Secretin family evolved from the Adhesion GPCR receptor family before the split of nematodes. Insect GPCRs appear to be in their own group and Taste2 is identified as descending from Rhodopsin. Note that the Secretin/Adhesion split is based on presumed function rather than signature, as the classical Class B (7tm_2, Pfam PF00002) is used to identify both in the studies.
== See also ==
G protein-coupled receptors database
List of MeSH codes (D12.776)
Metabotropic receptor
Orphan receptor
Pepducins, a class of drug candidates targeted at GPCRs
Receptor activated solely by a synthetic ligand, a technique for control of cell signaling through synthetic GPCRs
TOG superfamily
== References ==
== Further reading ==
Vassilatis DK, Hohmann JG, Zeng H, Li F, Ranchalis JE, Mortrud MT, et al. (April 2003). "The G protein-coupled receptor repertoires of human and mouse". Proceedings of the National Academy of Sciences of the United States of America. 100 (8): 4903–8. Bibcode:2003PNAS..100.4903V. doi:10.1073/pnas.0230374100. PMC 153653. PMID 12679517.
"GPCR Reference Library". Retrieved 11 August 2008. Reference for molecular and mathematical models for the initial receptor response
"The Nobel Prize in Chemistry 2012" (PDF). Archived (PDF) from the original on 18 October 2012. Retrieved 10 October 2012.
== External links ==
G-protein-coupled+receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
GPCR Cell Line Archived 3 April 2015 at the Wayback Machine
"IUPHAR/BPS Guide to PHARMACOLOGY Database (GPCRs)". IUPHAR Database. University of Edinburgh / International Union of Basic and Clinical Pharmacology. Retrieved 6 February 2019.
"GPCRdb". Data, diagrams and web tools for G protein-coupled receptors (GPCRs).; Munk C, Isberg V, Mordalski S, Harpsøe K, Rataj K, Hauser AS, et al. (July 2016). "GPCRdb: the G protein-coupled receptor database - an introduction". British Journal of Pharmacology. 173 (14): 2195–207. doi:10.1111/bph.13509. PMC 4919580. PMID 27155948.
"G Protein-Coupled Receptors on the NET". Archived from the original on 23 July 2011. Retrieved 10 November 2010. a classification of GPCRs
"PSI GPCR Network Center". Archived from the original on 25 July 2013. Retrieved 11 July 2013. a Protein Structure Initiative:Biology Network Center aimed at determining the 3D structures of representative GPCR family proteins
GPCR-HGmod Archived 1 February 2016 at the Wayback Machine, a database of 3D structural models of all human G-protein coupled receptors, built by the GPCR-I-TASSER pipeline Zhang J, Yang J, Jang R, Zhang Y (August 2015). "GPCR-I-TASSER: A Hybrid Approach to G Protein-Coupled Receptor Structure Modeling and the Application to the Human Genome". Structure. 23 (8): 1538–1549. doi:10.1016/j.str.2015.06.007. PMC 4526412. PMID 26190572. | Wikipedia/G_protein-coupled_receptor |
In crystallography, direct methods are a family of methods for estimating the phases of the Fourier transform of the scattering density from the corresponding magnitudes. The methods generally exploit constraints or statistical correlations between the phases of different Fourier components that result from the fact that the scattering density must be a positive real number.
In two dimensions, it is relatively easy to solve the phase problem directly, but not so in three dimensions. The key step was taken by Hauptman and Karle, who developed a practical method to employ the Sayre equation for which they were awarded the 1985 Nobel prize in Chemistry. The Nobel Prize citation was "for their outstanding achievements in the development of direct methods for the determination of crystal structures."
At present, direct methods are the preferred method for phasing crystals of small molecules having up to 1000 atoms in the asymmetric unit. However, they are generally not feasible by themselves for larger molecules such as proteins.
Several software packages implement direct methods.
== See also ==
Direct methods (electron microscopy)
Phase problem
X-ray crystallography
== References == | Wikipedia/Hauptman-Karle_method |
Energy-dispersive X-ray diffraction (EDXRD) is an analytical technique for characterizing materials. It differs from conventional X-ray diffraction by using polychromatic photons as the source and is usually operated at a fixed angle. With no need for a goniometer, EDXRD is able to collect full diffraction patterns very quickly. EDXRD is almost exclusively used with synchrotron radiation which allows for measurement within real engineering materials.
== History ==
EDXRD was originally proposed independently by Buras et al. and Giessen and Gordon in 1968.
== Advantages ==
The advantages of EDXRD are (1) it uses a fixed scattering angle, (2) it works directly in reciprocal space, (3) fast collection time, and (4) parallel data collection. The fixed scattering angle geometry makes EDXRD especially suitable for in situ studies in special environments (e.g. under very low or high temperatures and pressures). When the EDXRD method is used, only one entrance and one exit window are needed. The fixed scattering angle also allows for measurement of the diffraction vector directly. This allows for high-accuracy measurement of lattice parameters. It allows for rapid structure analysis and the ability to study materials that are unstable and only exist for short periods of time. Because the whole spectrum of diffracted radiation is obtained simultaneously, it enables parallel data collection studies where structural changes can be determined over time.
== Facilities ==
== References == | Wikipedia/Energy-dispersive_X-ray_diffraction |
The Scherrer equation, in X-ray diffraction and crystallography, is a formula that relates the size of sub-micrometre crystallites in a solid to the broadening of a peak in a diffraction pattern. It is often referred to, incorrectly, as a formula for particle size measurement or analysis. It is named after Paul Scherrer. It is used in the determination of size of crystals in the form of powder.
The Scherrer equation can be written as:
τ
=
K
λ
β
cos
θ
{\displaystyle \tau ={\frac {K\lambda }{\beta \cos \theta }}}
where:
τ
{\displaystyle \tau }
is the mean size of the ordered (crystalline) domains, which may be smaller or equal to the grain size, which may be smaller or equal to the particle size;
K
{\displaystyle K}
is a dimensionless shape factor, with a value close to unity. The shape factor has a typical value of about 0.9, but varies with the actual shape of the crystallite;
λ
{\displaystyle \lambda }
is the X-ray wavelength;
β
{\displaystyle \beta }
is the line broadening at half the maximum intensity (FWHM), after subtracting the instrumental line broadening, in radians. This quantity is also sometimes denoted as
Δ
(
2
θ
)
{\displaystyle \Delta \left(2\theta \right)}
;
θ
{\displaystyle \theta }
is the Bragg angle.
== Applicability ==
The Scherrer equation is limited to nano-scale crystallites, or more-strictly, the coherently scattering domain size, which can be smaller than the crystallite size (due to factors mentioned below). It is not applicable to grains larger than about 0.1 to 0.2 μm, which precludes those observed in most metallographic and ceramographic microstructures.
The Scherrer equation provides a lower bound on the coherently scattering domain size, referred to here as the crystallite size for readability. The reason for this is that a variety of factors can contribute to the width of a diffraction peak besides instrumental effects and crystallite size; the most important of these are usually inhomogeneous strain and crystal lattice imperfections. The following sources of peak broadening are dislocations, stacking faults, twinning, microstresses, grain boundaries, sub-boundaries, coherency strain, chemical heterogeneities, and crystallite smallness. These and other imperfections may also result in peak shift, peak asymmetry, anisotropic peak broadening, or other peak shape effects.
If all of these other contributions to the peak width, including instrumental broadening, were zero, then the peak width would be determined solely by the crystallite size and the Scherrer equation would apply. If the other contributions to the width are non-zero, then the crystallite size can be larger than that predicted by the Scherrer equation, with the "extra" peak width coming from the other factors. The concept of crystallinity can be used to collectively describe the effect of crystal size and imperfections on peak broadening.
Although "particle size" is often used in reference to crystallite size, this term should not be used in association with the Scherrer method because particles are often agglomerations of many crystallites, and XRD gives no information on the particle size. Other techniques, such as sieving, image analysis, or visible light scattering do directly measure particle size. The crystallite size can be thought of as a lower limit of particle size.
== Derivation for a simple stack of planes ==
To see where the Scherrer equation comes from, it is useful to consider the simplest possible example: a set of N planes separated by the distance, a. The derivation for this simple, effectively one-dimensional case, is straightforward. First, the structure factor for this case is derived, and then an expression for the peak widths is determined.
=== Structure factor for a set of N equally spaced planes ===
This system, effectively a one dimensional perfect crystal, has a structure factor or scattering function S(q):
S
(
q
)
=
1
N
∑
j
,
k
=
1
N
e
−
i
q
(
x
j
−
x
k
)
{\displaystyle S(q)={\frac {1}{N}}\sum _{j,k=1}^{N}\mathrm {e} ^{-iq(x_{j}-x_{k})}}
where for N planes,
x
j
=
a
j
{\displaystyle x_{j}=aj}
:
S
(
q
)
=
1
N
∑
k
=
1
N
e
−
i
q
a
k
×
∑
j
=
1
N
e
i
q
a
j
{\displaystyle S(q)={\frac {1}{N}}\sum _{k=1}^{N}\mathrm {e} ^{-iqak}\times \sum _{j=1}^{N}\mathrm {e} ^{iqaj}}
each sum is a simple geometric series, defining
y
=
exp
(
i
q
a
)
{\displaystyle y=\exp(iqa)}
,
∑
j
=
1
N
y
j
=
(
y
−
y
N
+
1
)
/
(
1
−
y
)
{\textstyle \sum _{j=1}^{N}y^{j}=(y-y^{N+1})/(1-y)}
, and the other series analogously gives:
S
(
q
)
=
1
N
[
e
−
i
q
a
−
e
−
i
q
a
(
N
+
1
)
]
[
1
−
e
−
i
q
a
]
×
[
e
i
q
a
−
e
i
q
a
(
N
+
1
)
]
[
1
−
e
i
q
a
]
{\displaystyle S(q)={\frac {1}{N}}{\frac {\left[{\rm {e}}^{-iqa}-{\rm {e}}^{-iqa(N+1)}\right]}{\left[1-e^{-iqa}\right]}}\times {\frac {\left[{\rm {e}}^{iqa}-{\rm {e}}^{iqa(N+1)}\right]}{\left[1-e^{iqa}\right]}}}
S
(
q
)
=
1
N
2
−
e
i
q
a
N
−
e
−
i
q
a
N
2
−
e
i
q
a
−
e
−
i
q
a
{\displaystyle S(q)={\frac {1}{N}}{\frac {2-{\rm {e}}^{iqaN}-{\rm {e}}^{-iqaN}}{2-{\rm {e}}^{iqa}-{\rm {e}}^{-iqa}}}}
which is further simplified by converting to trigonometric functions:
S
(
q
)
=
1
N
1
−
cos
[
N
q
a
]
1
−
cos
[
q
a
]
{\displaystyle S(q)={\frac {1}{N}}{\frac {1-\cos[Nqa]}{1-\cos[qa]}}}
and finally:
S
(
q
)
=
1
N
sin
2
[
N
q
a
/
2
]
sin
2
[
q
a
/
2
]
{\displaystyle S(q)={\frac {1}{N}}{\frac {\sin ^{2}[Nqa/2]}{\sin ^{2}[qa/2]}}}
which gives a set of peaks at
q
P
=
0
,
2
π
/
a
,
4
π
/
a
,
…
{\textstyle q_{P}=0,2\pi /a,4\pi /a,\ldots }
, all with heights
S
(
q
P
)
=
N
{\displaystyle S(q_{P})=N}
.
=== Determination of the profile near the peak, and hence the peak width ===
From the definition of FWHM, for a peak at
q
P
{\textstyle q_{P}}
and with a FWHM of
Δ
q
{\textstyle \Delta q}
,
S
(
q
P
±
Δ
q
/
2
)
=
S
(
q
P
)
/
2
=
N
/
2
{\displaystyle S(q_{P}\pm \Delta q/2)=S(q_{P})/2=N/2}
, as the peak height is N. If we take the plus sign (peak is symmetric so either sign will do)
S
(
q
P
+
Δ
q
/
2
)
=
1
N
sin
2
[
N
a
(
q
P
+
Δ
q
/
2
)
/
2
]
sin
2
[
a
(
q
P
+
Δ
q
/
2
)
/
2
]
=
1
N
[
sin
[
N
a
(
q
P
+
Δ
q
/
2
)
/
2
]
sin
[
a
(
q
P
+
Δ
q
/
2
)
/
2
]
]
2
=
N
/
2
{\displaystyle S(q_{P}+\Delta q/2)={\frac {1}{N}}{\frac {\sin ^{2}[Na(q_{P}+\Delta q/2)/2]}{\sin ^{2}[a(q_{P}+\Delta q/2)/2]}}={\frac {1}{N}}\left[{\frac {\sin[Na(q_{P}+\Delta q/2)/2]}{\sin[a(q_{P}+\Delta q/2)/2]}}\right]^{2}=N/2}
and
sin
[
N
a
(
q
P
+
Δ
q
/
2
)
/
2
]
sin
[
a
(
q
P
+
Δ
q
/
2
)
/
2
]
=
sin
[
N
a
Δ
q
/
4
]
sin
[
a
Δ
q
/
4
]
=
N
2
1
/
2
{\displaystyle {\frac {\sin[Na(q_{P}+\Delta q/2)/2]}{\sin[a(q_{P}+\Delta q/2)/2]}}={\frac {\sin[Na\Delta q/4]}{\sin[a\Delta q/4]}}={\frac {N}{2^{1/2}}}}
if N is not too small. If
Δ
q
{\displaystyle \Delta q}
is small , then
sin
[
Δ
q
a
/
4
]
≃
Δ
q
a
/
4
{\displaystyle \sin[\Delta qa/4]\simeq \Delta qa/4}
, and we can write the equation as a single non-linear equation
sin
(
x
)
−
(
x
/
2
1
/
2
)
=
0
{\displaystyle \sin(x)-(x/2^{1/2})=0}
, for
x
=
N
a
Δ
q
/
4
{\displaystyle x=Na\Delta q/4}
. The solution to this equation is
x
=
1.39
{\displaystyle x=1.39}
. Therefore, the size of the set of planes is related to the FWHM in q by
τ
=
N
a
=
5.56
Δ
q
{\displaystyle \tau =Na={\frac {5.56}{\Delta q}}}
To convert to an expression for crystal size in terms of the peak width in the scattering angle
2
θ
{\displaystyle 2\theta }
used in X-ray powder diffraction, we note that the scattering vector
q
=
(
4
π
/
λ
)
sin
(
θ
/
2
)
{\displaystyle q=(4\pi /\lambda )\sin(\theta /2)}
, where the
θ
{\displaystyle \theta }
here is the angle between the incident wavevector and the scattered wavevector, which is different from the
θ
{\displaystyle \theta }
in the
2
θ
{\displaystyle 2\theta }
scan. Then the peak width in the variable
2
θ
{\displaystyle 2\theta }
is approximately
β
≃
2
Δ
q
/
[
d
q
/
d
θ
]
=
2
Δ
q
/
[
(
4
π
/
λ
)
cos
(
θ
)
]
{\displaystyle \beta \simeq 2\Delta q/[{\rm {d}}q/{\rm {d}}\theta ]=2\Delta q/[(4\pi /\lambda )\cos(\theta )]}
, and so
τ
=
N
a
=
5.56
λ
2
π
β
cos
(
θ
)
=
0.88
λ
β
cos
(
θ
)
{\displaystyle \tau =Na={\frac {5.56\lambda }{2\pi \beta \cos(\theta )}}={\frac {0.88\lambda }{\beta \cos(\theta )}}}
which is the Scherrer equation with K = 0.88.
This only applies to a perfect 1D set of planes. In the experimentally relevant 3D case, the form of
S
(
q
)
{\displaystyle S(q)}
and hence the peaks, depends on the crystal lattice type, and the size and shape of the nanocrystallite. The underlying mathematics becomes more involved than in this simple illustrative example. However, for simple lattices and shapes, expressions have been obtained for the FWHM, for example by Patterson. Just as in 1D, the FWHM varies as the inverse of the characteristic size. For example, for a spherical crystallite with a cubic lattice, the factor of 5.56 simply becomes 6.96, when the size is the diameter D, i.e., the diameter of a spherical nanocrystal is related to the peak FWHM by
D
=
6.96
Δ
q
{\displaystyle D={\frac {6.96}{\Delta q}}}
or in
θ
{\displaystyle \theta }
:
D
=
1.11
λ
β
cos
(
θ
)
{\displaystyle D={\frac {1.11\lambda }{\beta \cos(\theta )}}}
== Peak broadening due to disorder of the second kind ==
The finite size of a crystal is not the only possible reason for broadened peaks in X-ray diffraction. Fluctuations of atoms about the ideal lattice positions that preserve the long-range order of the lattice only give rise to the Debye-Waller factor, which reduces peak heights but does not broaden them. However, fluctuations that cause the correlations between nearby atoms to decrease as their separation increases, does broaden peaks. This can be studied and quantified using the same simple one-dimensional stack of planes as above. The derivation follows that in chapter 9 of Guinier's textbook. This model was pioneered by and applied to a number of materials by Hosemann and collaborators over a number of years. They termed this disorder of the second kind, and referred to this imperfect crystalline ordering as paracrystalline ordering. Disorder of the first kind is the source of the Debye-Waller factor.
To derive the model we start with the definition of the structure factor
S
(
q
)
=
1
N
∑
j
,
k
=
1
N
e
−
i
q
(
x
j
−
x
k
)
{\displaystyle S(q)={\frac {1}{N}}\sum _{j,k=1}^{N}\mathrm {e} ^{-iq(x_{j}-x_{k})}}
but now we want to consider, for simplicity an infinite crystal, i.e.,
N
→
∞
{\displaystyle N\to \infty }
, and we want to consider pairs of lattice sites. For large
N
{\displaystyle N}
, for each of these
N
{\displaystyle N}
planes, there are two neighbours
m
{\displaystyle m}
planes away, so the above double sum becomes a single sum over pairs of neighbours either side of an atom, at positions
−
m
{\displaystyle -m}
and
m
{\displaystyle m}
lattice spacings away, times
N
{\displaystyle N}
. So, then
S
(
q
)
=
1
+
2
N
∑
m
=
1
N
∫
−
∞
∞
d
(
Δ
x
)
p
m
(
Δ
x
)
cos
(
m
q
Δ
x
)
{\displaystyle S(q)=1+{\frac {2}{N}}\sum _{m=1}^{N}\int _{-\infty }^{\infty }{\rm {d}}(\Delta x)p_{m}(\Delta x)\cos \left(mq\Delta x\right)}
where
p
m
(
Δ
x
)
{\displaystyle p_{m}(\Delta x)}
is the probability density function for the separation
Δ
x
{\displaystyle \Delta x}
of a pair of planes,
m
{\displaystyle m}
lattice spacings apart. For the separation of neighbouring planes we assume for simplicity that the fluctuations around the mean neighbour spacing of a are Gaussian, i.e., that
p
1
(
Δ
x
)
=
1
(
2
π
σ
2
2
)
1
/
2
exp
[
−
(
Δ
x
−
a
)
2
/
(
2
σ
2
2
)
]
{\displaystyle p_{1}(\Delta x)={\frac {1}{\left(2\pi \sigma _{2}^{2}\right)^{1/2}}}\exp \left[-\left(\Delta x-a\right)^{2}/(2\sigma _{2}^{2})\right]}
and we also assume that the fluctuations between a plane and its neighbour, and between this neighbour and the next plane, are independent. Then
p
2
(
Δ
x
)
{\displaystyle p_{2}(\Delta x)}
is just the convolution of two
p
1
(
Δ
x
)
{\displaystyle p_{1}(\Delta x)}
s, etc. As the convolution of two Gaussians is just another Gaussian, we have that
p
m
(
Δ
x
)
=
1
(
2
π
m
σ
2
2
)
1
/
2
exp
[
−
(
Δ
x
−
m
a
)
2
/
(
2
m
σ
2
2
)
]
{\displaystyle p_{m}(\Delta x)={\frac {1}{\left(2\pi m\sigma _{2}^{2}\right)^{1/2}}}\exp \left[-\left(\Delta x-ma\right)^{2}/(2m\sigma _{2}^{2})\right]}
The sum in
S
(
q
)
{\displaystyle S(q)}
is then just a sum of Fourier Transforms of Gaussians, and so
S
(
q
)
=
1
+
2
∑
m
=
1
∞
r
m
cos
(
m
q
a
)
{\displaystyle S(q)=1+2\sum _{m=1}^{\infty }r^{m}\cos \left(mqa\right)}
for
r
=
exp
[
−
q
2
σ
2
2
/
2
]
{\displaystyle r=\exp[-q^{2}\sigma _{2}^{2}/2]}
. The sum is just the real part of the sum
∑
m
=
1
∞
[
r
exp
(
i
q
a
)
]
m
{\displaystyle \sum _{m=1}^{\infty }[r\exp(iqa)]^{m}}
and so the structure factor of the infinite but disordered crystal is
S
(
q
)
=
1
−
r
2
1
+
r
2
−
2
r
cos
(
q
a
)
{\displaystyle S(q)={\frac {1-r^{2}}{1+r^{2}-2r\cos(qa)}}}
This has peaks at maxima
q
p
=
2
n
π
/
a
{\displaystyle q_{p}=2n\pi /a}
, where
cos
(
q
P
a
)
=
1
{\displaystyle \cos(q_{P}a)=1}
. These peaks have heights
S
(
q
P
)
=
1
+
r
1
−
r
≈
4
q
P
2
σ
2
2
=
a
2
n
2
π
2
σ
2
2
{\displaystyle S(q_{P})={\frac {1+r}{1-r}}\approx {\frac {4}{q_{P}^{2}\sigma _{2}^{2}}}={\frac {a^{2}}{n^{2}\pi ^{2}\sigma _{2}^{2}}}}
i.e., the height of successive peaks drop off as the order of the peak (and so
q
{\displaystyle q}
) squared. Unlike finite-size effects that broaden peaks but do not decrease their height, disorder lowers peak heights. Note that here we assuming that the disorder is relatively weak, so that we still have relatively well defined peaks. This is the limit
q
σ
2
≪
1
{\displaystyle q\sigma _{2}\ll 1}
, where
r
≃
1
−
q
2
σ
2
2
/
2
{\displaystyle r\simeq 1-q^{2}\sigma _{2}^{2}/2}
. In this limit, near a peak we can approximate
cos
(
q
a
)
≃
1
−
(
Δ
q
)
2
a
2
/
2
{\displaystyle \cos(qa)\simeq 1-(\Delta q)^{2}a^{2}/2}
, with
Δ
q
=
q
−
q
P
{\displaystyle \Delta q=q-q_{P}}
and obtain
S
(
q
)
≈
S
(
q
P
)
1
+
r
(
1
−
r
)
2
Δ
q
2
a
2
≈
S
(
q
P
)
1
+
Δ
q
2
[
q
P
2
σ
2
2
/
2
a
]
2
{\displaystyle S(q)\approx {\frac {S(q_{P})}{1+{\frac {r}{(1-r)^{2}}}\Delta q^{2}a^{2}}}\approx {\frac {S(q_{P})}{1+{\frac {\Delta q^{2}}{[q_{P}^{2}\sigma _{2}^{2}/2a]^{2}}}}}}
which is a Lorentzian or Cauchy function, of FWHM
q
P
2
σ
2
2
/
a
=
4
π
2
n
2
(
σ
2
/
a
)
2
/
a
{\displaystyle q_{P}^{2}\sigma _{2}^{2}/a=4\pi ^{2}n^{2}(\sigma _{2}/a)^{2}/a}
, i.e., the FWHM increases as the square of the order of peak, and so as the square of the wavevector
q
{\displaystyle q}
at the peak. Finally, the product of the peak height and the FWHM is constant and equals
4
/
a
{\displaystyle 4/a}
, in the
q
σ
2
≪
1
{\displaystyle q\sigma _{2}\ll 1}
limit. For the first few peaks where
n
{\displaystyle n}
is not large, this is just the
σ
2
/
a
≪
1
{\displaystyle \sigma _{2}/a\ll 1}
limit.
Thus finite-size and this type of disorder both cause peak broadening, but there are qualitative differences. Finite-size effects broadens all peaks equally, and does not affect peak heights, while this type of disorder both reduces peak heights and broadens peaks by an amount that increases as
n
2
{\displaystyle n^{2}}
. This, in principle, allows the two effects to be distinguished. Also, it means that the Scherrer equation is best applied to the first peak, as disorder of this type affects the first peak the least.
=== Coherence length ===
Within this model the degree of correlation between a pair of planes decreases as the distance between these planes increases, i.e., a pair of planes 10 planes apart have positions that are more weakly correlated than a pair of planes that are nearest neighbours. The correlation is given by
p
m
{\displaystyle p_{m}}
, for a pair of planes m planes apart. For sufficiently large m the pair of planes are essentially uncorrelated, in the sense that the uncertainty in their relative positions is so large that it is comparable to the lattice spacing, a. This defines a correlation length,
λ
{\displaystyle \lambda }
, defined as the separation when the width of
p
m
{\displaystyle p_{m}}
, which is
m
1
/
2
σ
2
{\displaystyle m^{1/2}\sigma _{2}}
equals a. This gives
λ
=
a
3
σ
2
2
{\displaystyle \lambda ={\frac {a^{3}}{\sigma _{2}^{2}}}}
which is in effect an order-of-magnitude estimate for the size of domains of coherent crystalline lattices. Note that the FWHM of the first peak scales as
σ
2
2
/
a
3
{\displaystyle \sigma _{2}^{2}/a^{3}}
, so the coherence length is approximately 1/FWHM for the first peak.
== Further reading ==
B.D. Cullity & S.R. Stock, Elements of X-Ray Diffraction, 3rd Ed., Prentice-Hall Inc., 2001, p 96-102, ISBN 0-201-61091-4.
R. Jenkins & R.L. Snyder, Introduction to X-ray Powder Diffractometry, John Wiley & Sons Inc., 1996, p 89-91, ISBN 0-471-51339-3.
H.P. Klug & L.E. Alexander, X-Ray Diffraction Procedures, 2nd Ed., John Wiley & Sons Inc., 1974, p 687-703, ISBN 978-0-471-49369-3.
B.E. Warren, X-Ray Diffraction, Addison-Wesley Publishing Co., 1969, p 251-254, ISBN 0-201-08524-0.
== References == | Wikipedia/Scherrer_equation |
Comptes rendus de l'Académie des Sciences (French pronunciation: [kɔ̃t ʁɑ̃dy də lakademi de sjɑ̃s], Proceedings of the Academy of Sciences), or simply Comptes rendus, is a French scientific journal published since 1835. It is the proceedings of the French Academy of Sciences. It is currently split into seven sections, published on behalf of the Academy until 2020 by Elsevier: Mathématique, Mécanique, Physique, Géoscience, Palévol, Chimie, and Biologies. As of 2020, the Comptes Rendus journals are published by the Academy with a diamond open access model.
== Naming history ==
The journal has had several name changes and splits over the years.
=== 1835–1965 ===
Comptes rendus was initially established in 1835 as Comptes rendus hebdomadaires des séances de l'Académie des Sciences. It began as an alternative publication pathway for more prompt publication than the Mémoires de l'Académie des Sciences, which had been published since 1666. The Mémoires, which continued to be published alongside the Comptes rendus throughout the nineteenth century, had a publication cycle which resulted in memoirs being published years after they had been presented to the Academy. Some academicians continued to publish in the Mémoires because of the strict page limits in the Comptes rendus.
=== 1966–1980 ===
After 1965 this title was split into five sections:
Série A (Sciences mathématiques) – mathematics
Série B (Sciences physiques) – physics and geosciences
Série C (Sciences chimiques) – chemistry
Série D (Sciences naturelles) – life sciences
Vie académique – academy notices and miscellanea (between 1968 and 1970, and again between 1979 and 1983)
Series A and B were published together in one volume except in 1974.
=== 1981–1993 ===
The areas were rearranged as follows:
Série I - (Sciences Mathématiques) - mathematics
Série II (Mécanique-physique, Chimie, Sciences de l'univers, Sciences de la Terre) - physics, chemistry, astronomy and geosciences
Série III - (Sciences de la vie) - life sciences
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Vie des sciences – A renamed Vie académique (from 1984 to 1996)
=== 1994–2001 ===
These publications remained the same:
Série I (Sciences mathématiques) – mathematics
Série III (Sciences de la Vie) – life sciences
Vie des sciences – A renamed Vie académique (until 1996)
The areas published in Série II were slowly split into other publications in ways that caused some confusion.
In 1994, Série II, which covered physics, chemistry, astronomy and geosciences, was replaced by Série IIA and Série IIB. Série IIA was exclusive to geosciences, and Série IIB covered chemistry and astronomy and the now-distinct mechanics and physics.
In 1998, Série IIB covered mechanics, physics and astronomy; chemistry got its separate publication, Série IIC.
In 2000, Série IIB became dedicated exclusively to mechanics in May. Astronomy got redefined as astrophysics, which along with physics was covered by the new Série IV. Série IV began publishing in March; however, Séries IIB published two more issues on physics and astrophysics in April and May before starting the new run.
=== 2002 onwards ===
The present naming and subject assignment was established in 2002:
Comptes Rendus Biologies – life sciences except paleontology and evolutionary biology. Continues in part Série IIC (biochemistry) and III.
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== Online open archives ==
The Comptes rendus de l'Académie des Sciences publications are available through the National Library of France as part of its free online library and archive of other historical documents and works of art, Gallica. The publications available online are:
Comptes rendus hebdomadaires des séances de l'Académie des science (1835–1965)
Séries A et B, Sciences Mathématiques et Sciences Physiques (1966–1973)
Série A, Sciences Mathématiques, (1974)
Série B, Sciences Physiques, (1974)
Séries A et B, Sciences Mathématiques et Sciences Physiques (1975–1980)
Besides the material for this timeframe, this collection also has a separate set of scans of all the material of Série I - Mathématique from 1981 to 1990
Série C, Sciences Chimique
Série D, Sciences Naturelle
Vie Académique (1968–1970)
Vie Académique (1979–1983)
Série I - Mathématique
Séries A et B, Sciences Mathématiques et Sciences Physiques (1975–1980) has a different set of scans for all of this material.
Série II - Mécanique-physique, Chimie, Sciences de l'univers, Sciences de la Terr
The link to Série I - Mathématique (1984–1996) includes a different set of scans for the first 3 issues of 1981 of this series.
Série III - Sciences de la vie
Série I - Mathématique
Séries A et B, Sciences Mathématiques et Sciences Physiques (1975–1980) has a different set of scans for this series' material until 1990.
This collection contains a different set of scans of the 1981 material of Série II - Mécanique-physique, Chimie, Sciences de l'univers, Sciences de la Terr (1981–1983).
Série II - Mécanique-physique, Chimie, Sciences de l'univers, Sciences de la Terre (1984–1994)
The first year of material (1994) of material of Série IIb - Mécanique, physique, chimie, astronomie (1995–1996) is misfiled in this collection.
Série IIa - Sciences de la terre et des planètes (1994–1996)
Série IIb - Mécanique, physique, chimie, astronomie (1995–1996)
The first year of material (1994) is misfiled together with Série II - Mécanique-physique, Chimie, Sciences de l'univers, Sciences de la Terre (1994–1996).
Série III - Sciences de la vie
Vie des sciences
All publications from 1997 to 2019 were published commercially by Elsevier. From 2020 on, the Comptes Rendus Palevol have been published by the Muséum National d'Histoire Naturelle (Paris) for the Académie des Sciences. All other series of the Comptes Rendus of the Acamémie des Sciences have been published (from 2020 on) by Mersenne under a Diamond Open Access model.
== References ==
== External links ==
"Comptes Rendus official website". French Academy of Sciences. Retrieved 23 May 2024.
Comptes Rendus de l'Académie des sciences numérisés sur le site de la Bibliothèque nationale de France
Scholarly Societies project: French Academy of Sciences page; provides information on naming and publication history up to 1980, as well as on previous journals of the Academy. Retrieved 2006-DEC-10.
Bibliothèque nationale de France: Catalog record and full-text scans of Comptes rendus. Retrieved 2009-JUN-22.
Comptes rendus series: [1]
ScienceDirect list of titles (from 1997 onwards): https://www.sciencedirect.com/browse/journals-and-books?searchPhrase=comptes | Wikipedia/Comptes_rendus_hebdomadaires_des_séances_de_l'Académie_des_sciences |
X-ray fluorescence holography (XFH) is a holography method with atomic resolution based on atomic fluorescence. It is a relatively new technique that benefits greatly from the coherent high-power X-rays available from synchrotron sources, such as the Japanese SPring-8 facility.
== Imaging ==
Fluorescent X-rays are scattered by atoms in a sample and provide the object wave, which is referenced to non-scattered X-rays. A holographic pattern is recorded by scanning a detector around the sample, which allows researchers to investigate the local 3D structure around a specific element in a sample.
== Applications ==
It is useful for investigating the effects of irradiation on high temperature superconductors.
== Twin picture ==
One of the criticisms for this method is that it suffers from twin images. D. Gabor. Barton proposed that reconstructed phased images of holograms will suppress twin images effects.
== References == | Wikipedia/X-ray_fluorescence_holography |
Ptychography (/t(a)ɪˈkɒgrəfi/ t(a)i-KO-graf-ee) is a computational microscopy method and a major advance of coherent diffractive imaging (CDI), which was first experimentally demonstrated in 1999 using synchrotron X-rays and iterative phase retrieval. It unifies principles from microscopy and crystallography to reconstruct high-resolution, quantitative images by analyzing a series of overlapping coherent diffraction patterns acquired as a focused beam is scanned across the sample. Its defining characteristic is translational invariance, which means that the interference patterns are generated by one constant function (e.g. a field of illumination or an aperture stop) moving laterally by a known amount with respect to another constant function (the specimen itself or a wave field). The interference patterns occur some distance away from these two components, so that the scattered waves spread out and "fold" (Ancient Greek: πτυχή, "ptychē" is 'fold') into one another as shown in the figure.
Ptychography can be used with visible light, X-rays, extreme ultraviolet (EUV) or electrons. Unlike conventional lens imaging, ptychography is unaffected by lens-induced aberrations or diffraction effects caused by limited numerical aperture. This is particularly important for atomic-scale wavelength imaging, where it is difficult and expensive to make good-quality lenses with high numerical aperture. Another important advantage of the technique is that it allows transparent objects to be seen very clearly. This is because it is sensitive to the phase of the radiation that has passed through a specimen, and so it does not rely on the object absorbing radiation. In the case of visible-light biological microscopy, this means that cells do not need to be stained or labelled to create contrast.
== Phase recovery ==
Although the interference patterns used in ptychography can only be measured in intensity, the mathematical constraints provided by the translational invariance of the two functions (illumination and object), together with the known shifts between them, means that the phase of the wavefield can be recovered by an inverse computation. Ptychography thus provides a comprehensive solution to the so-called "phase problem". Once this is achieved, all the information relating to the scattered wave (modulus and phase) has been recovered, and so virtually perfect images of the object can be obtained. There are various strategies for performing this inverse phase-retrieval calculation, including direct Wigner distribution deconvolution (WDD) and iterative methods. The difference map algorithm developed by Thibault and co-workers is available in a downloadable package called PtyPy.
== Optical configurations ==
There are many optical configurations for ptychography: mathematically, it requires two invariant functions that move across one another while an interference pattern generated by the product of the two functions is measured. The interference pattern can be a diffraction pattern, a Fresnel diffraction pattern or, in the case of Fourier ptychography, an image. The "ptycho" convolution in a Fourier ptychographic image derived from the impulse response function of the lens.
=== The single aperture ===
This is conceptually the simplest ptychographical arrangement. The detector can either be a long way from the object (i.e. in the Fraunhofer diffraction plane), or closer by, in the Fresnel regime. An advantage of the Fresnel regime is that there is no longer a very high-intensity beam at the centre of the diffraction pattern, which can otherwise saturate the detector pixels there.
=== Focused-probe ptychography ===
A lens is used to form a tight crossover of the illuminating beam at the plane of the specimen. The configuration is used in the scanning transmission electron microscope (STEM), and often in high-resolution X-ray ptychography. The specimen is sometimes shifted up or downstream of the probe crossover so as to allow the size of the patch of illumination to be increased, thus requiring fewer diffraction patterns to scan a wide field of view.
=== Near-field ptychography ===
This uses a wide field of illumination. To provide magnification, a diverging beam is incident on the specimen. An out-of-focus image, which appears as a Fresnel interference pattern, is projected onto the detector. The illumination must have phase distortions in it, often provided by a diffuser that scrambles the phase of the incident wave before it reaches the specimen, otherwise the image remains constant as the specimen is moved, so there is no new ptychographical information from one position to the next. In the electron microscope, a lens can be used to map the magnified Fresnel image onto the detector.
=== Fourier ptychography ===
A conventional microscope is used with a relatively small numerical aperture objective lens. The specimen is illuminated from a series of different angles. Parallel beams coming out of the specimen are brought to a focus in the back focal plane of the objective lens, which is therefore a Fraunhofer diffraction pattern of the specimen exit wave (Abbe’s theorem). Tilting the illumination has the effect of shifting the diffraction pattern across the objective aperture (which also lies in the back focal plane). Now the standard ptychographical shift invariance principle applies, except that the diffraction pattern is acting as the object and the back focal plane stop is acting like the illumination function in conventional ptychography. The image is in the Fraunhofer diffraction plane of these two functions (another consequence of Abbe's theorem), just like in conventional ptychography. The only difference is that the method reconstructs the diffraction pattern, which is much wider than the aperture stop limitation. A final Fourier transform must be undertaken to produce the high-resolution image. All the reconstruction algorithms used in conventional ptychography apply to Fourier ptychography, and indeed nearly all the diverse extensions of conventional ptychography have been used in Fourier ptychography.
=== Imaging ptychography ===
A lens is used to make a conventional image. An aperture in the image plane acts equivalently to the illumination in conventional ptychography, while the image corresponds to the specimen. The detector lies in the Fraunhofer or Fresnel diffraction plane downstream of the image and aperture.
=== Bragg ptychography or reflection ptychography ===
This geometry can be used either to map surface features or to measure strain in crystalline specimens. Shifts in the specimen surface, or the atomic Bragg planes perpendicular to the surface, appear in the phase of the ptychographic image.
=== Vectorial ptychography ===
Vectorial ptychography needs to be invoked when the multiplicative model of the interaction between the probe and the specimen cannot be described by scalar quantities. This happens typically when polarized light probes an anisotropic specimen, and when this interaction modifies the state of polarization of light. In that case, the interaction needs to be described by the Jones formalism, where field and object are described by a two-component complex vector and a 2×2 complex matrix respectively. The optical configuration for vectorial ptychography is similar to that of classical (scalar) ptychography, although a control of light polarization (before and after the specimen) needs to be implemented in the setup. Jones maps of the specimens can be retrieved, allowing the quantification of a wide range of optical properties (phase, birefringence, orientation of neutral axes, diattenuation, etc.). Similarly to scalar ptychography, the probes used for the measurement can be jointly estimated together with the specimen. As a consequence, vectorial ptychography is also an elegant approach for quantitative imaging of coherent vectorial light beams (mixing wavefront and polarization features).
== Advantages ==
=== Lens insensitive ===
Ptychography can be undertaken without using any lenses at all, although most implementations use a lens of some type, if only to condense radiation onto the specimen. The detector can measure high angles of scatter, which do not need to pass through a lens. The resolution is therefore only limited by the maximal angle of scatter that reaches the detector, and so avoids the effects of diffraction broadening due to a lens of small numerical aperture or aberrations within the lens. This is key in X-ray, electron and EUV ptychography, where conventional lenses are difficult and expensive to make.
=== Image phase ===
Ptychography solves for the phase induced by the real part of the refractive index of the specimen, as well as absorption (the imaginary part of the refractive index). This is crucial for seeing transparent specimens that do not have significant natural absorption contrast, for example biological cells (at visible light wavelengths), thin high-resolution electron microscopy specimens, and almost all materials at hard X-ray wavelengths. In the latter case, the (linear) phase signal is also ideal for high-resolution X-ray ptychographic tomography. The strength and contrast of the phase signal also means that far fewer photon or electron counts are needed to make an image: this is very important in electron ptychography, where damage to the specimen is a major issue that must be avoided at all costs.
=== Tolerance to incoherence ===
Unlike holography, ptychography uses the object itself as an interferometer. It does not require a reference beam. Although holography can solve the image phase problem, it is very difficult to implement in the electron microscope, where the reference beam is extremely sensitive to magnetic interference or other sources of instability. This is why ptychography is not limited by the conventional "information limit" in conventional electron imaging. Furthermore, ptychographical data is sufficiently diverse to remove the effects of partial coherence that would otherwise affect the reconstructed image.
=== Self-calibration ===
The ptychographical data set can be posed as a blind deconvolution problem. It has sufficient diversity to solve for both the moving functions (illumination and object), which appear symmetrically in the mathematics of the inversion process. This is now routinely done in any ptychographical experiment, even if the illumination optics have been previously well characterised. Diversity can also be used to solve retrospectively for errors in the offsets of the two functions, blurring in the scan, detector faults, like missing pixels, etc.
=== Inversion of multiple scattering ===
In conventional imaging, multiple scattering in a thick sample can seriously complicate, or even entirely invalidate, simple interpretation of an image. This is especially true in electron imaging (where multiple scattering is called "dynamical scattering"). Conversely, ptychography generates estimates of hundreds or thousands of exit waves, each of which contains different scattering information. This can be used to retrospectively remove multiple scattering effects.
=== Robustness to noise ===
The number counts required for a ptychography experiment is the same as for a conventional image, even though the counts are distributed over very many diffraction patterns. This is because dose fractionation applies to ptychography. Maximum-likelihood methods can be employed to reduce the effects of Poisson noise.
== Applications ==
Applications of ptychography are diverse because it can be used with any type of radiation that can be prepared as a quasi-monochromatic propagating wave.
Ptychographic imaging, along with advances in detectors and computing, has resulted in the development of X-ray microscopes. Coherent beams are required in order to obtain far-field diffraction patterns with speckle patterns. Coherent X-ray beams can be produced by modern synchrotron radiation sources, free-electron lasers and high-harmonic sources. In terms of routine analysis, X-ray ptychotomography is today the most commonly used technique. It has been applied to many materials problems including, for example, the study of paint, imaging battery chemistry, imaging stacked layers of tandem solar cells, and the dynamics of fracture. In the X-ray regime, ptychography has also been used to obtain a 3D mapping of the disordered structure in the white Cyphochilus beetle, and a 2D imaging of the domain structure in a bulk heterojunction for polymer solar cells.
Visible-light ptychography has been used for imaging live biological cells and studying their growth, reproduction and motility. In its vectorial version, it can also be used for mapping quantitative optical properties of anisotropic materials such as biominerals or metasurfaces
Electron ptychography is uniquely (amongst other electron imaging modes) sensitive to both heavy and light atoms simultaneously. It has been used, for example, in the study of nanostructure drug-delivery mechanisms by looking at drug molecules stained by heavy atoms within light carbon nanotubes cages. With electron beams, shorter-wavelength, higher-energy electrons used for higher-resolution imaging can cause damage to the sample by ionising it and breaking bonds, but electron-beam ptychography has now produced record-breaking images of molybdenum disulphide with a resolution of 0.039 nm using a lower-energy electron beam and detectors that are able to detect single electrons, so atoms can be located with more precision.
Ptychography has several applications in the semiconductor industry, including imaging their surfaces using EUV, their 3D bulk structure using X-rays, and mapping strain fields by Bragg ptychography, for example, in nanowires.
== History ==
=== Beginnings in crystallography ===
The name "ptychography" was coined by Hegerl and Hoppe in 1970 to describe a solution to the crystallographic phase problem first suggested by Hoppe in 1969. The idea required the specimen to be highly ordered (a crystal) and to be illuminated by a precisely engineered wave so that only two pairs of diffraction peaks interfere with one another at a time. A shift in the illumination changes the interference condition (by the Fourier shift theorem). The two measurements can be used to solve for the relative phase between the two diffraction peaks by breaking a complex-conjugate ambiguity that would otherwise exist. Although the idea encapsulates the underlying concept of interference by convolution (ptycho) and translational invariance, crystalline ptychography cannot be used for imaging of continuous objects, because very many (up to millions) of beams interfere at the same time, and so the phase differences are inseparable. Hoppe abandoned his concept of ptychography in 1973.
=== Development of inversion methods ===
Between 1989 and 2007 Rodenburg and co-workers developed various inversion methods for the general imaging ptychographic phase problem, including Wigner-distribution deconvolution (WDD), SSB, the "PIE" iterative method (a precursor of the "ePIE" algorithm), demonstrating proof-of-principles at various wavelengths. Chapman used the WDD inversion method to demonstrate the first implementation of X-ray ptychography in 1996. The smallness of computers and poor quality of detectors at that time may account for the fact that ptychography was not at first taken up by other workers.
=== General uptake ===
Widespread interest in ptychography only started after the first demonstration of iterative phase-retrieval X-ray ptychography in 2007 at the Swiss Light Source (SLS). The conceptual framework of modern ptychography builds on coherent diffractive imaging (CDI), which was first experimentally demonstrated in 1999 by Miao and colleagues using synchrotron X-rays and iterative phase retrieval. Progress at X-ray wavelengths was then quick. By 2010, the SLS had developed X-ray ptychotomography, now a major application of the technique. Thibault, also working at the SLS, developed the difference-map (DM) iterative inversion algorithm and mixed-state ptychography. Since 2010, several groups have developed the capabilities of ptychography to characterize and improve reflective and refractive X-ray optics. Bragg ptychography, for measuring strain in crystals, was demonstrated by Hruszkewycz in 2012. In 2012 it was also shown that electron ptychography could improve on the resolution of an electron lens by a factor of five, a method which was used in 2018 to provide the highest-resolution transmission image ever obtained earning a Guinness world record, and once again in 2021 to achieve an even better resolution. Real-space light ptychography became available in a commercial system for live-cell imaging in 2013. Fourier ptychography using iterative methods was also demonstrated by Zheng et al. in 2013, a field which is growing rapidly. The group of Margaret Murnane and Henry Kapteyn at JILA, CU Boulder demonstrated EUV reflection ptychographic imaging in 2014.
== See also ==
Jianwei (John) Miao – led the first experimental demonstration of coherent diffractive imaging (CDI) and contributed to its evolution into computational microscopy techniques such as atomic electron tomography (AET) and ptychographic AET (pAET).
Coherent diffractive imaging (CDI)
Phase retrieval
Computational imaging
Fourier ptychography
== References ==
== External links ==
Cornell researchers see atoms at record resolution, cornell.edu at 20 May 2021 | Wikipedia/Ptychography |
The Cambridge Crystallographic Data Centre (CCDC) is a non-profit organisation based in Cambridge, England. Its primary activity is the compilation and maintenance of the Cambridge Structural Database, a database of small molecule crystal structures. They also perform analysis on the database for the benefit of the scientific community, and write and distribute computer software to allow others to do the same.
== History ==
In 1962, Dr. Olga Kennard OBE FRS set up a chemical crystallography group within the Department of Chemistry, University of Cambridge. In 1965 she founded the CCDC and established the associated Cambridge Structural Database. At that time, there were only about 3,000 published X-ray structures, and the work involved converting these into a machine-readable form. Kennard invited Frank Allen to join the group, which he did in 1970, becoming Scientific Director and then Executive Director before retiring in 2008.
In 1992, the CCDC moved into its own building adjacent to the Cambridge chemistry department. This new headquarters was designed by the Danish architect Professor Erik Christian Sørensen and won The Sunday Times Building of the Year Award in 1993.
The CCDC still retains very close links as a University Partner Institution that trains students for postgraduate research degrees but from 1987 became an independent company. By 2019 the database had grown to over a million structures.
== Current research ==
The staff at the CCDC curate the database of small-molecule organic and metal-organic crystal structures and make these available for download by the public. They also create and maintain a suite of cheminformatics software that may be used to apply the data to applications in the life sciences, including crystal engineering and materials science.
=== Programs Developed ===
CCDC developed programs such as ConQuest and Mercury that run under Windows, various types of Linux, and macOS. ConQuest is a search interface to the Cambridge Structural Database (CSD). Mercury is a crystal structure visualizer tool, of which later versions released in 2015 and later provide the functionality to generate 3D prints.
== See also ==
List of chemical databases
CrystalExplorer
== References ==
== External links ==
The Cambridge Crystallographic Data Centre | Wikipedia/Cambridge_Crystallographic_Data_Centre |
X-ray lithography is a process used in semiconductor device fabrication industry to selectively remove parts of a thin film of photoresist. It uses X-rays to transfer a geometric pattern from a mask to a light-sensitive chemical photoresist, or simply "resist," on the substrate to reach extremely small topological size of a feature. A series of chemical treatments then engraves the produced pattern into the material underneath the photoresist.
It's less commonly used in commercial production due to prohibitively high costs of materials (such as gold used for X-rays blocking) etc.
== Mechanisms ==
X-ray lithography originated as a candidate for next-generation lithography for the semiconductor industry[1], with batches of microprocessors successfully produced. Having short wavelengths (below 1 nm), X-rays overcome the diffraction limits of optical lithography, allowing smaller feature sizes. If the X-ray source isn't collimated, as with a synchrotron radiation, elementary collimating mirrors or diffractive lenses are used in the place of the refractive lenses used in optics. The X-rays illuminate a mask placed in proximity of a resist-coated wafer. The X-rays are broadband, typically from a compact synchrotron radiation source, allowing rapid exposure. Deep X-ray lithography (DXRL) uses yet shorter wavelengths on the order of 0.1 nm and modified procedures such as the LIGA process, to fabricate deep and even three-dimensional structures.
The mask consists of an X-ray absorber, typically of gold or compounds of tantalum or tungsten, on a membrane that is transparent to X-rays, typically of silicon carbide or diamond. The pattern on the mask is written by direct-write electron beam lithography onto a resist that is developed by conventional semiconductor processes. The membrane can be stretched for overlay accuracy.
Most X-ray lithography demonstrations have been performed by copying with image fidelity (without magnification) on the line of fuzzy contrast as illustrated in the figure. However, with the increasing need for high resolution, X-ray lithography is now performed on what is called the "sweet spot", using local "demagnification by bias".[2][3] Dense structures are developed by multiple exposures with translation. The advantages of using 3x demagnification include the mask to wafer gap and contrast increasing, as well as the mask being more easily fabricated. The technique is extensible to dense 15 nm prints.
X-rays generate secondary electrons as in the cases of extreme ultraviolet lithography and electron beam lithography. While the fine pattern definition is due principally to secondaries from Auger electrons with a short path length, the primary electrons will sensitize the resist over a larger region than the X-ray exposure. While this does not affect the pattern pitch resolution, which is determined by wavelength and gap, the image exposure contrast (max-min)/(max+min) is reduced because the pitch is on the order of the primary photo-electron range. The sidewall roughness and slopes are influenced by these secondary electrons as they can travel few micrometers in the area under the absorber, depending on exposure X-ray energy.[4] Several prints at about 30 nm have been published.[5]
Another manifestation of the photoelectron effect is exposure to X-ray generated electrons from thick gold films used for making daughter masks.[6] Simulations suggest that photoelectron generation from the gold substrate may affect dissolution rates.
== Photoelectrons, secondary electrons and Auger electrons ==
Secondary electrons have energies of 25 eV or less, and can be generated by any ionizing radiation (VUV, EUV, X-rays, ions and other electrons). Auger electrons have energies of hundreds of electronvolts. The secondaries (generated by and outnumbering the Auger and primary photoelectrons) are the main agents for resist exposure.
The relative ranges of photoelectron primaries and Auger electrons depend on their respective energies. These energies depend on the energy of incident radiation and on the composition of the resist. There is considerable room for optimum selection (reference 3 of the article). When Auger electrons have lower energies than primary photoelectrons, they have shorter ranges. Both decay to secondaries which interact with chemical bonds.[7] When secondary energies are too low, they fail to break the chemical bonds and cease to affect print resolution. Experiments prove that the combined range is less than 20 nm. On the other hand, the secondaries follow a different trend below ≈30 eV: the lower the energy, the longer the mean free path though they are not then able to affect resist development.
As they decay, primary photo-electrons and Auger electrons eventually become physically indistinguishable (as in Fermi–Dirac statistics) from secondary electrons. The range of low-energy secondary electrons is sometimes larger than the range of primary photo-electrons or of Auger electrons. What matters for X-ray lithography is the effective range of electrons that have sufficient energy to make or break chemical bonds in negative or positive resists.
== Lithographic electron range ==
X-rays do not charge. The relatively large mean free path (~20 nm) of secondary electrons hinders resolution control at nanometer scale. In particular, electron beam lithography suffers negative charging by incident electrons and consequent beam spread which limits resolution. It is difficult therefore to isolate the effective range of secondaries which may be less than 1 nm.
The combined electron mean free path results in an image blur, which is usually modeled as a Gaussian function (where σ = blur) that is convolved with the expected image. As the desired resolution approaches the blur, the dose image becomes broader than the aerial image of the incident X-rays. The blur that matters is the latent image that describes the making or breaking of bonds during the exposure of resist. The developed image is the final relief image produced by the selected high contrast development process on the latent image.
The range of primary, Auger, secondary and ultralow energy higher-order generation electrons which print (as STM studies proved) can be large (tens of nm) or small (nm), according to various cited publications. Because this range is not a fixed number, it is hard to quantify. Line edge roughness is aggravated by the associated uncertainty. Line edge roughness is supposedly statistical in origin and only indirectly dependent on mean range. Under commonly practiced lithography conditions, the various electron ranges can be controlled and utilized.
== Charging ==
X-rays carry no charge, but at the energies involved, Auger decay of ionized species in a specimen is more probable than radiative decay. High-energy radiation exceeding the ionization potential also generates free electrons which are negligible compared to those produced by electron beams which are charged. Charging of the sample following ionization is an extremely weak possibility when it cannot be guaranteed the ionized electrons leaving the surface or remaining in the sample are adequately balanced from other sources in time. The energy transfer to electrons as a result of ionizing radiation results in separated positive and negative charges which quickly recombine due partly to the long range of the Coulomb force. Insulating films like gate oxides and resists have been observed to charge to a positive or negative potential under electron-beam irradiation. Insulating films are eventually neutralized locally by space charge (electrons entering and exiting the surface) at the resist-vacuum interface and Fowler-Nordheim injection from the substrate.[8] The range of the electrons in the film can be affected by the local electric field. The situation is complicated by the presence of holes (positively charged electron vacancies) which are generated along with the secondary electrons, and which may be expected to follow them around. As neutralization proceeds, any initial charge concentration effectively starts to spread out. The final chemical state of the film is reached after neutralization is completed, after all the electrons have eventually slowed down. Usually, excepting X-ray steppers, charging can be further controlled by flood gun or resist thickness or charge dissipation layer.
== See also ==
Photolithography
Excimer laser
Extreme ultraviolet lithography
Electron beam lithography
Ion beam lithography
== Notes ==
^ Y. Vladimirsky, "Lithography" in Vacuum Ultraviolet Spectroscopy II Eds. J.A.Samson and D.L.Ederer, Ch 10 pp 205–223, Academic Press (1998).
^ Vladimirsky, Yuli; Bourdillon, Antony; Vladimirsky, Olga; Jiang, Wenlong; Leonard, Quinn (1999). "Demagnification in proximity x-ray lithography and extensibility to 25 nm by optimizing Fresnel diffraction". Journal of Physics D: Applied Physics. 32 (22): 114. Bibcode:1999JPhD...32..114V. doi:10.1088/0022-3727/32/22/102.
^ Antony Bourdillon and Yuli Vladimirsky, X-ray Lithography on the Sweet Spot, UHRL, San Jose, (2006) ISBN 978-0-9789839-0-1
^ Vora, K D; Shew, B Y; Harvey, E C; Hayes, J P; Peele, A G (2008). "Sidewall slopes of SU-8 HARMST using deep x-ray lithography". Journal of Micromechanics and Microengineering. 18 (3): 035037. Bibcode:2008JMiMi..18c5037V. doi:10.1088/0960-1317/18/3/035037.
^ Early, K; Schattenburg, M; Smith, H (1990). "Absence of resolution degradation in X-ray lithography for λ from 4.5nm to 0.83nm". Microelectronic Engineering. 11: 317. doi:10.1016/0167-9317(90)90122-A.
^ Carter, D. J. D. (1997). "Direct measurement of the effect of substrate photoelectrons in x-ray nanolithography". Journal of Vacuum Science and Technology B. 15 (6): 2509. Bibcode:1997JVSTB..15.2509C. doi:10.1116/1.589675.
^ Lud, Simon Q.; Steenackers, Marin; Jordan, Rainer; Bruno, Paola; Gruen, Dieter M.; Feulner, Peter; Garrido, Jose A.; Stutzmann, Martin (2006). "Chemical Grafting of Biphenyl Self-Assembled Monolayers on Ultrananocrystalline Diamond". Journal of the American Chemical Society. 128 (51): 16884–91. doi:10.1021/ja0657049. PMID 17177439.
^ Glavatskikh, I. A.; Kortov, V. S.; Fitting, H.-J. (2001). "Self-consistent electrical charging of insulating layers and metal-insulator-semiconductor structures". Journal of Applied Physics. 89: 440. Bibcode:2001JAP....89..440G. doi:10.1063/1.1330242.
== References == | Wikipedia/X-ray_lithography |
X-ray diffraction computed tomography is an experimental technique that combines X-ray diffraction with the computed tomography data acquisition approach. X-ray diffraction (XRD) computed tomography (CT) was first introduced in 1987 by Harding et al. using a laboratory diffractometer and a monochromatic X-ray pencil beam. The first implementation of the technique at synchrotron facilities was performed in 1998 by Kleuker et al.
X-ray diffraction computed tomography can be divided into two main categories depending on how the XRD data are being treated, specifically the XRD data can be treated either as powder diffraction or single crystal diffraction data and this depends on the sample properties. If the sample contains small and randomly oriented crystals, then it generates smooth powder diffraction "rings" when using a 2D area detector. If the sample contains large crystals, then it generates "spotty" 2D diffraction patterns. The latter can be performed using also a letterbox, cone and parallel X-ray beam and yields 2D or 3D images corresponding to maps of the crystallites or "grains" present in the sample and their properties, such as stress or strain. There exist several variations of this approach including 3DXRD, X-ray diffraction contrast tomography (DCT) and high energy X-ray diffraction microscopy (HEDM)
X-ray diffraction computed tomography, often abbreviated as XRD-CT, typically refers to the technique invented by Harding et al. which assumes that the acquired data are powder diffraction data. For this reason, it has also been mentioned as powder diffraction computed tomography and diffraction scattering computed tomography (DSCT), however they both refer to the same method.
== Data acquisition ==
XRD-CT employs a monochromatic pencil beam scanning approach and captures the diffraction signal in transmission geometry, producing a diffraction projection dataset. In this setup, the sample moves along an axis perpendicular to the beam's direction. It is illuminated with a monochromatic finely collimated or focused "pencil" X-ray beam. A 2D area detector then records the scattered X-rays, optimizing for best counting statistics and speed. Typically, the translational scan's size surpasses the sample's diameter, ensuring its full coverage at all assessed angles. The size of the translation step is commonly aligned with the X-ray beam's horizontal size. In a perfect scenario for any pencil-beam scanning tomographic method, the measured angles should match the number of translation steps multiplied by π/2, adhering to the Nyquist sampling theorem. However, this number can often be reduced in practice be equal to the number of translation steps without substantially compromising the quality of reconstructed images. The usual angular range spans from 0 to π.
== Data reconstruction ==
In most studies, the predominant data reconstruction approach is the 'reverse analysis' introduced by Bleuet et al. where each sinogram is treated independently yielding a new CT image. Most often the filtered back projection reconstruction algorithm is employed to reconstruct the XRD-CT images. The outcome is an image in which every pixel, or more accurately voxel, equates to a local diffraction pattern. The reconstructed data can also be seen as a stack of 2D square images, where each image corresponds to an X-ray scattering angle.
== Reconstruction artefacts ==
XRD-CT makes the following assumptions:
The sample is small and there are no significant parallax artefacts in the acquired diffraction data; when this assumption is not valid the reconstructed patterns contain a wide range of artefacts, such as inaccurate peak positions, peak shapes and even arteficial peak splitting
The acquired XRD data are powder diffraction-like and do not contain spotty data
The sample is not strongly absorbing the X-rays and there are no significant self-absorption problems in the acquired data
The chemistry of the sample is not changing significantly during the XRD-CT scan
In practise, one or more of these assumptions are not valid and the data suffer from artefacts. There are strategies to remove or significantly all of these artefacts:
Rather than employing the filtered back projection reconstruction algorithm to reconstruct the XRD-CT images, it is possible to use another reconstruction approach, termed "Direct Least Squares Reconstruction" (DLSR) to perform simultaneously peak fitting and tomographic reconstruction which takes into account the geometry of the experimental setup and yields parallax artefact-free reconstructed images. Performing a 0 to 2π XRD-CT scan instead of 0 to π can lead to reconstructed patterns with accurate peak position but not peak shape.
Spotty 2D XRD data acquired during the XRD-CT scan lead to streak or line artefacts in the reconstructed XRD-CT data; it is possible to remove or suppress these artefacts by applying filters during the azimuthal integration of the raw 2D diffraction patterns
The data can be corrected for self-absorption artefacts using an X-ray absorption-contrast CT scan of the same sample.
If the solid-state chemistry of the sample is changing during the XRD-CT scan, then other data acquisition approaches can be employed that can improve the temporal resolution of the method, such as the interlaced approach
== Data analysis ==
Analyzing the local diffraction patterns can range from basic single-peak sequential batch fitting to a comprehensive one-step full-profile analysis, known as 'Rietveld-CT' (Wragg et al., 2015 ). The latter method stands out for its efficiency over the typical sequential method since it shares global parameters across all local models. Examples of these parameters include zero error and instrumental broadening, which enhance the refinement process's stability. To elaborate, each voxel in the restructured images is made up of a local model (like multi-phase scale factors, lattice parameters, and crystallite sizes) tailored to match the corresponding local diffraction pattern. This implies that only the overarching parameters are consistent across local models. However, the application of Rietveld-CT has been limited to small images, specifically those of 60 × 60 voxels, with the feasibility for larger images hinging on the computer memory available. Most often though full profile analysis of the local diffraction patterns is performed on a pixel-by-pixel or line-by-line basis using conventional XRD data analysis methods, such LeBail, Pawley and Rietveld. All these methods employ fitting based on the restructured diffraction patterns. Another approach which is also computational expensive is the DLSR which performs the tomographic data reconstruction and peak fitting in a single step. Regardless of the chosen analytical method, the final output comprises images filled with localized physico-chemical information. Each physico-chemical image corresponds to the refined parameters present in the local models, which might include maps that correspond to scale factors, lattice parameters, and crystallite sizes.
== See also ==
X-ray diffraction
computed tomography
powder diffraction
3DXRD
synchrotron
== References == | Wikipedia/X-ray_diffraction_computed_tomography |
A panoramic radiograph is a panoramic scanning dental X-ray of the upper and lower jaw. It shows a two-dimensional view of a half-circle from ear to ear. Panoramic radiography is a form of focal plane tomography; thus, images of multiple planes are taken to make up the composite panoramic image, where the maxilla and mandible are in the focal trough and the structures that are superficial and deep to the trough are blurred.
Other nonproprietary names for a panoramic radiograph are dental panoramic radiograph and pantomogram; Abbreviations include PAN, DPR, OPT, and OPG (the latter, based on genericizing a trade name, are often avoided in medical editing).
== Types ==
Dental panoramic radiography equipment consists of a horizontal rotating arm which holds an X-ray source and a moving film mechanism (carrying a film) arranged at opposed extremities. The patient's skull sits between the X-ray generator and the film. The X-ray source is rectangular collimated beam. Also the height of that beam covers the mandibles and the maxilla regions. The arm moves and its movement may be described as a rotation around an instant center which shifts on a dedicated trajectory.
The manufacturers propose different solutions for moving the arm, trying to maintain constant distance between the teeth to the film and generator. Also those moving solutions try to project the teeth arch as orthogonally as possible. It is impossible to select an ideal movement as the anatomy varies very much from person to person. Finally a compromise is selected by each manufacturer and results in magnification factors which vary strongly along the film (15%-30%). The patient positioning is very critical in regard to both sharpness and distortions.
=== Films ===
There are two kinds of film moving mechanisms, one using a sliding flat cassette which holds the film, and another using a rotating cylinder around which the film is wound. There are two standard sizes for dental panoramic films: 30 cm × 12 cm (12″ × 5″) and 30 cm x 15 cm (12″ × 6″). The smaller size film receives 8% less X-ray dosage on it compared to the bigger size.
=== Digital ===
Dental X-rays' radiology is moving from film technology (involving a chemical developing process) to digital X-ray technology, which is based on electronic sensors and computers. One of the principal advantages compared to film based systems is the much greater exposure latitude. This means many fewer repeated scans, which reduces costs and also reduces patient exposure to radiation. Lost X-rays can also be reprinted if the digital file is saved. Other significant advantages include instantly viewable images, the ability to enhance images, the ability to email images to practitioners and clients (without needing to digitize them first), easy and reliable document handling, reduced X-ray exposure, that no darkroom is required, and that no chemicals are used.
One particular type of digital system uses a photostimulable phosphor plate (aka PSP - Phosphor Plate) in place of the film. After X-ray exposure the plate (sheet) is placed in a special scanner where the latent formed image is retrieved point by point and digitized, using a laser light scanning. The digitized images are stored and displayed on the computer screen. This method is in between old film based technology and the current direct digital imaging technology. It is similar to the film process because it involves the same image support handling and differs because the chemical development process is replaced by the scanning process. This is not much faster than film processing and the resolution and sensitivity performances are contested. However it has the clear advantage of being able to fit with any existing equipment without any modification because it replaces just the existing film.
Also sometimes the term "digital X-rays" is used to designate the scanned film documents which further are handled by computers.
The other types of digital imaging technologies use electronic sensors. A majority of them first convert the X-rays in light (using a GdO2S or CsI layer) which is further captured using a CCD or a CMOS image sensor. Few of them use a hybrid analog-to-digital arrangement which first converts the X-ray into electricity (using a CdTe layer) and then this electricity is rendered as an image by a reading section based on CMOS technology.
In current state-of-the-art digital systems, the image quality is vastly superior to conventional film-based systems. The latest advancements have also seen the addition on Cone Beam 3D Technology to standard digital panoramic devices.
== Indications ==
Orthopantomograms (OPTs) are used by health care professionals to provide information on:
Impacted wisdom teeth diagnosis and treatment planning - the most common use is to determine the status of wisdom teeth and trauma to the jaws.
Periodontal bone loss and periapical involvement.
Finding the source of dental pain, and when carrying out tooth-by-tooth diagnosis.
Assessment for the placement of dental implants
Orthodontic assessment. pre and post operative
Diagnosis of developmental anomalies such as cherubism, cleido cranial dysplasia
Carcinoma in relation to the jaws
Temporomandibular joint dysfunctions and ankylosis.
Diagnosis of osteosarcoma, ameloblastoma, renal osteodystrophy affecting jaws and hypophosphatemia.
Diagnosis, and pre- and post-surgical assessment of oral and maxillofacial trauma, e.g. dentoalveolar fractures and mandibular fractures.
Salivary stones (Sialolithiasis).
Other diagnostic and treatment applications.
== Mechanism ==
Normally, the person bites on a plastic spatula so that all the teeth, especially the crowns, can be viewed individually. The whole orthopantomogram process takes about one minute. The patient's actual radiation exposure time varies between 5.5 and 22 seconds for the machine's excursion around the skull.
The collimation of the machine means that, while rotating, the X-rays project only a limited portion of the anatomy onto the film at any given instant but, as the rotation progresses around the skull, a composite picture of the maxillo-facial block is created. While the arm rotates, the film moves in a such way that the projected partial skull image (limited by the beam section) scrolls over it and exposes it entirely. Not all of the overlapping individual images projected on the film have the same magnification because the beam is divergent and the images have differing focus points. Also not all the element images move with the same velocity on the target film as some of them are more distant from and others closer to the instant rotation center. The velocity of the film is controlled in such fashion to fit exactly the velocity of projection of the anatomical elements of the dental arch side which is closest to the film. Therefore, they are recorded sharply while the elements in different places are recorded blurred as they scroll at different velocity.
The dental panoramic image suffers from important distortions because a vertical zoom and a horizontal zoom both vary differently along the image. The vertical and horizontal zooms are determined by the relative position of the recorded element versus film and generator. Features closer to the generator receive more vertical zoom. The horizontal zoom is also dependent on the relative position of the element to the focal path. Features inside the focal path arch receive more horizontal zoom and are blurred; features outside receive less horizontal zoom and are blurred.
The result is an image showing sharply the section along the mandible arch, and blurred elsewhere. For example, the more radio-opaque anatomical region, the cervical vertebrae (neck), shows as a wide and blurred vertical pillar overlapping the front teeth. The path where the anatomical elements are recorded sharply is called "focal path".
=== Principal advantage of panoramic images ===
Broad coverage of facial bone and teeth
Low patient radiation dose
Convenience of examination for the patient (films need not be placed inside the mouth)
Ability to be used in patients who cannot open the mouth or when the opening is restricted e.g.: due to trismus
Short time required for making the image
Patient's ready understandability of panoramic films, making them a useful visual aid in patient education and case presentation.
Easy to store compared to the large set of intra oral x-rays which are typically used.
== Preparation ==
Persons who are to undergo panoramic radiography usually are required to remove any earrings, jewellery, hair pins, glasses, dentures or orthodontic appliances. If these articles are not removed, they may create artifacts on the image (especially if they contain metal) and reduce its usefulness. There is also a need for the person to stay absolutely still during the 18 or so second cycle it takes for the machine to expose the film. For this reason, radiographers often explain to the person beforehand how the machine will move.
== Adverse effects ==
Like any medical imaging utilizing ionizing radiation, there will be a minute degree of direct ionizing damage and indirect damage from free radicals created during the ionization of water molecules within cells. A rough estimate of the risk of fatal cancer from a panoramic radiograph is about 1 in 20,000,000. The age of the person being imaged also alters the risk, with younger people having a slightly higher risk. E.g. the 1 in 20,000,000 risk would be doubled for someone in the 1-10 age group (1 in 10,000,000).
== History ==
=== Historical milestones for digital panoramic systems ===
1985–1991 – The first attempt to build a dental digital panoramic was of McDavid et al. at UTHSCSA. Their idea was based on a linear pixel array(single pixel column) sensor which was not appropriate for such an application because: a) there is no tomographic effect; b) huge difficulties to collimate the X-rays beam and to control the X-ray dose delivered to the patient; c) poor generator efficiency.
1995 – DXIS, the first dental digital panoramic X-rays system available on the market, created by Catalin Stoichita at Signet (France). DXIS targeted to retrofit all the panoramic models.
1997 – SIDEXIS, of Siemens (currently Sirona Dental Systems, Germany) offered a digital option for Ortophos Plus panoramic unit, DigiPan of Trophy Radiology (France) offered a digital option for the OP100 panoramic made by Instrumentarium (Finland).
1998–2004 – many panoramic manufacturers offered their own digital systems.
== Research ==
Panoramic radiographs have the capability to demonstrate a portion of the neck and display atheromas (calcifications in the carotid artery) which are an indication of both local and generalized (systemic) atherosclerosis. Atherosclerosis of the coronary arteries leading to myocardial infarction (heart attack), and atherosclerosis of the carotid artery leading to stroke are the number one and number three most common causes of death in the United States.
There is interest to look at panoramic radiographs as a screening tool, however further data is needed with regards if it is able to make a meaningful difference in outcomes.
=== Epidemiology: general public and high risk groups ===
Additional research projects have further determined the prevalence rate of these atheromas in the general population (3–5%) and among high-risk groups (over 25% in: recent stroke victims, individuals with obstructive sleep apnea syndrome, postmenopausal women, type 2 diabetics, individuals with dilated cardiomyopathy, and among individuals who have received radiotherapy directed at the neck,). These findings have been corroborated by other several other researchers.
=== Dental infection and atherosclerosis ===
Atherosclerosis is attributed to risk factors that include cigarette smoking, hyperlipidemia, obesity, diabetes mellitus, and hypertension (high blood pressure). These factors, however, do not fully account for the risk of disease. Atherosclerosis has been conceptualized as a chronic inflammatory response to endothelial cell injury and dysfunction possibly arising from chronic dental infection. In 2010, using the previously validated Mattila panoramic radiographic index to quantify the totality of dental infection (i.e., periapical and furcal lesions, pericoronitis sites, carious tooth roots, teeth with pulpal caries, and vertical bony defects), Friedlander's group determined that individuals with carotid artery atheromas on their panoramic radiographs had significantly greater amounts of dental infection/inflammation than atherogenic risk-matched controls devoid of radiographic atheromas. While the Mattila index had been previously used to relate the extent of dental infection to coronary artery disease, this research is the first to link the full range of dental disease that it measures to panoramic radiographs evidencing calcified carotid artery atherosclerosis.
== See also ==
Oral and maxillofacial radiology
== References == | Wikipedia/Panoramic_radiograph |
In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins, or a member of this family. PKC enzymes in turn are activated by signals such as increases in the concentration of diacylglycerol (DAG) or calcium ions (Ca2+). Hence PKC enzymes play important roles in several signal transduction cascades.
In biochemistry, the PKC family consists of fifteen isozymes in humans. They are divided into three subfamilies, based on their second messenger requirements: conventional (or classical), novel, and atypical. Conventional (c)PKCs contain the isoforms α, βI, βII, and γ. These require Ca2+, DAG, and a phospholipid such as phosphatidylserine for activation. Novel (n)PKCs include the δ, ε, η, and θ isoforms, and require DAG, but do not require Ca2+ for activation. Thus, conventional and novel PKCs are activated through the same signal transduction pathway as phospholipase C. On the other hand, atypical (a)PKCs (including protein kinase Mζ and ι / λ isoforms) require neither Ca2+ nor diacylglycerol for activation. The term "protein kinase C" usually refers to the entire family of isoforms. The different classes of PKCs found in jawed vertebrates originate from 5 ancestral PKC family members (PKN, aPKC, cPKC, nPKCE, nPKCD) that expanded due to genome duplication. The broader PKC family is ancient and can be found back in fungi, which means that the PKC family was present in the last common ancestor of opisthokonts.
== Human isozymes ==
conventional - require DAG, Ca2+, and phospholipid for activation
PKC-α (PRKCA)
PKC-β1 (PRKCB)
PKC-β2 (PRKCB)
PKC-γ (PRKCG)
novel - require DAG but not Ca2+ for activation
PKC-δ (PRKCD)
PKC-ε (PRKCE)
PKC-η (PRKCH)
PKC-θ (PRKCQ)
atypical - require neither Ca2+ nor DAG for activation (require phosphatidyl serine)
PKC-ι (PRKCI)
PKC-ζ (PRKCZ)
related PKD
PKD1 (PRKD1)
PKD2 (PRKD2)
PKD3 (PRKD3)
related PKN
PK-N1 (PKN1)
PK-N2 (PKN2)
PK-N3 (PKN3)
== Structure ==
The structure of all PKCs consists of a regulatory domain and a catalytic domain (active site) tethered together by a hinge region. The catalytic region is highly conserved among the different isoforms, as well as, to a lesser degree, among the catalytic region of other serine/threonine kinases. The second messenger requirement differences in the isoforms are a result of the regulatory region, which are similar within the classes, but differ among them. Most of the crystal structure of the catalytic region of PKC has not been determined, except for PKC theta and iota. Due to its similarity to other kinases whose crystal structure have been determined, the structure can be strongly predicted.
=== Regulatory ===
The regulatory domain or the amino-terminus of the PKCs contains several shared subregions. The C1 domain, present in all of the isoforms of PKC has a binding site for DAG as well as non-hydrolysable, non-physiological analogues called phorbol esters. This domain is functional and capable of binding DAG in both conventional and novel isoforms, however, the C1 domain in atypical PKCs is incapable of binding to DAG or phorbol esters. The C2 domain acts as a Ca2+ sensor and is present in both conventional and novel isoforms, but functional as a Ca2+ sensor only in the conventional. The pseudosubstrate region, which is present in all three classes of PKC, is a small sequence of amino acids that mimic a substrate and bind the substrate-binding cavity in the catalytic domain, lack critical serine, threonine phosphoacceptor residues, keeping the enzyme inactive. When Ca2+ and DAG are present in sufficient concentrations, they bind to the C2 and C1 domain, respectively, and recruit PKC to the membrane. This interaction with the membrane results in release of the pseudosubstrate from the catalytic site and activation of the enzyme. In order for these allosteric interactions to occur, however, PKC must first be properly folded and in the correct conformation permissive for catalytic action. This is contingent upon phosphorylation of the catalytic region, discussed below.
=== Catalytic ===
The catalytic region or kinase core of the PKC allows for different functions to be processed; PKB (also known as Akt) and PKC kinases contains approximately 40% amino acid sequence similarity. This similarity increases to ~ 70% across PKCs and even higher when comparing within classes. For example, the two atypical PKC isoforms, ζ and ι/λ, are 84% identical (Selbie et al., 1993). Of the over-30 protein kinase structures whose crystal structure has been revealed, all have the same basic organization. They are a bilobal structure with a β sheet comprising the N-terminal lobe and an α helix constituting the C-terminal lobe. Both the ATP-binding protein (ATP)- and the substrate-binding sites are located in the cleft formed by these two terminal lobes. This is also where the pseudosubstrate domain of the regulatory region binds.
Another feature of the PKC catalytic region that is essential to the viability of the kinase is its phosphorylation. The conventional and novel PKCs have three phosphorylation sites, termed: the activation loop, the turn motif, and the hydrophobic motif. The atypical PKCs are phosphorylated only on the activation loop and the turn motif. Phosphorylation of the hydrophobic motif is rendered unnecessary by the presence of a glutamic acid in place of a serine, which, as a negative charge, acts similar in manner to a phosphorylated residue. These phosphorylation events are essential for the activity of the enzyme, and 3-phosphoinositide-dependent protein kinase-1 (PDPK1) is the upstream kinase responsible for initiating the process by transphosphorylation of the activation loop.
The consensus sequence of protein kinase C enzymes is similar to that of protein kinase A, since it contains basic amino acids close to the Ser/Thr to be phosphorylated. Their substrates are, e.g., MARCKS proteins, MAP kinase, transcription factor inhibitor IκB, the vitamin D3 receptor VDR, Raf kinase, calpain, and the epidermal growth factor receptor.
== Activation ==
Upon activation, protein kinase C enzymes are translocated to the plasma membrane by RACK proteins (membrane-bound receptor for activated protein kinase C proteins). This localization also gives the enzyme access to substrate, an activation mechanism termed substrate presentation. The protein kinase C enzymes are known for their long-term activation: They remain activated after the original activation signal or the Ca2+-wave is gone. It is presumed that this is achieved by the production of diacylglycerol from phosphatidylinositol by a phospholipase; fatty acids may also play a role in long-term activation. A critical part of PKC activation is translocation to the cell membrane. Interestingly, this process is disrupted in microgravity, which causes immunodeficiency of astronauts.
== Function ==
A multiplicity of functions have been ascribed to PKC. Recurring themes are that PKC is involved in receptor desensitization, in modulating membrane structure events, in regulating transcription, in mediating immune responses, in regulating cell growth, and in learning and memory. PKC isoforms have been designated "memory kinases," and deficits in PKC signaling in neurons is an early abnormality in the brains of patients with Alzheimer's disease. These functions are achieved by PKC-mediated phosphorylation of other proteins. PKC plays an important role in the immune system through phosphorylation of CARD-CC family proteins and subsequent NF-κB activation. However, the substrate proteins present for phosphorylation vary, since protein expression is different between different kinds of cells. Thus, effects of PKC are cell-type-specific:
== Pathology ==
Protein kinase C, activated by tumor promoter phorbol ester, may phosphorylate potent activators of transcription, and thus lead to increased expression of oncogenes, promoting cancer progression, or interfere with other phenomena. Prolonged exposure to phorbol ester, however, promotes the down-regulation of Protein kinase C. Loss-of-function mutations and low PKC protein levels are prevalent in cancer, supporting a general tumor-suppressive role for Protein kinase C.
Protein kinase C enzymes are important mediators of vascular permeability and have been implicated in various vascular diseases including disorders associated with hyperglycemia in diabetes mellitus, as well as endothelial injury and tissue damage related to cigarette smoke. Low-level PKC activation is sufficient to reverse cell chirality through phosphatidylinositol 3-kinase/AKT signaling and alters junctional protein organization between cells with opposite chirality, leading to an unexpected substantial change in endothelial permeability, which often leads to inflammation and disease.
== Inhibitors ==
Protein kinase C inhibitors, such as ruboxistaurin, may potentially be beneficial in peripheral diabetic nephropathy.
Chelerythrine is a natural selective PKC inhibitor. Other naturally occurring PKCIs are miyabenol C, myricitrin, gossypol.
Bryostatin 1 can act as a PKC inhibitor; It was investigated for cancer.
Darovasertib is an investigational new drug in efficacy trials in treatment of metastatic uveal melanoma.
Other PKCIs include Verbascoside, BIM-1, Ro31-8220, and Tamoxifen.
== Activators ==
The Protein kinase C activator ingenol mebutate, derived from the plant Euphorbia peplus, is FDA-approved for the treatment of actinic keratosis.
Bryostatin 1 can act as a PKCe activator and as of 2016 is being investigated for Alzheimer's disease.
12-O-Tetradecanoylphorbol-13-acetate (PMA or TPA) is a diacylglycerol mimic that can activate the classical PKCs. It is often used together with ionomycin which provides the calcium-dependent signals needed for activation of some PKCs.
== See also ==
Serine/threonine-specific protein kinase
Signal transduction
Yasutomi Nishizuka, discovered protein kinase C
Ccdc60
== References ==
== External links ==
protein+kinase+c at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Eukaryotic Linear Motif resource motif class MOD_LATS_1 | Wikipedia/Protein_kinase_C |
Druglikeness is a qualitative concept used in drug design for how "druglike" a substance is with respect to factors like bioavailability. It is estimated from the molecular structure before the substance is even synthesized and tested. A druglike molecule has properties such as:
Solubility in both water and fat, as an orally administered drug needs to pass through the intestinal lining after it is consumed, be carried in aqueous blood and penetrate the lipid-based cell membrane to reach the inside of a cell. A model compound for the lipophilic cellular membrane is 1-octanol (a lipophilic medium-chain fatty alcohol), so the logarithm of the octanol-water partition coefficient, known as LogP, is used to predict the solubility of a potential oral drug. This coefficient can be experimentally measured or predicted computationally, in which case it is sometimes called "cLogP". As the lipophilicity of ionizable compounds is strongly dependent of pH, the distribution coefficient logD, or a logP vs pH curve may be used instead.
Potency at the biological target. High potency (high value of pIC50) is a desirable attribute in drug candidates, as it reduces the risk of non-specific, off-target pharmacology at a given concentration. When associated with low clearance, high potency also allows for low total dose, which lowers the risk of idiosyncratic drug reactions.
Ligand efficiency and lipophilic efficiency.
Molecular weight: The smaller the better, because diffusion is directly affected. The great majority of drugs on the market have molecular weights between 200 and 600 daltons, and particularly <500; they belong to the group of small molecules.
A traditional method to evaluate druglikeness is to check compliance of Lipinski's rule of five, which covers the numbers of hydrophilic groups, molecular weight and hydrophobicity.
Since the drug is transported in aqueous media like blood and intracellular fluid, it has to be sufficiently water-soluble in the absolute sense (i.e. must have a minimum chemical solubility in order to be effective). Solubility in water can be estimated from the number of hydrogen bond donors vs. alkyl sidechains in the molecule. Low water solubility translates to slow absorption and action. Too many hydrogen bond donors, on the other hand, lead to low fat solubility, so that the drug cannot penetrate the cell membrane to reach the inside of the cell.
Based on one definition, a drug-like molecule has a logarithm of partition coefficient (log P) between −0.4 and 5.6, molecular weight 160–480 g/mol, molar refractivity of 40–130, which is related to the volume and molecular weight of the molecule and has 20–70 atoms.
Substructures with known toxic, mutagenic or teratogenic properties affect the usefulness of a designed molecule. However, several poisons have a good druglikeness. Natural toxins are used in pharmacological research to find out their mechanism of action, and if it could be exploited for beneficial purposes. Alkylnitro compounds tend to be irritants, and Michael acceptors, such as enones, are alkylating agents and thus potentially mutagenic and carcinogenic.
Druglikeness indices are inherently limited tools. Druglikeness can be estimated for any molecule, and does not evaluate the actual specific effect that the drug achieves (biological activity). Simple rules are not always accurate and may unnecessarily limit the chemical space to search: many best-selling drugs have features that cause them to score low on various druglikeness indices. Furthermore, first-pass metabolism, which is biochemically selective, can destroy the pharmacological activity of a compound despite good druglikeness.
Druglikeness is not relevant for most biologics, since they are usually proteins that need to be injected, because proteins are digested if eaten.
== See also ==
Lipinski's rule of five (RO5)
Fragment-based lead discovery (FBLD)
== References ==
== External links ==
OSIRIS Property Explorer: Prediction of druglikeness
molinspiration Archived 2020-12-18 at the Wayback Machine free drug-likeness and bioactivity calculator | Wikipedia/Druglikeness |
Inorganic chemistry deals with synthesis and behavior of inorganic and organometallic compounds. This field covers chemical compounds that are not carbon-based, which are the subjects of organic chemistry. The distinction between the two disciplines is far from absolute, as there is much overlap in the subdiscipline of organometallic chemistry. It has applications in every aspect of the chemical industry, including catalysis, materials science, pigments, surfactants, coatings, medications, fuels, and agriculture.
== Occurrence ==
Many inorganic compounds are found in nature as minerals. Soil may contain iron sulfide as pyrite or calcium sulfate as gypsum. Inorganic compounds are also found multitasking as biomolecules: as electrolytes (sodium chloride), in energy storage (ATP) or in construction (the polyphosphate backbone in DNA).
== Bonding ==
Inorganic compounds exhibit a range of bonding properties. Some are ionic compounds, consisting of very simple cations and anions joined by ionic bonding. Examples of salts (which are ionic compounds) are magnesium chloride MgCl2, which consists of magnesium cations Mg2+ and chloride anions Cl−; or sodium hydroxide NaOH, which consists of sodium cations Na+ and hydroxide anions OH−. Some inorganic compounds are highly covalent, such as sulfur dioxide and iron pentacarbonyl. Many inorganic compounds feature polar covalent bonding, which is a form of bonding intermediate between covalent and ionic bonding. This description applies to many oxides, carbonates, and halides. Many inorganic compounds are characterized by high melting points. Some salts (e.g., NaCl) are very soluble in water.
When one reactant contains hydrogen atoms, a reaction can take place by exchanging protons in acid-base chemistry. In a more general definition, any chemical species capable of binding to electron pairs is called a Lewis acid; conversely any molecule that tends to donate an electron pair is referred to as a Lewis base. As a refinement of acid-base interactions, the HSAB theory takes into account polarizability and size of ions.
== Subdivisions of inorganic chemistry ==
Subdivisions of inorganic chemistry are numerous, but include:
organometallic chemistry, compounds with metal-carbon bonds. This area touches on organic synthesis, which employs many organometallic catalysts and reagents.
cluster chemistry, compounds with several metals bound together with metal–metal bonds or bridging ligands.
bioinorganic chemistry, biomolecules that contain metals. This area touches on medicinal chemistry.
materials chemistry and solid state chemistry, extended (i.e. polymeric) solids exhibiting properties not seen for simple molecules. Many practical themes are associated with these areas, including ceramics.
=== Industrial inorganic chemistry ===
Inorganic chemistry is a highly practical area of science. Traditionally, the scale of a nation's economy could be evaluated by their productivity of sulfuric acid.
An important man-made inorganic compound is ammonium nitrate, used for fertilization. The ammonia is produced through the Haber process. Nitric acid is prepared from the ammonia by oxidation. Another large-scale inorganic material is portland cement. Inorganic compounds are used as catalysts such as vanadium(V) oxide for the oxidation of sulfur dioxide and titanium(III) chloride for the polymerization of alkenes. Many inorganic compounds are used as reagents in organic chemistry such as lithium aluminium hydride.
== Descriptive inorganic chemistry ==
Descriptive inorganic chemistry focuses on the classification of compounds based on their properties. Partly the classification focuses on the position in the periodic table of the heaviest element (the element with the highest atomic weight) in the compound, partly by grouping compounds by their structural similarities
=== Coordination compounds ===
Classical coordination compounds feature metals bound to "lone pairs" of electrons residing on the main group atoms of ligands such as H2O, NH3, Cl−, and CN−. In modern coordination compounds almost all organic and inorganic compounds can be used as ligands. The "metal" usually is a metal from the groups 3–13, as well as the trans-lanthanides and trans-actinides, but from a certain perspective, all chemical compounds can be described as coordination complexes.
The stereochemistry of coordination complexes can be quite rich, as hinted at by Werner's separation of two enantiomers of [Co((OH)2Co(NH3)4)3]6+, an early demonstration that chirality is not inherent to organic compounds. A topical theme within this specialization is supramolecular coordination chemistry.
Examples: [Co(EDTA)]−, [Co(NH3)6]3+, TiCl4(THF)2.
Coordination compounds show a rich diversity of structures, varying from tetrahedral for titanium (e.g., TiCl4) to square planar for some nickel complexes to octahedral for coordination complexes of cobalt. A range of transition metals can be found in biologically important compounds, such as iron in hemoglobin.
Examples: iron pentacarbonyl, titanium tetrachloride, cisplatin
=== Main group compounds ===
These species feature elements from groups I, II, III, IV, V, VI, VII, 0 (excluding hydrogen) of the periodic table. Due to their often similar reactivity, the elements in group 3 (Sc, Y, and La) and group 12 (Zn, Cd, and Hg) are also generally included, and the lanthanides and actinides are sometimes included as well.
Main group compounds have been known since the beginnings of chemistry, e.g., elemental sulfur and the distillable white phosphorus. Experiments on oxygen, O2, by Lavoisier and Priestley not only identified an important diatomic gas, but opened the way for describing compounds and reactions according to stoichiometric ratios. The discovery of a practical synthesis of ammonia using iron catalysts by Carl Bosch and Fritz Haber in the early 1900s deeply impacted mankind, demonstrating the significance of inorganic chemical synthesis.
Typical main group compounds are SiO2, SnCl4, and N2O. Many main group compounds can also be classed as "organometallic", as they contain organic groups, e.g., B(CH3)3). Main group compounds also occur in nature, e.g., phosphate in DNA, and therefore may be classed as bioinorganic. Conversely, organic compounds lacking (many) hydrogen ligands can be classed as "inorganic", such as the fullerenes, buckytubes and binary carbon oxides.
Examples: tetrasulfur tetranitride S4N4, diborane B2H6, silicones, buckminsterfullerene C60.
Noble gas compounds include several derivatives of xenon and krypton.
Examples: xenon hexafluoride XeF6, xenon trioxide XeO3, and krypton difluoride KrF2
=== Organometallic compounds ===
Usually, organometallic compounds are considered to contain the M-C-H group. The metal (M) in these species can either be a main group element or a transition metal. Operationally, the definition of an organometallic compound is more relaxed to include also highly lipophilic complexes such as metal carbonyls and even metal alkoxides.
Organometallic compounds are mainly considered a special category because organic ligands are often sensitive to hydrolysis or oxidation, necessitating that organometallic chemistry employs more specialized preparative methods than was traditional in Werner-type complexes. Synthetic methodology, especially the ability to manipulate complexes in solvents of low coordinating power, enabled the exploration of very weakly coordinating ligands such as hydrocarbons, H2, and N2. Because the ligands are petrochemicals in some sense, the area of organometallic chemistry has greatly benefited from its relevance to industry.
Examples: Cyclopentadienyliron dicarbonyl dimer (C5H5)Fe(CO)2CH3, ferrocene Fe(C5H5)2, molybdenum hexacarbonyl Mo(CO)6, triethylborane Et3B, Tris(dibenzylideneacetone)dipalladium(0) Pd2(dba)3)
=== Cluster compounds ===
Clusters can be found in all classes of chemical compounds. According to the commonly accepted definition, a cluster consists minimally of a triangular set of atoms that are directly bonded to each other. But metal–metal bonded dimetallic complexes are highly relevant to the area. Clusters occur in "pure" inorganic systems, organometallic chemistry, main group chemistry, and bioinorganic chemistry. The distinction between very large clusters and bulk solids is increasingly blurred. This interface is the chemical basis of nanoscience or nanotechnology and specifically arise from the study of quantum size effects in cadmium selenide clusters. Thus, large clusters can be described as an array of bound atoms intermediate in character between a molecule and a solid.
Examples: Fe3(CO)12, B10H14, [Mo6Cl14]2−, 4Fe-4S
=== Bioinorganic compounds ===
By definition, these compounds occur in nature, but the subfield includes anthropogenic species, such as pollutants (e.g., methylmercury) and drugs (e.g., Cisplatin). The field, which incorporates many aspects of biochemistry, includes many kinds of compounds, e.g., the phosphates in DNA, and also metal complexes containing ligands that range from biological macromolecules, commonly peptides, to ill-defined species such as humic acid, and to water (e.g., coordinated to gadolinium complexes employed for MRI). Traditionally bioinorganic chemistry focuses on electron- and energy-transfer in proteins relevant to respiration. Medicinal inorganic chemistry includes the study of both non-essential and essential elements with applications to diagnosis and therapies.
Examples: hemoglobin, methylmercury, carboxypeptidase
=== Solid state compounds ===
This important area focuses on structure, bonding, and the physical properties of materials. In practice, solid state inorganic chemistry uses techniques such as crystallography to gain an understanding of the properties that result from collective interactions between the subunits of the solid. Included in solid state chemistry are metals and their alloys or intermetallic derivatives. Related fields are condensed matter physics, mineralogy, and materials science.
Examples: silicon chips, zeolites, YBa2Cu3O7
== Spectroscopy and magnetism ==
In contrast to most organic compounds, many inorganic compounds are magnetic and/or colored. These properties provide information on the bonding and structure. The magnetism of inorganic compounds can be comlex. For example, most copper(II) compounds are paramagnetic but CuII2(OAc)4(H2O)2 is almost diamagnetic below room temperature. The explanation is due to magnetic coupling between pairs of Cu(II) sites in the acetate.
=== Qualitative theories ===
Inorganic chemistry has greatly benefited from qualitative theories. Such theories are easier to learn as they require little background in quantum theory. Within main group compounds, VSEPR theory powerfully predicts, or at least rationalizes, the structures of main group compounds, such as an explanation for why NH3 is pyramidal whereas ClF3 is T-shaped. For the transition metals, crystal field theory allows one to understand the magnetism of many simple complexes, such as why [FeIII(CN)6]3− has only one unpaired electron, whereas [FeIII(H2O)6]3+ has five. A particularly powerful qualitative approach to assessing the structure and reactivity begins with classifying molecules according to electron counting, focusing on the numbers of valence electrons, usually at the central atom in a molecule.
=== Molecular symmetry group theory ===
A construct in chemistry is molecular symmetry, as embodied in Group theory. Inorganic compounds display a particularly diverse symmetries, so it is logical that Group Theory is intimately associated with inorganic chemistry. Group theory provides the language to describe the shapes of molecules according to their point group symmetry. Group theory also enables factoring and simplification of theoretical calculations.
Spectroscopic features are analyzed and described with respect to the symmetry properties of the, inter alia, vibrational or electronic states. Knowledge of the symmetry properties of the ground and excited states allows one to predict the numbers and intensities of absorptions in vibrational and electronic spectra. A classic application of group theory is the prediction of the number of C–O vibrations in substituted metal carbonyl complexes. The most common applications of symmetry to spectroscopy involve vibrational and electronic spectra.
Group theory highlights commonalities and differences in the bonding of otherwise disparate species. For example, the metal-based orbitals transform identically for WF6 and W(CO)6, but the energies and populations of these orbitals differ significantly. A similar relationship exists CO2 and molecular beryllium difluoride.
== Thermodynamics and inorganic chemistry ==
An alternative quantitative approach to inorganic chemistry focuses on energies of reactions. This approach is highly traditional and empirical, but it is also useful. Broad concepts that are couched in thermodynamic terms include redox potential, acidity, phase changes. A classic concept in inorganic thermodynamics is the Born–Haber cycle, which is used for assessing the energies of elementary processes such as electron affinity, some of which cannot be observed directly.
== Mechanistic inorganic chemistry ==
An important aspect of inorganic chemistry focuses on reaction pathways, i.e. reaction mechanisms.
=== Main group elements and lanthanides ===
The mechanisms of main group compounds of groups 13–18 are usually discussed in the context of organic chemistry (organic compounds are main group compounds, after all). Elements heavier than C, N, O, and F often form compounds with more electrons than predicted by the octet rule, as explained in the article on hypervalent molecules. The mechanisms of their reactions differ from organic compounds for this reason. Elements lighter than carbon (B, Be, Li) as well as Al and Mg often form electron-deficient structures that are electronically akin to carbocations. Such electron-deficient species tend to react via associative pathways. The chemistry of the lanthanides mirrors many aspects of chemistry seen for aluminium.
=== Transition metal complexes ===
Transition metal and main group compounds often react differently. The important role of d-orbitals in bonding strongly influences the pathways and rates of ligand substitution and dissociation. These themes are covered in articles on coordination chemistry and ligand. Both associative and dissociative pathways are observed.
An overarching aspect of mechanistic transition metal chemistry is the kinetic lability of the complex illustrated by the exchange of free and bound water in the prototypical complexes [M(H2O)6]n+:
[M(H2O)6]n+ + 6 H2O* → [M(H2O*)6]n+ + 6 H2O
where H2O* denotes isotopically enriched water, e.g., H217O
The rates of water exchange varies by 20 orders of magnitude across the periodic table, with lanthanide complexes at one extreme and Ir(III) species being the slowest.
==== Redox reactions ====
Redox reactions are prevalent for the transition elements. Two classes of redox reaction are considered: atom-transfer reactions, such as oxidative addition/reductive elimination, and electron-transfer. A fundamental redox reaction is "self-exchange", which involves the degenerate reaction between an oxidant and a reductant. For example, permanganate and its one-electron reduced relative manganate exchange one electron:
[MnO4]− + [Mn*O4]2− → [MnO4]2− + [Mn*O4]−
==== Reactions at ligands ====
Coordinated ligands display reactivity distinct from the free ligands. For example, the acidity of the ammonia ligands in [Co(NH3)6]3+ is elevated relative to NH3 itself. Alkenes bound to metal cations are reactive toward nucleophiles whereas alkenes normally are not. The large and industrially important area of catalysis hinges on the ability of metals to modify the reactivity of organic ligands. Homogeneous catalysis occurs in solution and heterogeneous catalysis occurs when gaseous or dissolved substrates interact with surfaces of solids. Traditionally homogeneous catalysis is considered part of organometallic chemistry and heterogeneous catalysis is discussed in the context of surface science, a subfield of solid state chemistry. But the basic inorganic chemical principles are the same. Transition metals, almost uniquely, react with small molecules such as CO, H2, O2, and C2H4. The industrial significance of these feedstocks drives the active area of catalysis. Ligands can also undergo ligand transfer reactions such as transmetalation.
== Characterization of inorganic compounds ==
Because of the diverse range of elements and the correspondingly diverse properties of the resulting derivatives, inorganic chemistry is closely associated with many methods of analysis. Older methods tended to examine bulk properties such as the electrical conductivity of solutions, melting points, solubility, and acidity. With the advent of quantum theory and the corresponding expansion of electronic apparatus, new tools have been introduced to probe the electronic properties of inorganic molecules and solids. Often these measurements provide insights relevant to theoretical models. Commonly encountered techniques are:
X-ray crystallography: This technique allows for the 3D determination of molecular structures.
Various forms of spectroscopy:
Ultraviolet-visible spectroscopy: Historically, this has been an important tool, since many inorganic compounds are strongly colored
NMR spectroscopy: Besides 1H and 13C many other NMR-active nuclei (e.g., 11B, 19F, 31P, and 195Pt) can give important information on compound properties and structure. The NMR of paramagnetic species can provide important structural information. Proton (1H) NMR is also important because the light hydrogen nucleus is not easily detected by X-ray crystallography.
Infrared spectroscopy: Mostly for absorptions from carbonyl ligands
Electron nuclear double resonance (ENDOR) spectroscopy
Mössbauer spectroscopy
Electron-spin resonance: ESR (or EPR) allows for the measurement of the environment of paramagnetic metal centres.
Electrochemistry: Cyclic voltammetry and related techniques probe the redox characteristics of compounds.
== Synthetic inorganic chemistry ==
Although some inorganic species can be obtained in pure form from nature, most are synthesized in chemical plants and in the laboratory.
Inorganic synthetic methods can be classified roughly according to the volatility or solubility of the component reactants. Soluble inorganic compounds are prepared using methods of organic synthesis. For metal-containing compounds that are reactive toward air, Schlenk line and glove box techniques are followed. Volatile compounds and gases are manipulated in "vacuum manifolds" consisting of glass piping interconnected through valves, the entirety of which can be evacuated to 0.001 mm Hg or less. Compounds are condensed using liquid nitrogen (b.p. 78K) or other cryogens. Solids are typically prepared using tube furnaces, the reactants and products being sealed in containers, often made of fused silica (amorphous SiO2) but sometimes more specialized materials such as welded Ta tubes or Pt "boats". Products and reactants are transported between temperature zones to drive reactions.
== See also ==
Important publications in inorganic chemistry
== References == | Wikipedia/inorganic_chemistry |
Iron–sulfur proteins are proteins characterized by the presence of iron–sulfur clusters containing sulfide-linked di-, tri-, and tetrairon centers in variable oxidation states. Iron–sulfur clusters are found in a variety of metalloproteins, such as the ferredoxins, as well as NADH dehydrogenase, hydrogenases, coenzyme Q – cytochrome c reductase, succinate – coenzyme Q reductase and nitrogenase. Iron–sulfur clusters are best known for their role in the oxidation-reduction reactions of electron transport in mitochondria and chloroplasts. Both Complex I and Complex II of oxidative phosphorylation have multiple Fe–S clusters. They have many other functions including catalysis as illustrated by aconitase, generation of radicals as illustrated by SAM-dependent enzymes, and as sulfur donors in the biosynthesis of lipoic acid and biotin. Additionally, some Fe–S proteins regulate gene expression. Fe–S proteins are vulnerable to attack by biogenic nitric oxide, forming dinitrosyl iron complexes. In most Fe–S proteins, the terminal ligands on Fe are thiolate, but exceptions exist.
The prevalence of these proteins on the metabolic pathways of most organisms leads to theories that iron–sulfur compounds had a significant role in the origin of life in the iron–sulfur world theory.
In some instances Fe–S clusters are redox-inactive, but are proposed to have structural roles. Examples include endonuclease III and MutY.
== Structural motifs ==
In almost all Fe–S proteins, the Fe centers are tetrahedral and the terminal ligands are thiolato sulfur centers from cysteinyl residues. The sulfide groups are either two- or three-coordinated. Three distinct kinds of Fe–S clusters with these features are most common.
=== Structure-function principles ===
Iron–sulfur proteins are involved in various biological electron transport processes, such as photosynthesis and cellular respiration, which require rapid electron transfer to sustain the energy or biochemical needs of the organism. To serve their various biological roles, iron-sulfur proteins effect rapid electron transfers and span the whole range of physiological redox potentials from -600 mV to +460 mV.
Fe3+-SR bonds have unusually high covalency which is expected. When comparing the covalency of Fe3+ with the covalency of Fe2+, Fe3+ has almost double the covalency of Fe2+ (20% to 38.4%). Fe3+ is also much more stabilized than Fe2+. Hard ions like Fe3+ normally have low covalency because of the energy mismatch of the metal lowest unoccupied molecular orbital with the ligand highest occupied molecular orbital.
External water molecules positioned close to the iron-sulfur active site reduces covalency; this can be shown by lyophilization experiments where water is removed from the protein. This reduction is because external water hydrogen bonds with cysteine S, decreasing the latter's lone pair electron donation to the Fe3+/2+ by pulling away S electrons. Since covalency stabilizes Fe3+ more than Fe2+, Fe3+ is more destabilized by the HOH-S hydrogen-bonding.
The Fe3+ 3d orbital energies follow the "inverted" bonding scheme which fortuitously has the Fe3+ d-orbitals closely matched in energy with the sulfur 3p orbitals, giving high covalency in the resulting bonding molecular orbital. This high covalency lowers the inner sphere reorganization energy and ultimately contributes to a rapid electron transfer.
=== 2Fe–2S clusters ===
The simplest polymetallic system, the [Fe2S2] cluster, is constituted by two iron ions bridged by two sulfide ions and coordinated by four cysteinyl ligands (in Fe2S2 ferredoxins) or by two cysteines and two histidines (in Rieske proteins). The oxidized proteins contain two Fe3+ ions, whereas the reduced proteins contain one Fe3+ and one Fe2+ ion. These species exist in two oxidation states, (FeIII)2 and FeIIIFeII. CDGSH iron sulfur domain is also associated with 2Fe-2S clusters.
The Rieske proteins contain Fe–S clusters that coordinate as a 2Fe–2S structure and can be found in the membrane bound cytochrome bc1 complex III in the mitochondria of eukaryotes and bacteria. They are also a part of the proteins of the chloroplast such as the cytochrome b6f complex in photosynthetic organisms. These photosynthetic organisms include plants, green algae, and cyanobacteria, the bacterial precursor to chloroplasts. Both are part of the electron transport chain of their respective organisms which is a crucial step in the energy harvesting for many organisms.
=== 4Fe–4S clusters ===
A common motif features a four iron ions and four sulfide ions placed at the vertices of a cubane-type cluster. The Fe centers are typically further coordinated by cysteinyl ligands. The [Fe4S4] electron-transfer proteins ([Fe4S4] ferredoxins) may be further subdivided into low-potential (bacterial-type) and high-potential (HiPIP) ferredoxins. Low- and high-potential ferredoxins are related by the following redox scheme:
In HiPIP, the cluster shuttles between [2Fe3+, 2Fe2+] (Fe4S42+) and [3Fe3+, Fe2+] (Fe4S43+). The potentials for this redox couple range from 0.4 to 0.1 V. In the bacterial ferredoxins, the pair of oxidation states are [Fe3+, 3Fe2+] (Fe4S4+) and [2Fe3+, 2Fe2+] (Fe4S42+). The potentials for this redox couple range from −0.3 to −0.7 V. The two families of 4Fe–4S clusters share the Fe4S42+ oxidation state. The difference in the redox couples is attributed to the degree of hydrogen bonding, which strongly modifies the basicity of the cysteinyl thiolate ligands. A further redox couple, which is still more reducing than the bacterial ferredoxins is implicated in the nitrogenase.
Some 4Fe–4S clusters bind substrates and are thus classified as enzyme cofactors. In aconitase, the Fe–S cluster binds aconitate at the one Fe centre that lacks a thiolate ligand. The cluster does not undergo redox, but serves as a Lewis acid catalyst to convert citrate to isocitrate. In radical SAM enzymes, the cluster binds and reduces S-adenosylmethionine to generate a radical, which is involved in many biosyntheses.
The second cubane shown here with mixed valence pairs (2 Fe3+ and 2 Fe2+), has a greater stability from covalent communication and strong covalent delocalization of the “extra” electron from the reduced Fe2+ that results in full ferromagnetic coupling.
=== 3Fe–4S clusters ===
Proteins are also known to contain [Fe3S4] centres, which feature one iron less than the more common [Fe4S4] cores. Three sulfide ions bridge two iron ions each, while the fourth sulfide bridges three iron ions. Their formal oxidation states may vary from [Fe3S4]+ (all-Fe3+ form) to [Fe3S4]2− (all-Fe2+ form). In a number of iron–sulfur proteins, the [Fe4S4] cluster can be reversibly converted by oxidation and loss of one iron ion to a [Fe3S4] cluster. E.g., the inactive form of aconitase possesses an [Fe3S4] and is activated by addition of Fe2+ and reductant.
=== Other Fe–S clusters ===
Examples include the active sites of a number of enzymes:
Nitrogenase include two P-clusters ([8Fe-7S]) and two FeMocos ([7Fe-9S-C-Mo-R homocitrate]).
Carbon monoxide dehydrogenase and acetyl coenzyme-A synthase each features an Fe-N-iS4 clusters.
[FeFe]-hydrogenase features an "H-cluster", consisting of a Fe4S4 bridge to Fe2 via a cystine. The Fe2 half features unique ligands: 3 CO, 2 CN−, and an azadithiolate HN(CH2S−)2.
A special 6 cysteine-coordinated [Fe4S3] cluster was found in oxygen-tolerant membrane-bound [NiFe] hydrogenases.
The "double cubane cluster" [Fe8S9], found in some nitrogenase-related ATPases, consists of two [Fe4S4] bridged by a cysteine. The functions of such proteins remain unclear.
== Biosynthesis ==
The biosynthesis of the Fe–S clusters has been well studied.
The biogenesis of iron sulfur clusters has been studied most extensively in the bacteria E. coli and A. vinelandii and yeast S. cerevisiae. At least three different biosynthetic systems have been identified so far, namely nif, suf, and isc systems, which were first identified in bacteria. The nif system is responsible for the clusters in the enzyme nitrogenase. The suf and isc systems are more general.
The yeast isc system is the best described. Several proteins constitute the biosynthetic machinery via the isc pathway. The process occurs in two major steps:
(1) the Fe/S cluster is assembled on a scaffold protein followed by (2) transfer of the preformed cluster to the recipient proteins.
The first step of this process occurs in the cytoplasm of prokaryotic organisms or in the mitochondria of eukaryotic organisms. In the higher organisms the clusters are therefore transported out of the mitochondrion to be incorporated into the extramitochondrial enzymes. These organisms also possess a set of proteins involved in the Fe/S clusters transport and incorporation processes that are not homologous to proteins found in prokaryotic systems.
== Synthetic analogues ==
Synthetic analogues of the naturally occurring Fe–S clusters were first reported by Holm and coworkers. Treatment of iron salts with a mixture of thiolates and sulfide affords derivatives such as (Et4N)2Fe4S4(SCH2Ph)4].
== See also ==
Bioinorganic chemistry
Iron-binding proteins
Mitosome
== References ==
Sticht, Heinrich; Rösch, Paul (1998-09-01). "The structure of iron–sulfur proteins". Progress in Biophysics and Molecular Biology. 70 (2): 95–136. doi:10.1016/S0079-6107(98)00027-3. ISSN 0079-6107. PMID 9785959.
== Further reading ==
Liu, J; Chakraborty, S; Hosseinzadeh, P; Yu, Y; Tian, S; Petrik, I; Bhagi, A; Lu, Y (23 April 2014). "Metalloproteins containing cytochrome, iron-sulfur, or copper redox centers". Chemical Reviews. 114 (8): 4366–469. doi:10.1021/cr400479b. PMC 4002152. PMID 24758379.
Beinert, H. (2000). "Iron-sulfur proteins: ancient structures, still full of surprises". J. Biol. Inorg. Chem. 5 (1): 2–15. doi:10.1007/s007750050002. PMID 10766431. S2CID 20714007.
Beinert, H.; Kiley, P.J. (1999). "Fe-S proteins in sensing and regulatory functions". Curr. Opin. Chem. Biol. 3 (2): 152–157. doi:10.1016/S1367-5931(99)80027-1. PMID 10226040.
Johnson, M.K. (1998). "Iron-sulfur proteins: new roles for old clusters". Curr. Opin. Chem. Biol. 2 (2): 173–181. doi:10.1016/S1367-5931(98)80058-6. PMID 9667933.
Nomenclature Committee of the International Union of Biochemistry (NC-IUB) (1979). "Nomenclature of iron-sulfur proteins. Recommendations 1978". Eur. J. Biochem. 93 (3): 427–430. doi:10.1111/j.1432-1033.1979.tb12839.x. PMID 421685.
Noodleman, L., Lovell, T., Liu, T., Himo, F. and Torres, R.A. (2002). "Insights into properties and energetics of iron-sulfur proteins from simple clusters to nitrogenase". Curr. Opin. Chem. Biol. 6 (2): 259–273. doi:10.1016/S1367-5931(02)00309-5. PMID 12039013.{{cite journal}}: CS1 maint: multiple names: authors list (link)
Spiro, T.G., Ed. (1982). Iron-sulfur proteins. New York: Wiley. ISBN 0-471-07738-0.{{cite book}}: CS1 maint: multiple names: authors list (link)
== External links ==
Iron-Sulfur+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Examples of iron-sulfur clusters | Wikipedia/Iron–sulfur_protein |
Materials science is an interdisciplinary field of researching and discovering materials. Materials engineering is an engineering field of finding uses for materials in other fields and industries.
The intellectual origins of materials science stem from the Age of Enlightenment, when researchers began to use analytical thinking from chemistry, physics, and engineering to understand ancient, phenomenological observations in metallurgy and mineralogy. Materials science still incorporates elements of physics, chemistry, and engineering. As such, the field was long considered by academic institutions as a sub-field of these related fields. Beginning in the 1940s, materials science began to be more widely recognized as a specific and distinct field of science and engineering, and major technical universities around the world created dedicated schools for its study.
Materials scientists emphasize understanding how the history of a material (processing) influences its structure, and thus the material's properties and performance. The understanding of processing -structure-properties relationships is called the materials paradigm. This paradigm is used to advance understanding in a variety of research areas, including nanotechnology, biomaterials, and metallurgy.
Materials science is also an important part of forensic engineering and failure analysis – investigating materials, products, structures or components, which fail or do not function as intended, causing personal injury or damage to property. Such investigations are key to understanding, for example, the causes of various aviation accidents and incidents.
== History ==
The material of choice of a given era is often a defining point. Phases such as Stone Age, Bronze Age, Iron Age, and Steel Age are historic, if arbitrary examples. Originally deriving from the manufacture of ceramics and its putative derivative metallurgy, materials science is one of the oldest forms of engineering and applied science. Modern materials science evolved directly from metallurgy, which itself evolved from the use of fire. A major breakthrough in the understanding of materials occurred in the late 19th century, when the American scientist Josiah Willard Gibbs demonstrated that the thermodynamic properties related to atomic structure in various phases are related to the physical properties of a material. Important elements of modern materials science were products of the Space Race; the understanding and engineering of the metallic alloys, and silica and carbon materials, used in building space vehicles enabling the exploration of space. Materials science has driven, and been driven by, the development of revolutionary technologies such as rubbers, plastics, semiconductors, and biomaterials.
Before the 1960s (and in some cases decades after), many eventual materials science departments were metallurgy or ceramics engineering departments, reflecting the 19th and early 20th-century emphasis on metals and ceramics. The growth of material science in the United States was catalyzed in part by the Advanced Research Projects Agency, which funded a series of university-hosted laboratories in the early 1960s, "to expand the national program of basic research and training in the materials sciences." In comparison with mechanical engineering, the nascent material science field focused on addressing materials from the macro-level and on the approach that materials are designed on the basis of knowledge of behavior at the microscopic level. Due to the expanded knowledge of the link between atomic and molecular processes as well as the overall properties of materials, the design of materials came to be based on specific desired properties. The materials science field has since broadened to include every class of materials, including ceramics, polymers, semiconductors, magnetic materials, biomaterials, and nanomaterials, generally classified into three distinct groups: ceramics, metals, and polymers. The prominent change in materials science during the recent decades is active usage of computer simulations to find new materials, predict properties and understand phenomena.
== Fundamentals ==
A material is defined as a substance (most often a solid, but other condensed phases can be included) that is intended to be used for certain applications. There are a myriad of materials around us; they can be found in anything from new and advanced materials that are being developed include nanomaterials, biomaterials, and energy materials to name a few.
The basis of materials science is studying the interplay between the structure of materials, the processing methods to make that material, and the resulting material properties. The complex combination of these produce the performance of a material in a specific application. Many features across many length scales impact material performance, from the constituent chemical elements, its microstructure, and macroscopic features from processing. Together with the laws of thermodynamics and kinetics materials scientists aim to understand and improve materials.
=== Structure ===
Structure is one of the most important components of the field of materials science. The very definition of the field holds that it is concerned with the investigation of "the relationships that exist between the structures and properties of materials". Materials science examines the structure of materials from the atomic scale, all the way up to the macro scale. Characterization is the way materials scientists examine the structure of a material. This involves methods such as diffraction with X-rays, electrons or neutrons, and various forms of spectroscopy and chemical analysis such as Raman spectroscopy, energy-dispersive spectroscopy, chromatography, thermal analysis, electron microscope analysis, etc.
Structure is studied in the following levels.
==== Atomic structure ====
Atomic structure deals with the atoms of the materials, and how they are arranged to give rise to molecules, crystals, etc. Much of the electrical, magnetic and chemical properties of materials arise from this level of structure. The length scales involved are in angstroms (Å). The chemical bonding and atomic arrangement (crystallography) are fundamental to studying the properties and behavior of any material.
===== Bonding =====
To obtain a full understanding of the material structure and how it relates to its properties, the materials scientist must study how the different atoms, ions and molecules are arranged and bonded to each other. This involves the study and use of quantum chemistry or quantum physics. Solid-state physics, solid-state chemistry and physical chemistry are also involved in the study of bonding and structure.
===== Crystallography =====
Crystallography is the science that examines the arrangement of atoms in crystalline solids. Crystallography is a useful tool for materials scientists. One of the fundamental concepts regarding the crystal structure of a material includes the unit cell, which is the smallest unit of a crystal lattice (space lattice) that repeats to make up the macroscopic crystal structure. Most common structural materials include parallelpiped and hexagonal lattice types. In single crystals, the effects of the crystalline arrangement of atoms is often easy to see macroscopically, because the natural shapes of crystals reflect the atomic structure. Further, physical properties are often controlled by crystalline defects. The understanding of crystal structures is an important prerequisite for understanding crystallographic defects. Examples of crystal defects consist of dislocations including edges, screws, vacancies, self inter-stitials, and more that are linear, planar, and three dimensional types of defects. New and advanced materials that are being developed include nanomaterials, biomaterials. Mostly, materials do not occur as a single crystal, but in polycrystalline form, as an aggregate of small crystals or grains with different orientations. Because of this, the powder diffraction method, which uses diffraction patterns of polycrystalline samples with a large number of crystals, plays an important role in structural determination. Most materials have a crystalline structure, but some important materials do not exhibit regular crystal structure. Polymers display varying degrees of crystallinity, and many are completely non-crystalline. Glass, some ceramics, and many natural materials are amorphous, not possessing any long-range order in their atomic arrangements. The study of polymers combines elements of chemical and statistical thermodynamics to give thermodynamic and mechanical descriptions of physical properties.
==== Nanostructure ====
Materials, which atoms and molecules form constituents in the nanoscale (i.e., they form nanostructures) are called nanomaterials. Nanomaterials are the subject of intense research in the materials science community due to the unique properties that they exhibit.
Nanostructure deals with objects and structures that are in the 1 – 100 nm range. In many materials, atoms or molecules agglomerate to form objects at the nanoscale. This causes many interesting electrical, magnetic, optical, and mechanical properties.
In describing nanostructures, it is necessary to differentiate between the number of dimensions on the nanoscale.
Nanotextured surfaces have one dimension on the nanoscale, i.e., only the thickness of the surface of an object is between 0.1 and 100 nm.
Nanotubes have two dimensions on the nanoscale, i.e., the diameter of the tube is between 0.1 and 100 nm; its length could be much greater.
Finally, spherical nanoparticles have three dimensions on the nanoscale, i.e., the particle is between 0.1 and 100 nm in each spatial dimension. The terms nanoparticles and ultrafine particles (UFP) often are used synonymously although UFP can reach into the micrometre range. The term 'nanostructure' is often used, when referring to magnetic technology. Nanoscale structure in biology is often called ultrastructure.
==== Microstructure ====
Microstructure is defined as the structure of a prepared surface or thin foil of material as revealed by a microscope above 25× magnification. It deals with objects from 100 nm to a few cm. The microstructure of a material (which can be broadly classified into metallic, polymeric, ceramic and composite) can strongly influence physical properties such as strength, toughness, ductility, hardness, corrosion resistance, high/low temperature behavior, wear resistance, and so on. Most of the traditional materials (such as metals and ceramics) are microstructured.
The manufacture of a perfect crystal of a material is physically impossible. For example, any crystalline material will contain defects such as precipitates, grain boundaries (Hall–Petch relationship), vacancies, interstitial atoms or substitutional atoms. The microstructure of materials reveals these larger defects and advances in simulation have allowed an increased understanding of how defects can be used to enhance material properties.
==== Macrostructure ====
Macrostructure is the appearance of a material in the scale millimeters to meters, it is the structure of the material as seen with the naked eye.
=== Properties ===
Materials exhibit myriad properties, including the following.
Mechanical properties, see Strength of materials
Chemical properties, see Chemistry
Electrical properties, see Electricity
Thermal properties, see Thermodynamics
Optical properties, see Optics and Photonics
Magnetic properties, see Magnetism
The properties of a material determine its usability and hence its engineering application.
=== Processing ===
Synthesis and processing involves the creation of a material with the desired micro-nanostructure. A material cannot be used in industry if no economically viable production method for it has been developed. Therefore, developing processing methods for materials that are reasonably effective and cost-efficient is vital to the field of materials science. Different materials require different processing or synthesis methods. For example, the processing of metals has historically defined eras such as the Bronze Age and Iron Age and is studied under the branch of materials science named physical metallurgy. Chemical and physical methods are also used to synthesize other materials such as polymers, ceramics, semiconductors, and thin films. As of the early 21st century, new methods are being developed to synthesize nanomaterials such as graphene.
=== Thermodynamics ===
Thermodynamics is concerned with heat and temperature and their relation to energy and work. It defines macroscopic variables, such as internal energy, entropy, and pressure, that partly describe a body of matter or radiation. It states that the behavior of those variables is subject to general constraints common to all materials. These general constraints are expressed in the four laws of thermodynamics. Thermodynamics describes the bulk behavior of the body, not the microscopic behaviors of the very large numbers of its microscopic constituents, such as molecules. The behavior of these microscopic particles is described by, and the laws of thermodynamics are derived from, statistical mechanics.
The study of thermodynamics is fundamental to materials science. It forms the foundation to treat general phenomena in materials science and engineering, including chemical reactions, magnetism, polarizability, and elasticity. It explains fundamental tools such as phase diagrams and concepts such as phase equilibrium.
=== Kinetics ===
Chemical kinetics is the study of the rates at which systems that are out of equilibrium change under the influence of various forces. When applied to materials science, it deals with how a material changes with time (moves from non-equilibrium to equilibrium state) due to application of a certain field. It details the rate of various processes evolving in materials including shape, size, composition and structure. Diffusion is important in the study of kinetics as this is the most common mechanism by which materials undergo change. Kinetics is essential in processing of materials because, among other things, it details how the microstructure changes with application of heat.
== Research ==
Materials science is a highly active area of research. Together with materials science departments, physics, chemistry, and many engineering departments are involved in materials research. Materials research covers a broad range of topics; the following non-exhaustive list highlights a few important research areas.
=== Nanomaterials ===
Nanomaterials describe, in principle, materials of which a single unit is sized (in at least one dimension) between 1 and 1000 nanometers (10−9 meter), but is usually 1 nm – 100 nm. Nanomaterials research takes a materials science based approach to nanotechnology, using advances in materials metrology and synthesis, which have been developed in support of microfabrication research. Materials with structure at the nanoscale often have unique optical, electronic, or mechanical properties. The field of nanomaterials is loosely organized, like the traditional field of chemistry, into organic (carbon-based) nanomaterials, such as fullerenes, and inorganic nanomaterials based on other elements, such as silicon. Examples of nanomaterials include fullerenes, carbon nanotubes, nanocrystals, etc.
=== Biomaterials ===
A biomaterial is any matter, surface, or construct that interacts with biological systems. Biomaterials science encompasses elements of medicine, biology, chemistry, tissue engineering, and materials science.
Biomaterials can be derived either from nature or synthesized in a laboratory using a variety of chemical approaches using metallic components, polymers, bioceramics, or composite materials. They are often intended or adapted for medical applications, such as biomedical devices which perform, augment, or replace a natural function. Such functions may be benign, like being used for a heart valve, or may be bioactive with a more interactive functionality such as hydroxylapatite-coated hip implants. Biomaterials are also used every day in dental applications, surgery, and drug delivery. For example, a construct with impregnated pharmaceutical products can be placed into the body, which permits the prolonged release of a drug over an extended period of time. A biomaterial may also be an autograft, allograft or xenograft used as an organ transplant material.
=== Electronic, optical, and magnetic ===
Semiconductors, metals, and ceramics are used today to form highly complex systems, such as integrated electronic circuits, optoelectronic devices, and magnetic and optical mass storage media. These materials form the basis of our modern computing world, and hence research into these materials is of vital importance.
Semiconductors are a traditional example of these types of materials. They are materials that have properties that are intermediate between conductors and insulators. Their electrical conductivities are very sensitive to the concentration of impurities, which allows the use of doping to achieve desirable electronic properties. Hence, semiconductors form the basis of the traditional computer.
This field also includes new areas of research such as superconducting materials, spintronics, metamaterials, etc. The study of these materials involves knowledge of materials science and solid-state physics or condensed matter physics.
=== Computational materials science ===
With continuing increases in computing power, simulating the behavior of materials has become possible. This enables materials scientists to understand behavior and mechanisms, design new materials, and explain properties formerly poorly understood. Efforts surrounding integrated computational materials engineering are now focusing on combining computational methods with experiments to drastically reduce the time and effort to optimize materials properties for a given application. This involves simulating materials at all length scales, using methods such as density functional theory, molecular dynamics, Monte Carlo, dislocation dynamics, phase field, finite element, and many more.
== Industry ==
Radical materials advances can drive the creation of new products or even new industries, but stable industries also employ materials scientists to make incremental improvements and troubleshoot issues with currently used materials. Industrial applications of materials science include materials design, cost-benefit tradeoffs in industrial production of materials, processing methods (casting, rolling, welding, ion implantation, crystal growth, thin-film deposition, sintering, glassblowing, etc.), and analytic methods (characterization methods such as electron microscopy, X-ray diffraction, calorimetry, nuclear microscopy (HEFIB), Rutherford backscattering, neutron diffraction, small-angle X-ray scattering (SAXS), etc.).
Besides material characterization, the material scientist or engineer also deals with extracting materials and converting them into useful forms. Thus ingot casting, foundry methods, blast furnace extraction, and electrolytic extraction are all part of the required knowledge of a materials engineer. Often the presence, absence, or variation of minute quantities of secondary elements and compounds in a bulk material will greatly affect the final properties of the materials produced. For example, steels are classified based on 1/10 and 1/100 weight percentages of the carbon and other alloying elements they contain. Thus, the extracting and purifying methods used to extract iron in a blast furnace can affect the quality of steel that is produced.
Solid materials are generally grouped into three basic classifications: ceramics, metals, and polymers. This broad classification is based on the empirical makeup and atomic structure of the solid materials, and most solids fall into one of these broad categories. An item that is often made from each of these materials types is the beverage container. The material types used for beverage containers accordingly provide different advantages and disadvantages, depending on the material used. Ceramic (glass) containers are optically transparent, impervious to the passage of carbon dioxide, relatively inexpensive, and are easily recycled, but are also heavy and fracture easily. Metal (aluminum alloy) is relatively strong, is a good barrier to the diffusion of carbon dioxide, and is easily recycled. However, the cans are opaque, expensive to produce, and are easily dented and punctured. Polymers (polyethylene plastic) are relatively strong, can be optically transparent, are inexpensive and lightweight, and can be recyclable, but are not as impervious to the passage of carbon dioxide as aluminum and glass.
=== Ceramics and glasses ===
Another application of materials science is the study of ceramics and glasses, typically the most brittle materials with industrial relevance. Many ceramics and glasses exhibit covalent or ionic-covalent bonding with SiO2 (silica) as a fundamental building block. Ceramics – not to be confused with raw, unfired clay – are usually seen in crystalline form. The vast majority of commercial glasses contain a metal oxide fused with silica. At the high temperatures used to prepare glass, the material is a viscous liquid which solidifies into a disordered state upon cooling. Windowpanes and eyeglasses are important examples. Fibers of glass are also used for long-range telecommunication and optical transmission. Scratch resistant Corning Gorilla Glass is a well-known example of the application of materials science to drastically improve the properties of common components.
Engineering ceramics are known for their stiffness and stability under high temperatures, compression and electrical stress. Alumina, silicon carbide, and tungsten carbide are made from a fine powder of their constituents in a process of sintering with a binder. Hot pressing provides higher density material. Chemical vapor deposition can place a film of a ceramic on another material. Cermets are ceramic particles containing some metals. The wear resistance of tools is derived from cemented carbides with the metal phase of cobalt and nickel typically added to modify properties.
Ceramics can be significantly strengthened for engineering applications using the principle of crack deflection. This process involves the strategic addition of second-phase particles within a ceramic matrix, optimizing their shape, size, and distribution to direct and control crack propagation. This approach enhances fracture toughness, paving the way for the creation of advanced, high-performance ceramics in various industries.
=== Composites ===
Another application of materials science in industry is making composite materials. These are structured materials composed of two or more macroscopic phases.
Applications range from structural elements such as steel-reinforced concrete, to the thermal insulating tiles, which play a key and integral role in NASA's Space Shuttle thermal protection system, which is used to protect the surface of the shuttle from the heat of re-entry into the Earth's atmosphere. One example is reinforced Carbon-Carbon (RCC), the light gray material, which withstands re-entry temperatures up to 1,510 °C (2,750 °F) and protects the Space Shuttle's wing leading edges and nose cap. RCC is a laminated composite material made from graphite rayon cloth and impregnated with a phenolic resin. After curing at high temperature in an autoclave, the laminate is pyrolized to convert the resin to carbon, impregnated with furfuryl alcohol in a vacuum chamber, and cured-pyrolized to convert the furfuryl alcohol to carbon. To provide oxidation resistance for reusability, the outer layers of the RCC are converted to silicon carbide.
Other examples can be seen in the "plastic" casings of television sets, cell-phones and so on. These plastic casings are usually a composite material made up of a thermoplastic matrix such as acrylonitrile butadiene styrene (ABS) in which calcium carbonate chalk, talc, glass fibers or carbon fibers have been added for added strength, bulk, or electrostatic dispersion. These additions may be termed reinforcing fibers, or dispersants, depending on their purpose.
=== Polymers ===
Polymers are chemical compounds made up of a large number of identical components linked together like chains. Polymers are the raw materials (the resins) used to make what are commonly called plastics and rubber. Plastics and rubber are the final product, created after one or more polymers or additives have been added to a resin during processing, which is then shaped into a final form. Plastics in former and in current widespread use include polyethylene, polypropylene, polyvinyl chloride (PVC), polystyrene, nylons, polyesters, acrylics, polyurethanes, and polycarbonates. Rubbers include natural rubber, styrene-butadiene rubber, chloroprene, and butadiene rubber. Plastics are generally classified as commodity, specialty and engineering plastics.
Polyvinyl chloride (PVC) is widely used, inexpensive, and annual production quantities are large. It lends itself to a vast array of applications, from artificial leather to electrical insulation and cabling, packaging, and containers. Its fabrication and processing are simple and well-established. The versatility of PVC is due to the wide range of plasticisers and other additives that it accepts. The term "additives" in polymer science refers to the chemicals and compounds added to the polymer base to modify its material properties.
Polycarbonate would be normally considered an engineering plastic (other examples include PEEK, ABS). Such plastics are valued for their superior strengths and other special material properties. They are usually not used for disposable applications, unlike commodity plastics.
Specialty plastics are materials with unique characteristics, such as ultra-high strength, electrical conductivity, electro-fluorescence, high thermal stability, etc.
The dividing lines between the various types of plastics is not based on material but rather on their properties and applications. For example, polyethylene (PE) is a cheap, low friction polymer commonly used to make disposable bags for shopping and trash, and is considered a commodity plastic, whereas medium-density polyethylene (MDPE) is used for underground gas and water pipes, and another variety called ultra-high-molecular-weight polyethylene (UHMWPE) is an engineering plastic which is used extensively as the glide rails for industrial equipment and the low-friction socket in implanted hip joints.
=== Metal alloys ===
The alloys of iron (steel, stainless steel, cast iron, tool steel, alloy steels) make up the largest proportion of metals today both by quantity and commercial value.
Iron alloyed with various proportions of carbon gives low, mid and high carbon steels. An iron-carbon alloy is only considered steel if the carbon level is between 0.01% and 2.00% by weight. For steels, the hardness and tensile strength of the steel is related to the amount of carbon present, with increasing carbon levels also leading to lower ductility and toughness. Heat treatment processes such as quenching and tempering can significantly change these properties, however. In contrast, certain metal alloys exhibit unique properties where their size and density remain unchanged across a range of temperatures. Cast iron is defined as an iron–carbon alloy with more than 2.00%, but less than 6.67% carbon. Stainless steel is defined as a regular steel alloy with greater than 10% by weight alloying content of chromium. Nickel and molybdenum are typically also added in stainless steels.
Other significant metallic alloys are those of aluminium, titanium, copper and magnesium. Copper alloys have been known for a long time (since the Bronze Age), while the alloys of the other three metals have been relatively recently developed. Due to the chemical reactivity of these metals, the electrolytic extraction processes required were only developed relatively recently. The alloys of aluminium, titanium and magnesium are also known and valued for their high strength to weight ratios and, in the case of magnesium, their ability to provide electromagnetic shielding. These materials are ideal for situations where high strength to weight ratios are more important than bulk cost, such as in the aerospace industry and certain automotive engineering applications.
=== Semiconductors ===
A semiconductor is a material that has a resistivity between a conductor and insulator. Modern day electronics run on semiconductors, and the industry had an estimated US$530 billion market in 2021. Its electronic properties can be greatly altered through intentionally introducing impurities in a process referred to as doping. Semiconductor materials are used to build diodes, transistors, light-emitting diodes (LEDs), and analog and digital electric circuits, among their many uses. Semiconductor devices have replaced thermionic devices like vacuum tubes in most applications. Semiconductor devices are manufactured both as single discrete devices and as integrated circuits (ICs), which consist of a number—from a few to millions—of devices manufactured and interconnected on a single semiconductor substrate.
Of all the semiconductors in use today, silicon makes up the largest portion both by quantity and commercial value. Monocrystalline silicon is used to produce wafers used in the semiconductor and electronics industry. Gallium arsenide (GaAs) is the second most popular semiconductor used. Due to its higher electron mobility and saturation velocity compared to silicon, it is a material of choice for high-speed electronics applications. These superior properties are compelling reasons to use GaAs circuitry in mobile phones, satellite communications, microwave point-to-point links and higher frequency radar systems. Other semiconductor materials include germanium, silicon carbide, and gallium nitride and have various applications.
== Relation with other fields ==
Materials science evolved, starting from the 1950s because it was recognized that to create, discover and design new materials, one had to approach it in a unified manner. Thus, materials science and engineering emerged in many ways: renaming and/or combining existing metallurgy and ceramics engineering departments; splitting from existing solid state physics research (itself growing into condensed matter physics); pulling in relatively new polymer engineering and polymer science; recombining from the previous, as well as chemistry, chemical engineering, mechanical engineering, and electrical engineering; and more.
The field of materials science and engineering is important both from a scientific perspective, as well as for applications field. Materials are of the utmost importance for engineers (or other applied fields) because usage of the appropriate materials is crucial when designing systems. As a result, materials science is an increasingly important part of an engineer's education.
Materials physics is the use of physics to describe the physical properties of materials. It is a synthesis of physical sciences such as chemistry, solid mechanics, solid state physics, and materials science. Materials physics is considered a subset of condensed matter physics and applies fundamental condensed matter concepts to complex multiphase media, including materials of technological interest. Current fields that materials physicists work in include electronic, optical, and magnetic materials, novel materials and structures, quantum phenomena in materials, nonequilibrium physics, and soft condensed matter physics. New experimental and computational tools are constantly improving how materials systems are modeled and studied and are also fields when materials physicists work in.
The field is inherently interdisciplinary, and the materials scientists or engineers must be aware and make use of the methods of the physicist, chemist and engineer. Conversely, fields such as life sciences and archaeology can inspire the development of new materials and processes, in bioinspired and paleoinspired approaches. Thus, there remain close relationships with these fields. Conversely, many physicists, chemists and engineers find themselves working in materials science due to the significant overlaps between the fields.
== Emerging technologies ==
== Subdisciplines ==
The main branches of materials science stem from the four main classes of materials: ceramics, metals, polymers and composites.
Ceramic engineering
Metallurgy
Polymer science and engineering
Composite engineering
There are additionally broadly applicable, materials independent, endeavors.
Materials characterization (spectroscopy, microscopy, diffraction)
Computational materials science
Materials informatics and selection
There are also relatively broad focuses across materials on specific phenomena and techniques.
Crystallography
Surface science
Tribology
Microelectronics
== Related or interdisciplinary fields ==
Condensed matter physics, solid-state physics and solid-state chemistry
Nanotechnology
Mineralogy
Supramolecular chemistry
Biomaterials science
== Professional societies ==
American Ceramic Society
ASM International
Association for Iron and Steel Technology
Materials Research Society
The Minerals, Metals & Materials Society
== See also ==
== References ==
=== Citations ===
=== Bibliography ===
Ashby, Michael; Hugh Shercliff; David Cebon (2007). Materials: engineering, science, processing and design (1st ed.). Butterworth-Heinemann. ISBN 978-0-7506-8391-3.
Askeland, Donald R.; Pradeep P. Phulé (2005). The Science & Engineering of Materials (5th ed.). Thomson-Engineering. ISBN 978-0-534-55396-8.
Callister, Jr., William D. (2000). Materials Science and Engineering – An Introduction (5th ed.). John Wiley and Sons. ISBN 978-0-471-32013-5.
Eberhart, Mark (2003). Why Things Break: Understanding the World by the Way It Comes Apart. Harmony. ISBN 978-1-4000-4760-4.
Gaskell, David R. (1995). Introduction to the Thermodynamics of Materials (4th ed.). Taylor and Francis Publishing. ISBN 978-1-56032-992-3.
González-Viñas, W. & Mancini, H.L. (2004). An Introduction to Materials Science. Princeton University Press. ISBN 978-0-691-07097-1.
Gordon, James Edward (1984). The New Science of Strong Materials or Why You Don't Fall Through the Floor (eissue ed.). Princeton University Press. ISBN 978-0-691-02380-9.
Mathews, F.L. & Rawlings, R.D. (1999). Composite Materials: Engineering and Science. Boca Raton: CRC Press. ISBN 978-0-8493-0621-1.
Lewis, P.R.; Reynolds, K. & Gagg, C. (2003). Forensic Materials Engineering: Case Studies. Boca Raton: CRC Press. ISBN 9780849311826.
Wachtman, John B. (1996). Mechanical Properties of Ceramics. New York: Wiley-Interscience, John Wiley & Son's. ISBN 978-0-471-13316-2.
Walker, P., ed. (1993). Chambers Dictionary of Materials Science and Technology. Chambers Publishing. ISBN 978-0-550-13249-9.
Mahajan, S. (2015). "The role of materials science in the evolution of microelectronics". MRS Bulletin. 12 (40): 1079–1088. Bibcode:2015MRSBu..40.1079M. doi:10.1557/mrs.2015.276.
== Further reading ==
Timeline of Materials Science Archived 2011-07-27 at the Wayback Machine at The Minerals, Metals & Materials Society (TMS) – accessed March 2007
Burns, G.; Glazer, A.M. (1990). Space Groups for Scientists and Engineers (2nd ed.). Boston: Academic Press, Inc. ISBN 978-0-12-145761-7.
Cullity, B.D. (1978). Elements of X-Ray Diffraction (2nd ed.). Reading, Massachusetts: Addison-Wesley Publishing Company. ISBN 978-0-534-55396-8.
Giacovazzo, C; Monaco HL; Viterbo D; Scordari F; Gilli G; Zanotti G; Catti M (1992). Fundamentals of Crystallography. Oxford: Oxford University Press. ISBN 978-0-19-855578-0.
Green, D.J.; Hannink, R.; Swain, M.V. (1989). Transformation Toughening of Ceramics. Boca Raton: CRC Press. ISBN 978-0-8493-6594-2.
Lovesey, S. W. (1984). Theory of Neutron Scattering from Condensed Matter; Volume 1: Neutron Scattering. Oxford: Clarendon Press. ISBN 978-0-19-852015-3.
Lovesey, S. W. (1984). Theory of Neutron Scattering from Condensed Matter; Volume 2: Condensed Matter. Oxford: Clarendon Press. ISBN 978-0-19-852017-7.
O'Keeffe, M.; Hyde, B.G. (1996). "Crystal Structures; I. Patterns and Symmetry". Zeitschrift für Kristallographie – Crystalline Materials. 212 (12). Washington, DC: Mineralogical Society of America, Monograph Series: 899. Bibcode:1997ZK....212..899K. doi:10.1524/zkri.1997.212.12.899. ISBN 978-0-939950-40-9.
Squires, G.L. (1996). Introduction to the Theory of Thermal Neutron Scattering (2nd ed.). Mineola, New York: Dover Publications Inc. ISBN 978-0-486-69447-4.
Young, R.A., ed. (1993). The Rietveld Method. Oxford: Oxford University Press & International Union of Crystallography. ISBN 978-0-19-855577-3.
== External links ==
MS&T conference organized by the main materials societies
MIT OpenCourseWare for MSE | Wikipedia/Materials_chemistry |
Isocitric acid is a structural isomer of citric acid. Since citric acid and isocitric acid are structural isomers, they share similar physical and chemical properties. Due to these similar properties, it is difficult to separate the isomers. Salts and esters of isocitric acid are known as isocitrates. The isocitrate anion is a substrate of the citric acid cycle. Isocitrate is formed from citrate with the help of the enzyme aconitase, and is acted upon by isocitrate dehydrogenase.
Isocitric acid is commonly used as a marker to detect the authenticity and quality of fruit products, most often citrus juices. In authentic orange juice, for example, the ratio of citric acid to D-isocitric acid is usually less than 130. An isocitric acid value higher than this may be indicative of fruit juice adulteration.
Isocitric acid has largely been used as a biochemical agent due to limited amounts. However, isocitric acid has been shown to have pharmaceutical and therapeutic effects. Isocitric acid has been shown to effectively treat iron deficient anemia. Additionally, isocitric acid could be used to treat Parkinson's disease. Yarrowia lipolytica can be used to produce isocitric acid and is inexpensive compared to other methods. Furthermore, other methods produce unequal amounts of citric acid to isocitric acid ratio, mostly producing citric acid. Use of Yarrowia lipolytica produces a better yield, making equal amounts of citric acid to isocitric acid.
== Interactive pathway map ==
Click on genes, proteins and metabolites below to link to respective articles.
== See also ==
Citric acid, also fluorocitric acid and chlorocitric acid
Tartaric acid
Malic acid
== References == | Wikipedia/Isocitrate |
Metalloprotein is a generic term for a protein that contains a metal ion cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins (out of ~20,000) contain zinc-binding protein domains although there may be up to 3000 human zinc metalloproteins.
== Abundance ==
It is estimated that approximately half of all proteins contain a metal. In another estimate, about one quarter to one third of all proteins are proposed to require metals to carry out their functions. Thus, metalloproteins have many different functions in cells, such as storage and transport of proteins, enzymes and signal transduction proteins, or infectious diseases. The abundance of metal binding proteins may be inherent to the amino acids that proteins use, as even artificial proteins without evolutionary history will readily bind metals.
Most metals in the human body are bound to proteins. For instance, the relatively high concentration of iron in the human body is mostly due to the iron in hemoglobin.
== Coordination chemistry principles ==
In metalloproteins, metal ions are usually coordinated by nitrogen, oxygen or sulfur centers belonging to amino acid residues of the protein. These donor groups are often provided by side-chains on the amino acid residues. Especially important are the imidazole substituent in histidine residues, thiolate substituents in cysteine residues, and carboxylate groups provided by aspartate. Given the diversity of the metalloproteome, virtually all amino acid residues have been shown to bind metal centers. The peptide backbone also provides donor groups; these include deprotonated amides and the amide carbonyl oxygen centers. Lead(II) binding in natural and artificial proteins has been reviewed.
In addition to donor groups that are provided by amino acid residues, many organic cofactors function as ligands. Perhaps most famous are the tetradentate N4 macrocyclic ligands incorporated into the heme protein. Inorganic ligands such as sulfide and oxide are also common.
== Storage and transport metalloproteins ==
These are the second stage product of protein hydrolysis obtained by treatment with slightly stronger acids and alkalies.
=== Oxygen carriers ===
Hemoglobin, which is the principal oxygen-carrier in humans, has four subunits in which the iron(II) ion is coordinated by the planar macrocyclic ligand protoporphyrin IX (PIX) and the imidazole nitrogen atom of a histidine residue. The sixth coordination site contains a water molecule or a dioxygen molecule. By contrast the protein myoglobin, found in muscle cells, has only one such unit. The active site is located in a hydrophobic pocket. This is important as without it the iron(II) would be irreversibly oxidized to iron(III). The equilibrium constant for the formation of HbO2 is such that oxygen is taken up or released depending on the partial pressure of oxygen in the lungs or in muscle. In hemoglobin the four subunits show a cooperativity effect that allows for easy oxygen transfer from hemoglobin to myoglobin.
In both hemoglobin and myoglobin it is sometimes incorrectly stated that the oxygenated species contains iron(III). It is now known that the diamagnetic nature of these species is because the iron(II) atom is in the low-spin state. In oxyhemoglobin the iron atom is located in the plane of the porphyrin ring, but in the paramagnetic deoxyhemoglobin the iron atom lies above the plane of the ring. This change in spin state is a cooperative effect due to the higher crystal field splitting and smaller ionic radius of Fe2+ in the oxyhemoglobin moiety.
Hemerythrin is another iron-containing oxygen carrier. The oxygen binding site is a binuclear iron center. The iron atoms are coordinated to the protein through the carboxylate side chains of a glutamate and aspartate and five histidine residues. The uptake of O2 by hemerythrin is accompanied by two-electron oxidation of the reduced binuclear center to produce bound peroxide (OOH−). The mechanism of oxygen uptake and release have been worked out in detail.
Hemocyanins carry oxygen in the blood of most mollusks, and some arthropods such as the horseshoe crab. They are second only to hemoglobin in biological popularity of use in oxygen transport. On oxygenation the two copper(I) atoms at the active site are oxidized to copper(II) and the dioxygen molecules are reduced to peroxide, O2−2.
Chlorocruorin (as the larger carrier erythrocruorin) is an oxygen-binding hemeprotein present in the blood plasma of many annelids, particularly certain marine polychaetes.
=== Cytochromes ===
Oxidation and reduction reactions are not common in organic chemistry as few organic molecules can act as oxidizing or reducing agents. Iron(II), on the other hand, can easily be oxidized to iron(III). This functionality is used in cytochromes, which function as electron-transfer vectors. The presence of the metal ion allows metalloenzymes to perform functions such as redox reactions that cannot easily be performed by the limited set of functional groups found in amino acids. The iron atom in most cytochromes is contained in a heme group. The differences between those cytochromes lies in the different side-chains. For instance cytochrome a has a heme a prosthetic group and cytochrome b has a heme b prosthetic group. These differences result in different Fe2+/Fe3+ redox potentials such that various cytochromes are involved in the mitochondrial electron transport chain.
Cytochrome P450 enzymes perform the function of inserting an oxygen atom into a C−H bond, an oxidation reaction.
=== Rubredoxin ===
Rubredoxin is an electron-carrier found in sulfur-metabolizing bacteria and archaea. The active site contains an iron ion coordinated by the sulfur atoms of four cysteine residues forming an almost regular tetrahedron. Rubredoxins perform one-electron transfer processes. The oxidation state of the iron atom changes between the +2 and +3 states. In both oxidation states the metal is high spin, which helps to minimize structural changes.
=== Plastocyanin ===
Plastocyanin is one of the family of blue copper proteins that are involved in electron transfer reactions. The copper-binding site is described as distorted trigonal pyramidal. The trigonal plane of the pyramidal base is composed of two nitrogen atoms (N1 and N2) from separate histidines and a sulfur (S1) from a cysteine. Sulfur (S2) from an axial methionine forms the apex. The distortion occurs in the bond lengths between the copper and sulfur ligands. The Cu−S1 contact is shorter (207 pm) than Cu−S2 (282 pm).
The elongated Cu−S2 bonding destabilizes the Cu(II) form and increases the redox potential of the protein. The blue color (597 nm peak absorption) is due to the Cu−S1 bond where S(pπ) to Cu(dx2−y2) charge transfer occurs.
In the reduced form of plastocyanin, His-87 will become protonated with a pKa of 4.4. Protonation prevents it acting as a ligand and the copper site geometry becomes trigonal planar.
=== Metal-ion storage and transfer ===
==== Iron ====
Iron is stored as iron(III) in ferritin. The exact nature of the binding site has not yet been determined. The iron appears to be present as a hydrolysis product such as FeO(OH). Iron is transported by transferrin whose binding site consists of two tyrosines, one aspartic acid and one histidine. The human body has no controlled mechanism for excretion of iron. This can lead to iron overload problems in patients treated with blood transfusions, as, for instance, with β-thalassemia. Iron is actually excreted in urine and is also concentrated in bile which is excreted in feces.
==== Copper ====
Ceruloplasmin is the major copper-carrying protein in the blood. Ceruloplasmin exhibits oxidase activity, which is associated with possible oxidation of Fe(II) into Fe(III), therefore assisting in its transport in the blood plasma in association with transferrin, which can carry iron only in the Fe(III) state.
==== Calcium ====
Osteopontin is involved in mineralization in the extracellular matrices of bones and teeth.
== Metalloenzymes ==
Metalloenzymes all have one feature in common, namely that the metal ion is bound to the protein with one labile coordination site. As with all enzymes, the shape of the active site is crucial. The metal ion is usually located in a pocket whose shape fits the substrate. The metal ion catalyzes reactions that are difficult to achieve in organic chemistry.
=== Carbonic anhydrase ===
In aqueous solution, carbon dioxide forms carbonic acid
CO2 + H2O ⇌ H2CO3
This reaction is very slow in the absence of a catalyst, but quite fast in the presence of the hydroxide ion
CO2 + OH− ⇌ HCO−3
A reaction similar to this is almost instantaneous with carbonic anhydrase. The structure of the active site in carbonic anhydrases is well known from a number of crystal structures. It consists of a zinc ion coordinated by three imidazole nitrogen atoms from three histidine units. The fourth coordination site is occupied by a water molecule. The coordination sphere of the zinc ion is approximately tetrahedral. The positively-charged zinc ion polarizes the coordinated water molecule, and nucleophilic attack by the negatively-charged hydroxide portion on carbon dioxide proceeds rapidly. The catalytic cycle produces the bicarbonate ion and the hydrogen ion as the equilibrium:
H2CO3 ⇌ HCO−3 + H+
favouring dissociation of carbonic acid at biological pH values.
=== Vitamin B12-dependent enzymes ===
The cobalt-containing Vitamin B12 (also known as cobalamin) catalyzes the transfer of methyl (−CH3) groups between two molecules, which involves the breaking of C−C bonds, a process that is energetically expensive in organic reactions. The metal ion lowers the activation energy for the process by forming a transient Co−CH3 bond. The structure of the coenzyme was famously determined by Dorothy Hodgkin and co-workers, for which she received a Nobel Prize in Chemistry. It consists of a cobalt(II) ion coordinated to four nitrogen atoms of a corrin ring and a fifth nitrogen atom from an imidazole group. In the resting state there is a Co−C sigma bond with the 5′ carbon atom of adenosine. This is a naturally occurring organometallic compound, which explains its function in trans-methylation reactions, such as the reaction carried out by methionine synthase.
=== Nitrogenase (nitrogen fixation) ===
The fixation of atmospheric nitrogen is an energy-intensive process, as it involves breaking the very stable triple bond between the nitrogen atoms. The nitrogenases catalyze the process. One such enzyme occurs in Rhizobium bacteria. There are three components to its action: a molybdenum atom at the active site, iron–sulfur clusters that are involved in transporting the electrons needed to reduce the nitrogen, and an abundant energy source in the form of magnesium ATP. This last is provided by a mutualistic symbiosis between the bacteria and a host plant, often a legume. The reaction may be written symbolically as
N2 + 16 MgATP + 8 e− → 2 NH3 + 16 MgADP +16 Pi + H2
where Pi stands for inorganic phosphate. The precise structure of the active site has been difficult to determine. It appears to contain a MoFe7S8 cluster that is able to bind the dinitrogen molecule and, presumably, enable the reduction process to begin. The electrons are transported by the associated "P" cluster, which contains two cubical Fe4S4 clusters joined by sulfur bridges.
=== Superoxide dismutase ===
The superoxide ion, O−2 is generated in biological systems by reduction of molecular oxygen. It has an unpaired electron, so it behaves as a free radical. It is a powerful oxidizing agent. These properties render the superoxide ion very toxic and are deployed to advantage by phagocytes to kill invading microorganisms. Otherwise, the superoxide ion must be destroyed before it does unwanted damage in a cell. The superoxide dismutase enzymes perform this function very efficiently.
The formal oxidation state of the oxygen atoms is −1⁄2. In solutions at neutral pH, the superoxide ion disproportionates to molecular oxygen and hydrogen peroxide.
2 O−2 + 2 H+ → O2 + H2O2
In biology this type of reaction is called a dismutation reaction. It involves both oxidation and reduction of superoxide ions. The superoxide dismutase (SOD) group of enzymes increase the rate of reaction to near the diffusion-limited rate. The key to the action of these enzymes is a metal ion with variable oxidation state that can act either as an oxidizing agent or as a reducing agent.
Oxidation: M(n+1)+ + O−2 → Mn+ + O2
Reduction: Mn+ + O−2 + 2 H+ → M(n+1)+ + H2O2.
In human SOD, the active metal is copper, as Cu(II) or Cu(I), coordinated tetrahedrally by four histidine residues. This enzyme also contains zinc ions for stabilization and is activated by copper chaperone for superoxide dismutase (CCS). Other isozymes may contain iron, manganese or nickel. The activity of Ni-SOD involves nickel(III), an unusual oxidation state for this element. The active site nickel geometry cycles from square planar Ni(II), with thiolate (Cys2 and Cys6) and backbone nitrogen (His1 and Cys2) ligands, to square pyramidal Ni(III) with an added axial His1 side chain ligand.
=== Chlorophyll-containing proteins ===
Chlorophyll plays a crucial role in photosynthesis. It contains a magnesium enclosed in a chlorin ring. However, the magnesium ion is not directly involved in the photosynthetic function and can be replaced by other divalent ions with little loss of activity. Rather, the photon is absorbed by the chlorin ring, whose electronic structure is well-adapted for this purpose.
Initially, the absorption of a photon causes an electron to be excited into a singlet state of the Q band. The excited state undergoes an intersystem crossing from the singlet state to a triplet state in which there are two electrons with parallel spin. This species is, in effect, a free radical, and is very reactive and allows an electron to be transferred to acceptors that are adjacent to the chlorophyll in the chloroplast. In the process chlorophyll is oxidized. Later in the photosynthetic cycle, chlorophyll is reduced back again. This reduction ultimately draws electrons from water, yielding molecular oxygen as a final oxidation product.
=== Hydrogenase ===
Hydrogenases are subclassified into three different types based on the active site metal content: iron–iron hydrogenase, nickel–iron hydrogenase, and iron hydrogenase.
All hydrogenases catalyze reversible H2 uptake, but while the [FeFe] and [NiFe] hydrogenases are true redox catalysts, driving H2 oxidation and H+ reduction
H2 ⇌ 2 H+ + 2 e−
the [Fe] hydrogenases catalyze the reversible heterolytic cleavage of H2.
H2 ⇌ H+ + H−
=== Ribozyme and deoxyribozyme ===
Since discovery of ribozymes by Thomas Cech and Sidney Altman in the early 1980s, ribozymes have been shown to be a distinct class of metalloenzymes. Many ribozymes require metal ions in their active sites for chemical catalysis; hence they are called metalloenzymes. Additionally, metal ions are essential for structural stabilization of ribozymes. Group I intron is the most studied ribozyme which has three metals participating in catalysis. Other known ribozymes include group II intron, RNase P, and several small viral ribozymes (such as hammerhead, hairpin, HDV, and VS) and the large subunit of ribosomes. Several classes of ribozymes have been described.
Deoxyribozymes, also called DNAzymes or catalytic DNA, are artificial DNA-based catalysts that were first produced in 1994. Almost all DNAzymes require metal ions. Although ribozymes mostly catalyze cleavage of RNA substrates, a variety of reactions can be catalyzed by DNAzymes including RNA/DNA cleavage, RNA/DNA ligation, amino acid phosphorylation and dephosphorylation, and carbon–carbon bond formation. Yet, DNAzymes that catalyze RNA cleavage reaction are the most extensively explored ones. 10-23 DNAzyme, discovered in 1997, is one of the most studied catalytic DNAs with clinical applications as a therapeutic agent. Several metal-specific DNAzymes have been reported including the GR-5 DNAzyme (lead-specific), the CA1-3 DNAzymes (copper-specific), the 39E DNAzyme (uranyl-specific) and the NaA43 DNAzyme (sodium-specific).
== Signal-transduction metalloproteins ==
=== Calmodulin ===
Calmodulin is an example of a signal-transduction protein. It is a small protein that contains four EF-hand motifs, each of which is able to bind a Ca2+ ion.
In an EF-hand loop protein domain, the calcium ion is coordinated in a pentagonal bipyramidal configuration. Six glutamic acid and aspartic acid residues involved in the binding are in positions 1, 3, 5, 7 and 9 of the polypeptide chain. At position 12, there is a glutamate or aspartate ligand that behaves as a bidentate ligand, providing two oxygen atoms. The ninth residue in the loop is necessarily glycine due to the conformational requirements of the backbone. The coordination sphere of the calcium ion contains only carboxylate oxygen atoms and no nitrogen atoms. This is consistent with the hard nature of the calcium ion.
The protein has two approximately symmetrical domains, separated by a flexible "hinge" region. Binding of calcium causes a conformational change to occur in the protein. Calmodulin participates in an intracellular signaling system by acting as a diffusible second messenger to the initial stimuli.
=== Troponin ===
In both cardiac and skeletal muscles, muscular force production is controlled primarily by changes in the intracellular calcium concentration. In general, when calcium rises, the muscles contract and, when calcium falls, the muscles relax. Troponin, along with actin and tropomyosin, is the protein complex to which calcium binds to trigger the production of muscular force.
=== Transcription factors ===
Many transcription factors contain a structure known as a zinc finger, a structural module in which a region of protein folds around a zinc ion. The zinc does not directly contact the DNA that these proteins bind to. Instead, the cofactor is essential for the stability of the tightly folded protein chain. In these proteins, the zinc ion is usually coordinated by pairs of cysteine and histidine side-chains.
== Other metalloenzymes ==
There are two types of carbon monoxide dehydrogenase: one contains iron and molybdenum, the other contains iron and nickel. Parallels and differences in catalytic strategies have been reviewed.
Pb2+ (lead) can replace Ca2+ (calcium) as, for example, with calmodulin or Zn2+ (zinc) as with metallocarboxypeptidases.
Some other metalloenzymes are given in the following table, according to the metal involved.
== See also ==
== References ==
== External links ==
Metalloprotein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Catherine Drennan's Seminar: Snapshots of Metalloproteins | Wikipedia/Metalloprotein |
Ammonium ferric citrate (also known as ferric ammonium citrate or ammoniacal ferrous citrate) has the formula [NH4]y[Fex(C6H4O7)]. The iron in this compound is trivalent. All three carboxyl groups and the central hydroxyl group of citric acid are deprotonated. A distinguishing feature of this compound is that it is very soluble in water, in contrast to ferric citrate which is not very soluble.
In its crystal structure each moiety of citric acid has lost four protons. The deprotonated hydroxyl group and two of the carboxylate groups ligate to the ferric center, while the third carboxylate group coordinates with the ammonium.
== Uses ==
Ammonium ferric citrate has a range of uses, including:
As a food ingredient, it has an INS number 381, and is used as an acidity regulator. Most notably used in the Scottish beverage Irn-Bru.
Water purification
As a reducing agent of metal salts of low activity like gold and silver
With potassium ferricyanide as part of the cyanotype photographic process
Used in Kligler's Iron Agar (KIA) test to identify enterobacteriaceae bacteria by observing their metabolism of different sugars, producing hydrogen sulfide
In medical imaging, ammonium ferric citrate is used as a contrast medium.
As a hematinic
== See also ==
Food additive
List of food additives
== References == | Wikipedia/Ammonium_ferric_citrate |
Ferrous citrate, also known as iron(II) citrate or iron(2+) citrate, describes coordination complexes containing citrate anions with Fe2+ formed in aqueous solution. Although a number of complexes are possible (or even likely), only one complex has been crystallized. That complex is the coordination polymer with the formula [Fe(H2O)6]2+{[Fe(C6H5O7)(H2O)]−}2.2H2O, where C6H5O73- is HOC(CH2CO2−)2(CO2−, i.e., the triple conjugate base of citric acid wherein the three carboxylic acid groups are ionized. Ferrous citrates are all paramagnetic, reflecting the weak crystal field of the carboxylate ligands.
Ferrous citrates are produced by treating disodium citrate Na2C6H6O7 with sources of iron(II) aquo complexes, such as iron(II) sulfate. Ferrous citrates are all highly unstable in air, converting to ferric citrates.
It is a nutrient supplement approved by the FDA.
== See also ==
Iron(III) citrate
Ammonium ferric citrate
== References == | Wikipedia/Iron(II)_citrate |
In biochemistry, the iron–sulfur cluster biosynthesis describes the components and processes involved in the biosynthesis of iron–sulfur proteins. The topic is of interest because these proteins are pervasive. The iron sulfur proteins contain iron–sulfur clusters, some with elaborate structures, that feature iron and sulfide centers. One broad biosynthetic task is producing sulfide (S2-), which requires various families of enzymes. Another broad task is affixing the sulfide to iron, which is achieved on scaffolds, which are nonfunctional. Finally these Fe-S cluster is transferred to a target protein, which then become functional.
The formation of iron–sulfur clusters are produced by one of four pathways:
Nitrogen fixation (NIF) system, which is also found in bacteria that are not nitrogen-fixing.
Iron–sulfur cluster (ISC) system, in bacterial and mitochondria
Sulfur assimilation (SUF) system, in plastids and some bacteria
In addition to those three systems, the so-called Cystosolic Iron–sulfur Assembly (CIA) is invoked for cytosolic and nuclear Fe–S proteins.
== Mechanisms ==
The assembly of iron–sulfur clusters cluster begins with the production of the equivalent of a sulfur (sulfur atoms per se are not found in nature). The required sulfur atom is obtained from free cysteine by the action of so-called cysteine desulfurases. One prominent desulfurase is called IscS, a pyridoxal phosphate-dependent enzyme. The sulfur atom from the cysteine substrate is transferred to residue Cys-328 of IscS, forming a persulfide:
L-cysteine + [enzyme]-cysteine
⇌
{\displaystyle \rightleftharpoons }
L-alanine + [enzyme]-S-sulfanylcysteine
The persulfide functional group R-S-S-H functions as a source of "inorganic sulfur" that will be incorporated into Fe-S clusters. Subsequently, IscS transfers this "extra" sulfur to IscU. In addition to IscS and IscU, bacterial Fe-S assembly requires IscA, an 11 kDa protein of uncertain function.
The Suf system for iron–sulfur cluster biosynthesis is generally similar to the Isc system (and the Nif system). The analogy extends to the existence of SufA, SufS, and SufU. The Suf system operates with fewer chaperones.
== References == | Wikipedia/Iron-sulfur_cluster_biosynthesis_protein_family |
Trends is a series of 16 review journals in a range of areas of biology and chemistry published under its Cell Press imprint by Elsevier. The publisher in lieu is Danielle Loughlin.
The Trends series was established in 1976 with Trends in Biochemical Sciences, rapidly followed by Trends in Neurosciences, Trends in Pharmacological Sciences, and Immunology Today.
Immunology Today, Parasitology Today, and Molecular Medicine Today changed their names to Trends in... in 2001. Drug Discovery Today was spun off as an independent brand.
== Titles ==
The current set of Trends journals are all published monthly:
== References ==
== External links ==
Official website | Wikipedia/Trends_in_Biochemical_Sciences |
A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembrane proteins; that is they exist permanently within and span the membrane across which they transport substances. The proteins may assist in the movement of substances by facilitated diffusion, active transport, osmosis, or reverse diffusion. The two main types of proteins involved in such transport are broadly categorized as either channels or carriers (a.k.a. transporters, or permeases). Examples of channel/carrier proteins include the GLUT 1 uniporter, sodium channels, and potassium channels. The solute carriers and atypical SLCs are secondary active or facilitative transporters in humans. Collectively membrane transporters and channels are known as the transportome. Transportomes govern cellular influx and efflux of not only ions and nutrients but drugs as well.
== Difference between channels and carriers ==
A carrier is not open simultaneously to both the extracellular and intracellular environments. Either its inner gate is open, or outer gate is open. In contrast, a channel can be open to both environments at the same time, allowing the molecules to diffuse without interruption. Carriers have binding sites, but pores and channels do not. When a channel is opened, millions of ions can pass through the membrane per second, but only 100 to 1000 molecules typically pass through a carrier molecule in the same time. Each carrier protein is designed to recognize only one substance or one group of very similar substances. Research has correlated defects in specific carrier proteins with specific diseases.
== Active transport ==
Active transport is the movement of a substance across a membrane against its concentration gradient. This is usually to accumulate high concentrations of molecules that a cell needs, such as glucose or amino acids. If the process uses chemical energy, such as adenosine triphosphate (ATP), it is called primary active transport. Membrane transport proteins that are driven directly by the hydrolysis of ATP are referred to as ATPase pumps. These types of pumps direct the exergonic hydrolysis of ATP to the unfavorable movement of molecules against their concentration gradient. Examples of ATPase pumps include P-type ATPase's, V-type ATPases, F-type ATPases, and ABC binding cassettes.
Secondary active transport involves the use of an electrochemical gradient, and does not use energy produced in the cell. Secondary active transport commonly uses types of carrier proteins, typically symporters and antiporters. Symporter proteins couple the transport of one molecule down its concentration gradient to the transport of another molecule against its concentration gradient, and both molecules diffuse in the same direction. Antiporter proteins transport one molecule down its concentration gradient to transport another molecule against its concentration gradient, but the molecules diffuse in opposite directions. As symporters and antiporters are involved in coupling the transport of two molecules, they are commonly referred to as cotransporters. Unlike channel proteins which only transport substances through membranes passively, carrier proteins can transport ions and molecules either passively through facilitated diffusion, or via secondary active transport. A carrier protein is required to move particles from areas of low concentration to areas of high concentration. These carrier proteins have receptors that bind to a specific molecule (substrate) needing transport. The molecule or ion to be transported (the substrate) must first bind at a binding site at the carrier molecule, with a certain binding affinity. Following binding, and while the binding site is facing the same way, the carrier will capture or occlude (take in and retain) the substrate within its molecular structure and cause an internal translocation so that the opening in the protein now faces the other side of the plasma membrane. The carrier protein substrate is released at that site, according to its binding affinity there.
== Facilitated diffusion ==
Facilitated diffusion is the passage of molecules or ions across a biological membrane through specific transport proteins and requires no energy input. Facilitated diffusion is used especially in the case of large polar molecules and charged ions; once such ions are dissolved in water they cannot diffuse freely across cell membranes due to the hydrophobic nature of the fatty acid tails of the phospholipids that make up the bilayers.
The type of carrier proteins used in facilitated diffusion is slightly different from those used in active transport. They are still transmembrane carrier proteins, but these are gated transmembrane channels, meaning they do not internally translocate, nor require ATP to function. The substrate is taken in one side of the gated carrier, and without using ATP the substrate is released into the cell. Facilitated diffusion does not require the use of ATP as facilitated diffusion, like simple diffusion, transports molecules or ions along their concentration gradient.
== Osmosis ==
Osmosis is the passive diffusion of water across a cell membrane from an area of high concentration to an area of low concentration. Since Osmosis is a passive process, like facilitated diffusion and simple diffusion, it does not require the use of ATP. Osmosis is important in regulating the balance of water and salt within cells, thus it plays a critical role in maintaining homeostasis. Aquaporins are integral membrane proteins that allow for the rapid passage of water and glycerol through membranes. The aquaporin monomers consist of six transmembrane alpha-helix domains and these monomers can assemble to form the aquaporin proteins. As four of these monomers come together to form the aquaporin protein, it is known as a homotetramer, meaning it is made up of four identical subunits. All aquaporins are tetrameric membrane integral proteins, and the water passes through each individual monomer channel rather than between all of the four channels. Since aquaporins are transmembrane channels for the diffusion of water, the channels that make up the aquaporin are typically lined with hydrophilic side chains to allow water to pass through.
== Reverse diffusion ==
Reverse transport, or transporter reversal, is a phenomenon in which the substrates of a membrane transport protein are moved in the opposite direction to that of their typical movement by the transporter. Transporter reversal typically occurs when a membrane transport protein is phosphorylated by a particular protein kinase, which is an enzyme that adds a phosphate group to proteins.
== Types ==
(Grouped by Transporter Classification database categories)
=== 1: Channels/pores ===
α-helical protein channels such as voltage-gated ion channel (VIC), ligand-gated ion channels(LGICs)
β-barrel porins such as aquaporin
channel-forming toxins, including colicins, diphtheria toxin, and others
Nonribosomally synthesized channels such as gramicidin
Holins; which function in export of enzymes that digest bacterial cell walls in an early step of cell lysis.
Facilitated diffusion occurs in and out of the cell membrane via channels/pores and carriers/porters.
Note:
Channels:
Channels are either in open state or closed state. When a channel is opened with a slight conformational switch, it is open to both environment simultaneously (extracellular and intracellular)
Pores:
Pores are continuously open to these both environment, because they do not undergo conformational changes. They are always open and active.
=== 2: Electrochemical potential-driven transporters ===
Also named carrier proteins or secondary carriers.
2.A: Porters (uniporters, symporters, antiporters), SLCs.
Excitatory amino acid transporters (EAATs)
EAAT1
EAAT2
EAAT3
EAAT4
EAAT5
Glucose transporter
Monoamine transporters, including:
Dopamine transporter (DAT)
Norepinephrine transporter (NET)
Serotonin transporter (SERT)
Vesicular monoamine transporters (VMAT)
Adenine nucleotide translocator (ANT)
2.B: Nonribosomally synthesized porters, such as:
The Nigericin family
The Ionomycin family
2.C: Ion-gradient-driven energizers
=== 3: Primary Active Transporters ===
3.A: P-P-bond-hydrolysis-driven transporters (a.k.a. ATP-driven pumps, or transport ATPases):
ATP-binding cassette transporter (ABC transporter), such as MDR, CFTR
V-type ATPase ; ( "V" related to vacuolar ).
P-type ATPase ; ( "P" related to phosphorylation), such as:
Na+/K+-ATPase
Plasma membrane Ca2+ ATPase
Proton pump
F-type ATPase; ("F" related to factor), including: mitochondrial ATP synthase, chloroplast ATP synthase1
3.B: Decarboxylation-driven transporters
3.C: Methyltransfer-driven transporters
3.D: Oxidoreduction-driven transporters
3.E: Light absorption-driven transporters, such as rhodopsin
=== 4: Group translocators ===
The group translocators provide a special mechanism for the phosphorylation of sugars as they are transported into bacteria (PEP group translocation)
=== 5: Electron carriers ===
The transmembrane electron transfer carriers in the membrane include two-electron carriers, such as the disulfide bond oxidoreductases (DsbB and DsbD in E. coli) as well as one-electron carriers such as NADPH oxidase. Often these redox proteins are not considered transport proteins.
== Relevant Examples ==
=== GLUT 1 ===
Every carrier protein, especially within the same cell membrane, is specific to one type or family of molecules. GLUT1 is a named carrier protein found in almost all animal cell membranes that transports glucose across the bilayer. This protein is a uniporter, meaning it transports glucose along its concentration in a singular direction. It is an integral membrane protein carrier with a hydrophilic interior, which allows it to bind to glucose. As GLUT 1 is a type of carrier protein, it will undergo a conformational change to allow glucose to enter the other side of the plasma membrane. GLUT 1 is commonly found in the red blood cell membranes of mammals.
=== Sodium/Potassium Channels ===
While there are many examples of channels within the human body, two notable ones are sodium and potassium channels. Potassium channels are typically involved in the transport of potassium ions across the cell membrane to the outside of the cell, which helps maintain the negative membrane potential of cells. As there are more potassium channels than sodium channels, more potassium flows out of the cell than sodium into a cell, thus why the membrane potential is negative. Sodium channels are typically involved in the transport of sodium ions across the cell membrane into the cell. These channels are commonly associated with excitable neurons, as an influx of sodium can trigger depolarization, which in turn propagates an action potential. As these proteins are types of channel proteins, they do not undergo a change of conformation after binding their respective substrates.
=== Other Examples ===
Other specific carrier proteins also help the body function in important ways. Cytochromes operate in the electron transport chain as carrier proteins for electrons.
== Pathology ==
A number of inherited diseases involve defects in carrier proteins in a particular substance or group of cells. Cysteinuria (cysteine in the urine and the bladder) is such a disease involving defective cysteine carrier proteins in the kidney cell membranes. This transport system normally removes cysteine from the fluid destined to become urine and returns this essential amino acid to the blood. When this carrier malfunctions, large quantities of cysteine remain in the urine, where it is relatively insoluble and tends to precipitate. This is one cause of urinary stones. Some vitamin carrier proteins have been shown to be overexpressed in patients with malignant disease. For example, levels of riboflavin carrier protein (RCP) have been shown to be significantly elevated in people with breast cancer.
== See also ==
Cotransport
Cotransporter
C14orf102, a 3810bp protein-encoding gene
Ion channel
Permease
P-loop
Solute carrier family (classification)
TC number (classification)
Translocase
Flippases
Vesicular transport protein
Endocytosis
== References ==
== Sources ==
Sadava, David E; Hillis, David M; Heller, H Craig; Berenbaum, May (2011). Life: The Science of Biology. Macmillan. ISBN 978-1-4292-4644-6.
Han, Seong S.; Ashley, Ruth; Hann, Gary (1974). Cell Biology. University of Michigan. OCLC 1532651.
== External links ==
"Transport protein" at Dorland's Medical Dictionary | Wikipedia/Carrier_protein |
Disodium tetracarbonylferrate is the organoiron compound with the formula Na2[Fe(CO)4]. It is always used as a solvate, e.g., with tetrahydrofuran or dimethoxyethane, which bind to the sodium cation. An oxygen-sensitive colourless solid, it is a reagent in organometallic and organic chemical research. The dioxane solvated sodium salt is known as Collman's reagent, in recognition of James P. Collman, an early popularizer of its use.
== Structure ==
The dianion [Fe(CO)4]2− is isoelectronic with Ni(CO)4. The iron center is tetrahedral, with Na+---OCFe interactions. It is commonly used with dioxane complexed to the sodium cation.
== Synthesis ==
The reagent was originally generated in situ by reducing iron pentacarbonyl with sodium amalgam. Modern synthesis use sodium naphthalene or sodium benzophenone ketyls as the reducants:
Fe(CO)5 + 2 Na → Na2[Fe(CO)4] + CO
When a deficiency of sodium is used, the reduction affords deep yellow octacarbonyl diferrate:
2 Fe(CO)5 + 2 Na → Na2[Fe2(CO)8] + 2 CO
Some specialized methods do not start with iron carbonyl.
== Reactions ==
It is used to synthesise aldehydes from alkyl halides.
The reagent was originally described for the conversion of primary alkyl bromides to the corresponding aldehydes in a two-step, "one-pot" reaction:
Na2[Fe(CO)4] + RBr → Na[RFe(CO)4] + NaBr
This solution is then treated sequentially with PPh3 and then acetic acid to give the aldehyde, RCHO.
Disodium tetracarbonylferrate can be used to convert acyl chlorides to aldehydes. This reaction proceeds via the intermediacy of iron acyl complex.
Na2[Fe(CO)4] + RCOCl → Na[RC(O)Fe(CO)4] + NaCl
Na[RC(O)Fe(CO)4] + HCl → RCHO + "Fe(CO)4" + NaCl
Disodium tetracarbonylferrate reacts with alkyl halides (RX) to produce alkyl complexes:
Na2[Fe(CO)4] + RX → Na[RFe(CO)4] + NaX
Such iron alkyls can be converted to the corresponding carboxylic acid and acid halides:
Na[RFe(CO)4] + O2, H+ →→ RCO2H + Fe...
Na[RFe(CO)4] + 2 X2 → RC(O)X + FeX2 + 3 CO + NaX
== References ==
== Further reading ==
Collman, J. P. (1975). "Disodium Tetracarbonylferrate, a Transition Metal Analog of a Grignard Reagent". Accounts of Chemical Research. 8 (10): 342–347. doi:10.1021/ar50094a004.
Ungurenasu, C.; Cotzur, C. (1982). "Disodium Tetracarbonylferrate: A Reagent for Acid Functionalization of Halogenated Polymers". Polymer Bulletin. 6 (5–6): 299–303. doi:10.1007/BF00255401. S2CID 101154955.
Hieber, V. W.; Braun, G. (1959). "Notizen: "Rheniumcarbonylwasserstoff" und Methylpentacarbonylrhenium". Zeitschrift für Naturforschung B. 14 (2): 132–133. doi:10.1515/znb-1959-0214. S2CID 94402946. | Wikipedia/Disodium_tetracarbonylferrate |
Potassium ferrate is an inorganic compound with the formula K2FeO4. It is the potassium salt of ferric acid. Potassium ferrate is a powerful oxidizing agent with applications in green chemistry, organic synthesis, and cathode technology.
== Synthesis ==
Generally, there are three ways to produce hexavalent iron: dry oxidation, wet oxidation, and electrochemical synthesis. The methods used to produce potassium ferrate are similar to those used to produce sodium ferrate and barium ferrate.
=== Dry oxidation ===
The dry oxidation method entails heating or melting iron oxides in an alkaline, oxygenated environment. The combination of high temperature (200 °C - 800 °C) and oxygen presents an explosion hazard that has led many researchers to believe this method of production is not suitable from a safety viewpoint, although many attempts have been made to overcome this problem.
=== Wet oxidation ===
In the wet oxidation method, K2FeO4 is prepared by oxidizing an alkaline solution of an iron(III) salt. Generally, this method employs either ferrous (FeII) or ferric (FeIII) salts as the source of iron ions, calcium, sodium hypochlorite (Ca(ClO)2, NaClO), sodium thiosulfate (Na2S2O3) or chlorine (Cl2) as oxidizing agents and, finally, sodium hydroxide, sodium carbonate (NaOH, NaCO3) or potassium hydroxide (KOH) to increase the pH of the solution. For example:3 ClO− + 3 Fe(OH)3(H2O)3 + 4 K+ + 4 OH− → 3 Cl− + 2 K2FeO4 + 11 H2O
=== Electrochemical synthesis ===
Electrochemical methods used to synthesize potassium ferrate usually consist of an iron anode which electrolyzes a KOH solution.
== Properties ==
Potassium ferrate is a dark purple crystalline solid that dissolves in water to form a reddish-purple solution. The salt is paramagnetic and is isostructural with K2MnO4, K2SO4, and K2CrO4. The solid consists of K+ and the tetrahedral FeO2−4 anion, with Fe-O distances of 1.66 Å. Potassium ferrate decomposes rapidly in neutral and acidic water, e.g.:
4 K2FeO4 + 4 H2O → 3 O2 + 2 Fe2O3 + 8 KOH
In alkaline solution and as a dry solid, K2FeO4 is stable. Under the acidic conditions, the oxidation–reduction potential of the ferrate(VI) ions (2.2 V) is greater than that of ozone (2.0 V).
== Applications ==
Like sodium ferrate, K2FeO4 generally does not generate environmentally toxic by-products and can be used in water treatment processes. It can act as:
Oxidizing agent: promoting the oxidation of organic species in metal complexes.
Coagulator: allows removal of inorganic pollution compounds such as heavy metals, inorganic salts, trace elements and metal complexes.
Disinfectant: destroys human pathogens including viruses, spores, bacteria and protozoa.
In addition, potassium ferrate can be used as a bleeding stopper for fresh wounds. In organic synthesis, K2FeO4 oxidizes primary alcohols. K2FeO4 has also attracted attention as a potential cathode material in a "super iron battery."
Stabilised forms of potassium ferrate have been proposed for the removal of transuranium elements, both dissolved and suspended, from aqueous solutions. Tonnage quantities were proposed to help remediate the effects of the Chernobyl disaster in Belarus . This new technique was successfully applied for the removal of a broad range of heavy metals. Work on the use of potassium ferrate precipitation of transuranium elements and heavy metals was carried out in the Laboratories of IC Technologies Inc. in partnership with ADC Laboratories, in 1987 though 1992. The removal of the transuranium elements was demonstrated on samples from various Dept. of Energy nuclear sites in the USA.
Because the side products of its redox reactions are rust-like iron oxides, K2FeO4 has been described as an "environmentally friendly" oxidant. In contrast, related oxidants such as chromates are considered environmentally hazardous.
== History ==
In 1702, Georg Ernst Stahl (1660 – 1734) observed that the ignition product of potassium nitrate (saltpetre) and iron powder displayed a red-purple color in an aqueous solution, which was eventually attributed to hexavalent potassium ferrate. Eckenberg and Becquerel in 1834 reported that a red-purple color appeared during heating of a mixture of potassium hydroxide and iron ore. In 1840, Edmond Frémy (1814 – 1894) discovered that fusion of potassium hydroxide and iron(III) oxide in air produced a high-capacity iron compound that was soluble in water:
8 KOH + 2 Fe2O3 + 3 O2 → 4 K2FeO4 + 4 H2O
== References == | Wikipedia/Potassium_ferrate |
Barium ferrate is the chemical compound of formula BaFeO4. This is a rare compound containing iron in the +6 oxidation state. The ferrate(VI) ion has two unpaired electrons, making it paramagnetic. It is isostructural with BaSO4, and contains the tetrahedral [FeO4]2− anion.
== Structure ==
The ferrate(VI) anion is paramagnetic due to its two unpaired electrons and it has a tetrahedral molecular geometry.
X-ray diffraction has been used to determine the orthorhombic unit cell structure (lattice vectors a ≠ b ≠ c, interaxial angles α=β=γ=90°) of nanocrystalline BaFeO4. It crystallized in the Pnma space group (point group: D2h) with lattice parameters a = 0.8880 nm, b = 0.5512 nm and c = 0.7214 nm. The accuracy of the X-Ray diffraction data has been verified by the lattice fringe intervals from High-Resolution Transmission Electron Microscopy (HRTEM) and cell parameters calculated from Selected Area Diffraction (SAED).
=== Characterization ===
Infrared absorbance peaks of barium ferrate are observed at 870, 812, 780 cm−1.
BaFeO4 follows the Curie–Weiss law and has a magnetic moment of (2.92 ± 0.03) × 10−23 A m2 (3.45 ± 0.1 BM) with a Weiss constant of −89 K.
== Preparation and chemistry ==
Barium ferrate(VI) can be prepared by both wet and dry synthetic methods. Dry synthesis is usually performed using a thermal technique, such as by heating barium hydroxide and iron(II) hydroxide in the presence of oxygen to about 800 to 900 °C.
Ba(OH)2 + Fe(OH)2 + O2 → BaFeO4 + 2 H2O
Wet methods employ both chemical and electrochemical techniques. For example, the ferrate anion forms when a suitable iron salt is placed in alkaline conditions and a strong oxidising agent, such as sodium hypochlorite, is added.
2 Fe(OH)3 + 3 OCl− + 4 OH− → 2 FeO2−4 + 5 H2O + 3 Cl−
Barium ferrate is then precipitated from solution by adding a solution of a barium(II) salt. Addition of a soluble barium salt to an alkali metal ferrate solution produces a maroon precipitate of barium ferrate, a crystal which has the same structure as barium chromate and has approximately the same solubility. Barium ferrate has also been prepared by adding barium oxide to a mixture sodium hypochlorite and ferric nitrate at room temperature (or 0 °C). The purity of the product can be improved by carrying out the reaction at low temperature in the absence of carbon dioxide and by rapidly filtering and drying the precipitate, reducing the coprecipitation of barium hydroxide and barium carbonate as impurities.
== Uses ==
Barium ferrate is an oxidizing agent and is used as an oxidizing reagent in organic syntheses. Its other applications include removal of color, removal of cyanide, killing bacteria and contaminated and waste water treatment.
Salts of ferrate(VI) are energetic cathode materials in "super-iron" batteries. Cathodes containing ferrate(VI) compounds are referred to as "super-iron" cathodes due to their highly oxidized iron basis, multiple electron transfer, and high intrinsic energy. Among all ferrate(VI) salts, barium ferrate sustains unusually facile charge transfer, which is important for the high power domain of alkaline batteries.
== Reactions ==
Barium ferrate is the most stable of the ferrate(VI) compounds. It can be prepared in its purest state and has the most definite composition. Barium ferrate can be easily decomposed by all soluble acids, including carbonic acid. If carbon dioxide is passed through water on which hydrated barium ferrate is suspended, barium ferrate will decompose completely to form barium carbonate, ferric hydroxide and oxygen gas. Alkaline sulfates decompose barium ferrate that has not been dried, forming barium sulfate, ferric hydroxide and oxygen gas.
== See also ==
Potassium ferrate
Ferrate(VI)
Barium
== References == | Wikipedia/Barium_ferrate |
Ferrocenium tetrafluoroborate is an organometallic compound with the formula [Fe(C5H5)2]BF4. This salt is composed of the cation [Fe(C5H5)2]+ and the tetrafluoroborate anion (BF−4). The related hexafluorophosphate is also a popular reagent with similar properties. The ferrocenium cation is often abbreviated Fc+ or Cp2Fe+. The salt is deep blue in color and paramagnetic.
Ferrocenium salts are sometimes used as one-electron oxidizing agents, and the reduced product, ferrocene, is inert and readily separated from ionic products. The ferrocene–ferrocenium couple is often used as a reference in electrochemistry. The standard potential of ferrocene-ferrocenium is dependent on specific electrochemical conditions.
== Preparation ==
Commercially available, this compound may be prepared by oxidizing ferrocene typically with ferric salts followed by addition of fluoroboric acid. A variety of other oxidants work well also, such as nitrosyl tetrafluoroborate. Many analogous ferrocenium salts are known.
== Structure ==
According to X-ray crystallography, the structures of the metallocene component of FcBF4 and the parent ferrocene are very similar. The Fe-C distances in the cation are 209.5 pm, about 2% longer than the Fe-C distances in ferrocene.
== References == | Wikipedia/Ferrocenium_tetrafluoroborate |
Iron(II) perchlorate is the inorganic compound with the formula Fe(ClO4)2·6H2O. A green, water-soluble solid, it is produced by the reaction of iron metal with dilute perchloric acid followed by evaporation of the solution:
Fe + 2 HClO4 + 6 H2O → Fe(ClO4)2·6H2O + H2
Although the ferrous cation is a reductant and the perchlorate anion is a strong oxidant, in the absence of atmospheric oxygen, dissolved ferrous perchlorate is stable in aqueous solution because the electron transfer between both species Fe2+ and ClO−4 is hindered by severe kinetic limitations. Being a weak Lewis base, the perchlorate anion is a poor ligand for the aqueous Fe2+ and does not contribute to the electron transfer by favoring the formation of an inner sphere complex giving rise to a possible reorganisation of the activated complex. The resulting high activation energy prohibits a thermodynamically spontaneous redox reaction (∆Gr < 0).
However, in aqueous solution, and under air, iron(II) perchlorate slowly oxidizes to iron(III) oxyhydroxide.
The hexahydrate consists of discrete hexa-aquo-iron(II) divalent cations and perchlorate anions. It crystallizes with an orthorhombic structure. It has minor phase transitions at 245 and 336 K.
== Uses ==
In organic chemistry, iron(II) perchlorate can be used as a source of ferrous ions for the Fenton oxidation.
== References == | Wikipedia/Iron(II)_perchlorate |
Iron-binding proteins are carrier proteins and metalloproteins that are important in iron metabolism and the immune response. Iron is required for life.
Iron-dependent enzymes catalyze a variety of biochemical reactions and can be divided into three broad classes depending on the structure of their active site: non-heme mono-iron, non-heme diiron , or heme centers. A well-known family of iron-dependent enzymes include oxygenases that facilitate hydroxyl group addition of one or both atoms from o2. Notable enzymes include tryptophan dioxygenase, ferredoxin, and 2-oxoglutarate dioxygenase.
== Heme proteins ==
Heme proteins are proteins that contain a heme prosthetic group. The heme group consists of a porphyrin ring coordinated with an iron ion. Four nitrogen atoms in the porphyrin ring act as a ligand for the iron in the center. In many cases, the equatorial porphyrin is complemented by one or two axial ligands. An example of this is in hemoglobin, where the porphyrin works together with a histidine side chain and a bound O2 molecule, forming an octahedral complex.
=== Hemoglobin ===
Hemoglobin is an oxygen-transport protein found in virtually all vertebrates. Hemoglobin A is the main type found in human adults. It is a tetramer consisting of two alpha and two beta subunits. Each of the four monomeric units contain a heme prosthetic group in which a ferric cation is bound between four nitrogen atoms of a porphyrin ring. Along with a histidine, the apo form has five ligands surrounding the iron atom. Oxygen binds to the empty sixth position to form an octahedral complex in the holo form. Oxygen binding is fully cooperative for each of the subunits because as the first oxygen binds to one of the four heme groups, the protein undergoes a drastic conformational change that sharply increases the oxygen affinity of the other three subunits.
Hemoglobin has various affinities, depending on pH, structure, and CO2 partial pressure. Fetal hemoglobin is a variant containing two gamma subunits instead of two beta subunits. Fetal hemoglobin is the predominant form up until the infant is several months old, and it has a greater oxygen affinity to compensate for the low oxygen tension of supplied maternal blood during pregnancy. Hemoglobin has a lower oxygen affinity at low pH. This allows for rapid dissociation as oxygenated hemoglobin is transported to cells throughout the body. Because of the CO2 production and aqueous formation of carbonic acid in respiring cells, oxygenated hemoglobin dissociates in order to deliver the necessary oxygen to the cells. Hemoglobin has a binding affinity for carbon monoxide that is 250 times greater than for oxygen. This is the basis of carbon monoxide poisoning, as hemoglobin can no longer transport oxygen to cells.
=== Cytochromes ===
Cytochromes are heme-containing enzymes that act as single-electron transporters, most notably as electron shuttles in oxidative phosphorylation and photosynthesis. Types of well-studied cytochromes include cytochromes a-c, cytochrome oxidase, and cytochrome P450. These proteins act as electron shuttles by switching the oxidation state of the heme iron atom between ferrous (Fe2+) and ferric (Fe3+). Various cytochromes in combination with other redox-active molecules form a gradient of standard reduction potentials that increases the efficiency of energy coupling during electron-transfer events.
== Iron-sulfur proteins ==
Iron-sulfur proteins are those with an iron structure that includes sulfur. There are a variety of forms iron and sulfur can take in proteins, but the most common are [2Fe 2S] and [4Fe 4S]. Clusters are often associated with cysteine residues in the protein chain.
== Non-heme proteins ==
=== Transferrin ===
Transferrin is found in human plasma, and it is used to traffic and import non-heme iron. It travels freely in the extracellular space. When its iron is needed by the cell, it is brought into the cytosol by a transferrin receptor. Transferrin can bind two Fe(III) ions, along with an anion (usually carbonate). To release the iron, the carbonate anion is protonated. This changes the carbonate's interaction with the protein, changing the conformation and allowing Fe(III) to be transferred.
Transferrin has a molecular weight of about 80 kDa. It is a glycoprotein, meaning that it has sugars attached to its amino acid chain.
=== Lactoferrin ===
Lactoferrin is a member of the transferrin family and is the predominant protein found in mammal exocrine secretions, such as tears, milk, and saliva. It is composed of approximately 700 residues and exists mainly as a tetramer, with the monomer:tetramer ratio being 1:4 at 10 μM protein concentrations. The tertiary structure is composed of two lobes, termed N and C lobes, each containing one iron-binding pocket. Each pocket contributes four amino acids (two tyrosines, one histidine, and one aspartate) and, along with two carbonate or bicarbonate anions, forms a six-membered coordinate around the iron cation. It is this specific combination that makes lactoferrin's iron affinity 300 times greater than transferrin.
Lactoferrin has significant antimicrobial properties. It is found in the highest concentration of 150 ng/mL in human colostrum (the type of milk produced at the end stages of pregnancy), providing much needed immune support to newly born infants. It was widely believed that lactoferrin was only a bacteriostatic agent due to its high iron affinity and its ability to sequester free iron atoms from pathogenic microbes. It is now known, however, that the major antimicrobial driving force lies in the bactericidal properties of its iron-bound pocket and a specific peptide lactoferricin located at the N-lobe. Lactoferrin is able to bind to the LPS (lipopolysaccharide) layer of bacteria, and in its holo form the iron atom oxidizes the lipopolysaccharides to lyse the outer membrane and simultaneously produce toxic hydrogen peroxide. Additionally, upon cleavage of lactoferrin by trypsin, the peptide lactoferricin is produced which binds to H+-ATPase, disrupting proton translocation and ultimately killing the cell.
=== Ferritin ===
Ferritin is an iron reservoir for an individual cell. It is found in all cells types and localized in the cytosol. Ferritin is a large protein composed of 24 subunits surrounding a core full of iron atoms. It is capable of holding 0-4500 iron atoms, which can be used as a reservoir for cellular needs. Iron is stored when there is excess, and retrieved when iron is needed again. The subunits are a mixture of H (heavy or heart) and L (light or liver). The subunits form a cluster 70-80 Angstroms wide, which is then filled with iron ferrihydrite.
Ferritin is a highly conserved protein through all domains of life. It is so conserved that subunits from horses and humans can assemble together into a functional protein. Each subunit is composed of five alpha helices.
Ferritin is used to diagnose low iron levels in humans. It can be used to indicate the level of bioavailable iron, which is helpful for diagnosing anemia. The usual range for men is 18-270 ng/mL and the range for women is 18-160 ng/mL.
== See also ==
Iron
== External links ==
Iron-binding+proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
== References == | Wikipedia/Iron-binding_proteins |
Iron(III) stearate (ferric stearate) is a metal-organic compound, a salt of iron and stearic acid with the chemical formula Fe(C17H35COO)3.
The compound is classified as a metallic soap, i.e. a metal derivative of a fatty acid.
== Synthesis ==
Reacting stearic acid with iron oxide.
Treating stearic acid with iron chloride in presence of DABCO.
== Physical properties ==
The compound forms orange-red or brown powder. Hygroscopic.
Insoluble in water. Soluble in hot ethanol, toluene, chloroform, acetone, benzene, turpentine.
== Uses ==
The compound is used as a catalyst in organic synthesis. Also, as a reagent in analytical chemistry, and as a stabilizer in biochemistry.
== Toxicity ==
Ferric stearate is low-toxic.
== References == | Wikipedia/Ferric_stearate |
Rieske proteins are iron–sulfur protein (ISP) components of cytochrome bc1 complexes and cytochrome b6f complexes and are responsible for electron transfer in some biological systems. John S. Rieske and co-workers first discovered the protein and in 1964 isolated an acetylated form of the bovine mitochondrial protein. In 1979, Trumpower's team isolated the "oxidation factor" from bovine mitochondria and showed it was a reconstitutively-active form of the Rieske iron-sulfur protein.
It is a unique [2Fe-2S] cluster in that one of the two Fe atoms is coordinated by two histidine residues rather than two cysteine residues. They have since been found in plants, animals, and bacteria with widely ranging electron reduction potentials from -150 to +400 mV.
== Biological function ==
Ubiquinol-cytochrome-c reductase (also known as bc1 complex or complex III) is an enzyme complex of bacterial and mitochondrial oxidative phosphorylation systems. It catalyses the oxidation-reduction reaction of the mobile components ubiquinol and cytochrome c, contributing to an electrochemical potential difference across the mitochondrial inner or bacterial membrane, which is linked to ATP synthesis.
The complex consists of three subunits in most bacteria, and nine in mitochondria: both bacterial and mitochondrial complexes contain cytochrome b and cytochrome c1 subunits, and an iron–sulfur 'Rieske' subunit, which contains a high potential 2Fe-2S cluster. The mitochondrial form also includes six other subunits that do not possess redox centres. Plastoquinone-plastocyanin reductase (b6f complex), present in cyanobacteria and the chloroplasts of plants, catalyses the oxidoreduction of plastoquinol and cytochrome f. This complex, which is functionally similar to ubiquinol-cytochrome c reductase, comprises cytochrome b6, cytochrome f and Rieske subunits.
The Rieske subunit acts by binding either a ubiquinol or plastoquinol anion, transferring an electron to the 2Fe-2S cluster, then releasing the electron to the cytochrome c or cytochrome f heme iron. The reduction of the Rieske center increases the affinity of the subunit by several orders of magnitude, stabilizing the semiquinone radical at the Q(P) site. The Rieske domain has a [2Fe-2S] center. Two conserved cysteines coordinate one Fe ion while the other Fe ion is coordinated by two conserved histidines. The 2Fe-2S cluster is bound in the highly conserved C-terminal region of the Rieske subunit.
== Rieske protein family ==
The homologues of the Rieske proteins include ISP components of cytochrome b6f complex, aromatic-ring-hydroxylating dioxygenases (phthalate dioxygenase, benzene, naphthalene and toluene 1,2-dioxygenases) and arsenite oxidase (EC 1.20.98.1). Comparison of amino acid sequences has revealed the following consensus sequence:
Cys-Xaa-His-(Xaa)15–17-Cys-Xaa-Xaa-His
== 3D structure ==
The overall fold of Rieske proteins, comprising two subdomains, is dominated by antiparallel β-structure and contains variable numbers of α-helices. The smaller "cluster-binding" subdomains in mitochondrial and chloroplast proteins are virtually identical, whereas the large subdomains are substantially different in spite of a common folding topology. The [Fe2S2] cluster-binding subdomains have the topology of an incomplete antiparallel β-barrel. One iron atom of the Rieske [Fe2S2] cluster in the domain is coordinated by two cysteine residues and the other is coordinated by two histidine residues through the Nδ atoms. The ligands coordinating the cluster originate from two loops; each loop contributes one Cys and one His.
== Subfamilies ==
Rieske iron–sulfur protein, C-terminal InterPro: IPR005805
Arsenite oxidase, small subunit InterPro: IPR014067
== Human proteins containing this domain ==
AIFM3; RFESD; UQCRFS1;
== References ==
== Further reading ==
== External links ==
PDB: 1RIE - X-ray structure of Rieske protein (water-soluble fragment) of the bovine mitochondrial cytochrome bc1 complex
PDB: 1RFS - X-ray structure of Rieske protein (water-soluble fragment) of the spinach chloroplast cytochrome b6 fcomplex
PDB: 1FQT - X-ray structure of Rieske-type ferredoxin associated with biphenyl dioxygenase from Burkholderia cepacia
PDB: 1G8J - X-ray structure of Rieske subunit of arsenite oxidase from Alcaligenes faecalis
PDB: 2I7F - X-ray structure of the Sphingomonas yanoikuyae B1 Rieske ferredoxin
PDB: 2QPZ - X-ray structure of the Pseudomonas Naphthalene 1,2-dioxygenase Rieske ferredoxin
InterPro: IPR005806 - InterPro entry for Rieske [2Fe-2S] region | Wikipedia/Rieske_protein |
In quantum mechanics, an energy level is degenerate if it corresponds to two or more different measurable states of a quantum system. Conversely, two or more different states of a quantum mechanical system are said to be degenerate if they give the same value of energy upon measurement. The number of different states corresponding to a particular energy level is known as the degree of degeneracy (or simply the degeneracy) of the level. It is represented mathematically by the Hamiltonian for the system having more than one linearly independent eigenstate with the same energy eigenvalue.: 48 When this is the case, energy alone is not enough to characterize what state the system is in, and other quantum numbers are needed to characterize the exact state when distinction is desired. In classical mechanics, this can be understood in terms of different possible trajectories corresponding to the same energy.
Degeneracy plays a fundamental role in quantum statistical mechanics. For an N-particle system in three dimensions, a single energy level may correspond to several different wave functions or energy states. These degenerate states at the same level all have an equal probability of being filled. The number of such states gives the degeneracy of a particular energy level.
== Mathematics ==
The possible states of a quantum mechanical system may be treated mathematically as abstract vectors in a separable, complex Hilbert space, while the observables may be represented by linear Hermitian operators acting upon them. By selecting a suitable basis, the components of these vectors and the matrix elements of the operators in that basis may be determined.
If A is a N × N matrix, X a non-zero vector, and λ is a scalar, such that
A
X
=
λ
X
{\displaystyle AX=\lambda X}
, then the scalar λ is said to be an eigenvalue of A and the vector X is said to be the eigenvector corresponding to λ. Together with the zero vector, the set of all eigenvectors corresponding to a given eigenvalue λ form a subspace of Cn, which is called the eigenspace of λ. An eigenvalue λ which corresponds to two or more different linearly independent eigenvectors is said to be degenerate, i.e.,
A
X
1
=
λ
X
1
{\displaystyle AX_{1}=\lambda X_{1}}
and
A
X
2
=
λ
X
2
{\displaystyle AX_{2}=\lambda X_{2}}
, where
X
1
{\displaystyle X_{1}}
and
X
2
{\displaystyle X_{2}}
are linearly independent eigenvectors. The dimension of the eigenspace corresponding to that eigenvalue is known as its degree of degeneracy, which can be finite or infinite. An eigenvalue is said to be non-degenerate if its eigenspace is one-dimensional.
The eigenvalues of the matrices representing physical observables in quantum mechanics give the measurable values of these observables while the eigenstates corresponding to these eigenvalues give the possible states in which the system may be found, upon measurement. The measurable values of the energy of a quantum system are given by the eigenvalues of the Hamiltonian operator, while its eigenstates give the possible energy states of the system. A value of energy is said to be degenerate if there exist at least two linearly independent energy states associated with it. Moreover, any linear combination of two or more degenerate eigenstates is also an eigenstate of the Hamiltonian operator corresponding to the same energy eigenvalue. This clearly follows from the fact that the eigenspace of the energy value eigenvalue λ is a subspace (being the kernel of the Hamiltonian minus λ times the identity), hence is closed under linear combinations.
== Effect of degeneracy on the measurement of energy ==
In the absence of degeneracy, if a measured value of energy of a quantum system is determined, the corresponding state of the system is assumed to be known, since only one eigenstate corresponds to each energy eigenvalue. However, if the Hamiltonian
H
^
{\displaystyle {\hat {H}}}
has a degenerate eigenvalue
E
n
{\displaystyle E_{n}}
of degree gn, the eigenstates associated with it form a vector subspace of dimension gn. In such a case, several final states can be possibly associated with the same result
E
n
{\displaystyle E_{n}}
, all of which are linear combinations of the gn orthonormal eigenvectors
|
E
n
,
i
⟩
{\displaystyle |E_{n,i}\rangle }
.
In this case, the probability that the energy value measured for a system in the state
|
ψ
⟩
{\displaystyle |\psi \rangle }
will yield the value
E
n
{\displaystyle E_{n}}
is given by the sum of the probabilities of finding the system in each of the states in this basis, i.e.,
P
(
E
n
)
=
∑
i
=
1
g
n
|
⟨
E
n
,
i
|
ψ
⟩
|
2
{\displaystyle P(E_{n})=\sum _{i=1}^{g_{n}}|\langle E_{n,i}|\psi \rangle |^{2}}
== Degeneracy in different dimensions ==
This section intends to illustrate the existence of degenerate energy levels in quantum systems studied in different dimensions. The study of one and two-dimensional systems aids the conceptual understanding of more complex systems.
=== Degeneracy in one dimension ===
In several cases, analytic results can be obtained more easily in the study of one-dimensional systems. For a quantum particle with a wave function
|
ψ
⟩
{\displaystyle |\psi \rangle }
moving in a one-dimensional potential
V
(
x
)
{\displaystyle V(x)}
, the time-independent Schrödinger equation can be written as
−
ℏ
2
2
m
d
2
ψ
d
x
2
+
V
ψ
=
E
ψ
{\displaystyle -{\frac {\hbar ^{2}}{2m}}{\frac {d^{2}\psi }{dx^{2}}}+V\psi =E\psi }
Since this is an ordinary differential equation, there are two independent eigenfunctions for a given energy
E
{\displaystyle E}
at most, so that the degree of degeneracy never exceeds two. It can be proven that in one dimension, there are no degenerate bound states for normalizable wave functions. A sufficient condition on a piecewise continuous potential
V
{\displaystyle V}
and the energy
E
{\displaystyle E}
is the existence of two real numbers
M
,
x
0
{\displaystyle M,x_{0}}
with
M
≠
0
{\displaystyle M\neq 0}
such that
∀
x
>
x
0
{\displaystyle \forall x>x_{0}}
we have
V
(
x
)
−
E
≥
M
2
{\displaystyle V(x)-E\geq M^{2}}
. In particular,
V
{\displaystyle V}
is bounded below in this criterion.
=== Degeneracy in two-dimensional quantum systems ===
Two-dimensional quantum systems exist in all three states of matter and much of the variety seen in three dimensional matter can be created in two dimensions. Real two-dimensional materials are made of monoatomic layers on the surface of solids. Some examples of two-dimensional electron systems achieved experimentally include MOSFET, two-dimensional superlattices of Helium, Neon, Argon, Xenon etc. and surface of liquid Helium.
The presence of degenerate energy levels is studied in the cases of Particle in a box and two-dimensional harmonic oscillator, which act as useful mathematical models for several real world systems.
=== Particle in a rectangular plane ===
Consider a free particle in a plane of dimensions
L
x
{\displaystyle L_{x}}
and
L
y
{\displaystyle L_{y}}
in a plane of impenetrable walls. The time-independent Schrödinger equation for this system with wave function
|
ψ
⟩
{\displaystyle |\psi \rangle }
can be written as
−
ℏ
2
2
m
(
∂
2
ψ
∂
x
2
+
∂
2
ψ
∂
y
2
)
=
E
ψ
{\displaystyle -{\frac {\hbar ^{2}}{2m}}\left({\frac {\partial ^{2}\psi }{{\partial x}^{2}}}+{\frac {\partial ^{2}\psi }{{\partial y}^{2}}}\right)=E\psi }
The permitted energy values are
E
n
x
,
n
y
=
π
2
ℏ
2
2
m
(
n
x
2
L
x
2
+
n
y
2
L
y
2
)
{\displaystyle E_{n_{x},n_{y}}={\frac {\pi ^{2}\hbar ^{2}}{2m}}\left({\frac {n_{x}^{2}}{L_{x}^{2}}}+{\frac {n_{y}^{2}}{L_{y}^{2}}}\right)}
The normalized wave function is
ψ
n
x
,
n
y
(
x
,
y
)
=
2
L
x
L
y
sin
(
n
x
π
x
L
x
)
sin
(
n
y
π
y
L
y
)
{\displaystyle \psi _{n_{x},n_{y}}(x,y)={\frac {2}{\sqrt {L_{x}L_{y}}}}\sin \left({\frac {n_{x}\pi x}{L_{x}}}\right)\sin \left({\frac {n_{y}\pi y}{L_{y}}}\right)}
where
n
x
,
n
y
=
1
,
2
,
3
,
…
{\displaystyle n_{x},n_{y}=1,2,3,\dots }
So, quantum numbers
n
x
{\displaystyle n_{x}}
and
n
y
{\displaystyle n_{y}}
are required to describe the energy eigenvalues and the lowest energy of the system is given by
E
1
,
1
=
π
2
ℏ
2
2
m
(
1
L
x
2
+
1
L
y
2
)
{\displaystyle E_{1,1}=\pi ^{2}{\frac {\hbar ^{2}}{2m}}\left({\frac {1}{L_{x}^{2}}}+{\frac {1}{L_{y}^{2}}}\right)}
For some commensurate ratios of the two lengths
L
x
{\displaystyle L_{x}}
and
L
y
{\displaystyle L_{y}}
, certain pairs of states are degenerate.
If
L
x
/
L
y
=
p
/
q
{\displaystyle L_{x}/L_{y}=p/q}
, where p and q are integers, the states
(
n
x
,
n
y
)
{\displaystyle (n_{x},n_{y})}
and
(
p
n
y
/
q
,
q
n
x
/
p
)
{\displaystyle (pn_{y}/q,qn_{x}/p)}
have the same energy and so are degenerate to each other.
=== Particle in a square box ===
In this case, the dimensions of the box
L
x
=
L
y
=
L
{\displaystyle L_{x}=L_{y}=L}
and the energy eigenvalues are given by
E
n
x
,
n
y
=
π
2
ℏ
2
2
m
L
2
(
n
x
2
+
n
y
2
)
{\displaystyle E_{n_{x},n_{y}}={\frac {\pi ^{2}\hbar ^{2}}{2mL^{2}}}(n_{x}^{2}+n_{y}^{2})}
Since
n
x
{\displaystyle n_{x}}
and
n
y
{\displaystyle n_{y}}
can be interchanged without changing the energy, each energy level has a degeneracy of at least two when
n
x
{\displaystyle n_{x}}
and
n
y
{\displaystyle n_{y}}
are different. Degenerate states are also obtained when the sum of squares of quantum numbers corresponding to different energy levels are the same. For example, the three states (nx = 7, ny = 1), (nx = 1, ny = 7) and (nx = ny = 5) all have
E
=
50
π
2
ℏ
2
2
m
L
2
{\displaystyle E=50{\frac {\pi ^{2}\hbar ^{2}}{2mL^{2}}}}
and constitute a degenerate set.
Degrees of degeneracy of different energy levels for a particle in a square box:
=== Particle in a cubic box ===
In this case, the dimensions of the box
L
x
=
L
y
=
L
z
=
L
{\displaystyle L_{x}=L_{y}=L_{z}=L}
and the energy eigenvalues depend on three quantum numbers.
E
n
x
,
n
y
,
n
z
=
π
2
ℏ
2
2
m
L
2
(
n
x
2
+
n
y
2
+
n
z
2
)
{\displaystyle E_{n_{x},n_{y},n_{z}}={\frac {\pi ^{2}\hbar ^{2}}{2mL^{2}}}(n_{x}^{2}+n_{y}^{2}+n_{z}^{2})}
Since
n
x
{\displaystyle n_{x}}
,
n
y
{\displaystyle n_{y}}
and
n
z
{\displaystyle n_{z}}
can be interchanged without changing the energy, each energy level has a degeneracy of at least three when the three quantum numbers are not all equal.
== Finding a unique eigenbasis in case of degeneracy ==
If two operators
A
^
{\displaystyle {\hat {A}}}
and
B
^
{\displaystyle {\hat {B}}}
commute, i.e.,
[
A
^
,
B
^
]
=
0
{\displaystyle [{\hat {A}},{\hat {B}}]=0}
, then for every eigenvector
|
ψ
⟩
{\displaystyle |\psi \rangle }
of
A
^
{\displaystyle {\hat {A}}}
,
B
^
|
ψ
⟩
{\displaystyle {\hat {B}}|\psi \rangle }
is also an eigenvector of
A
^
{\displaystyle {\hat {A}}}
with the same eigenvalue. However, if this eigenvalue, say
λ
{\displaystyle \lambda }
, is degenerate, it can be said that
B
^
|
ψ
⟩
{\displaystyle {\hat {B}}|\psi \rangle }
belongs to the eigenspace
E
λ
{\displaystyle E_{\lambda }}
of
A
^
{\displaystyle {\hat {A}}}
, which is said to be globally invariant under the action of
B
^
{\displaystyle {\hat {B}}}
.
For two commuting observables A and B, one can construct an orthonormal basis of the state space with eigenvectors common to the two operators. However,
λ
{\displaystyle \lambda }
is a degenerate eigenvalue of
A
^
{\displaystyle {\hat {A}}}
, then it is an eigensubspace of
A
^
{\displaystyle {\hat {A}}}
that is invariant under the action of
B
^
{\displaystyle {\hat {B}}}
, so the representation of
B
^
{\displaystyle {\hat {B}}}
in the eigenbasis of
A
^
{\displaystyle {\hat {A}}}
is not a diagonal but a block diagonal matrix, i.e. the degenerate eigenvectors of
A
^
{\displaystyle {\hat {A}}}
are not, in general, eigenvectors of
B
^
{\displaystyle {\hat {B}}}
. However, it is always possible to choose, in every degenerate eigensubspace of
A
^
{\displaystyle {\hat {A}}}
, a basis of eigenvectors common to
A
^
{\displaystyle {\hat {A}}}
and
B
^
{\displaystyle {\hat {B}}}
.
=== Choosing a complete set of commuting observables ===
If a given observable A is non-degenerate, there exists a unique basis formed by its eigenvectors. On the other hand, if one or several eigenvalues of
A
^
{\displaystyle {\hat {A}}}
are degenerate, specifying an eigenvalue is not sufficient to characterize a basis vector. If, by choosing an observable
B
^
{\displaystyle {\hat {B}}}
, which commutes with
A
^
{\displaystyle {\hat {A}}}
, it is possible to construct an orthonormal basis of eigenvectors common to
A
^
{\displaystyle {\hat {A}}}
and
B
^
{\displaystyle {\hat {B}}}
, which is unique, for each of the possible pairs of eigenvalues {a,b}, then
A
^
{\displaystyle {\hat {A}}}
and
B
^
{\displaystyle {\hat {B}}}
are said to form a complete set of commuting observables. However, if a unique set of eigenvectors can still not be specified, for at least one of the pairs of eigenvalues, a third observable
C
^
{\displaystyle {\hat {C}}}
, which commutes with both
A
^
{\displaystyle {\hat {A}}}
and
B
^
{\displaystyle {\hat {B}}}
can be found such that the three form a complete set of commuting observables.
It follows that the eigenfunctions of the Hamiltonian of a quantum system with a common energy value must be labelled by giving some additional information, which can be done by choosing an operator that commutes with the Hamiltonian. These additional labels required naming of a unique energy eigenfunction and are usually related to the constants of motion of the system.
=== Degenerate energy eigenstates and the parity operator ===
The parity operator is defined by its action in the
|
r
⟩
{\displaystyle |r\rangle }
representation of changing r to −r, i.e.
⟨
r
|
P
|
ψ
⟩
=
ψ
(
−
r
)
{\displaystyle \langle r|P|\psi \rangle =\psi (-r)}
The eigenvalues of P can be shown to be limited to
±
1
{\displaystyle \pm 1}
, which are both degenerate eigenvalues in an infinite-dimensional state space. An eigenvector of P with eigenvalue +1 is said to be even, while that with eigenvalue −1 is said to be odd.
Now, an even operator
A
^
{\displaystyle {\hat {A}}}
is one that satisfies,
A
~
=
P
A
^
P
{\displaystyle {\tilde {A}}=P{\hat {A}}P}
[
P
,
A
^
]
=
0
{\displaystyle [P,{\hat {A}}]=0}
while an odd operator
B
^
{\displaystyle {\hat {B}}}
is one that satisfies
P
B
^
+
B
^
P
=
0
{\displaystyle P{\hat {B}}+{\hat {B}}P=0}
Since the square of the momentum operator
p
^
2
{\displaystyle {\hat {p}}^{2}}
is even, if the potential V(r) is even, the Hamiltonian
H
^
{\displaystyle {\hat {H}}}
is said to be an even operator. In that case, if each of its eigenvalues are non-degenerate, each eigenvector is necessarily an eigenstate of P, and therefore it is possible to look for the eigenstates of
H
^
{\displaystyle {\hat {H}}}
among even and odd states. However, if one of the energy eigenstates has no definite parity, it can be asserted that the corresponding eigenvalue is degenerate, and
P
|
ψ
⟩
{\displaystyle P|\psi \rangle }
is an eigenvector of
H
^
{\displaystyle {\hat {H}}}
with the same eigenvalue as
|
ψ
⟩
{\displaystyle |\psi \rangle }
.
== Degeneracy and symmetry ==
The physical origin of degeneracy in a quantum-mechanical system is often the presence of some symmetry in the system. Studying the symmetry of a quantum system can, in some cases, enable us to find the energy levels and degeneracies without solving the Schrödinger equation, hence reducing effort.
Mathematically, the relation of degeneracy with symmetry can be clarified as follows. Consider a symmetry operation associated with a unitary operator S. Under such an operation, the new Hamiltonian is related to the original Hamiltonian by a similarity transformation generated by the operator S, such that
H
′
=
S
H
S
−
1
=
S
H
S
†
{\displaystyle H'=SHS^{-1}=SHS^{\dagger }}
, since S is unitary. If the Hamiltonian remains unchanged under the transformation operation S, we have
S
H
S
†
=
H
S
H
S
−
1
=
H
S
H
=
H
S
[
S
,
H
]
=
0
{\displaystyle {\begin{aligned}SHS^{\dagger }&=H\\[1ex]SHS^{-1}&=H\\[1ex]SH&=HS\\[1ex][S,H]&=0\end{aligned}}}
Now, if
|
α
⟩
{\displaystyle |\alpha \rangle }
is an energy eigenstate,
H
|
α
⟩
=
E
|
α
⟩
{\displaystyle H|\alpha \rangle =E|\alpha \rangle }
where E is the corresponding energy eigenvalue.
H
S
|
α
⟩
=
S
H
|
α
⟩
=
S
E
|
α
⟩
=
E
S
|
α
⟩
{\displaystyle HS|\alpha \rangle =SH|\alpha \rangle =SE|\alpha \rangle =ES|\alpha \rangle }
which means that
S
|
α
⟩
{\displaystyle S|\alpha \rangle }
is also an energy eigenstate with the same eigenvalue E. If the two states
|
α
⟩
{\displaystyle |\alpha \rangle }
and
S
|
α
⟩
{\displaystyle S|\alpha \rangle }
are linearly independent (i.e. physically distinct), they are therefore degenerate.
In cases where S is characterized by a continuous parameter
ϵ
{\displaystyle \epsilon }
, all states of the form
S
(
ϵ
)
|
α
⟩
{\displaystyle S(\epsilon )|\alpha \rangle }
have the same energy eigenvalue.
=== Symmetry group of the Hamiltonian ===
The set of all operators which commute with the Hamiltonian of a quantum system are said to form the symmetry group of the Hamiltonian. The commutators of the generators of this group determine the algebra of the group. An n-dimensional representation of the Symmetry group preserves the multiplication table of the symmetry operators. The possible degeneracies of the Hamiltonian with a particular symmetry group are given by the dimensionalities of the irreducible representations of the group. The eigenfunctions corresponding to a n-fold degenerate eigenvalue form a basis for a n-dimensional irreducible representation of the Symmetry group of the Hamiltonian.
== Types of degeneracy ==
Degeneracies in a quantum system can be systematic or accidental in nature.
=== Systematic or essential degeneracy ===
This is also called a geometrical or normal degeneracy and arises due to the presence of some kind of symmetry in the system under consideration, i.e. the invariance of the Hamiltonian under a certain operation, as described above. The representation obtained from a normal degeneracy is irreducible and the corresponding eigenfunctions form a basis for this representation.
=== Accidental degeneracy ===
It is a type of degeneracy resulting from some special features of the system or the functional form of the potential under consideration, and is related possibly to a hidden dynamical symmetry in the system. It also results in conserved quantities, which are often not easy to identify. Accidental symmetries lead to these additional degeneracies in the discrete energy spectrum. An accidental degeneracy can be due to the fact that the group of the Hamiltonian is not complete. These degeneracies are connected to the existence of bound orbits in classical Physics.
==== Examples: Coulomb and Harmonic Oscillator potentials ====
For a particle in a central 1/r potential, the Laplace–Runge–Lenz vector is a conserved quantity resulting from an accidental degeneracy, in addition to the conservation of angular momentum due to rotational invariance.
For a particle moving on a cone under the influence of 1/r and r2 potentials, centred at the tip of the cone, the conserved quantities corresponding to accidental symmetry will be two components of an equivalent of the Runge-Lenz vector, in addition to one component of the angular momentum vector. These quantities generate SU(2) symmetry for both potentials.
==== Example: Particle in a constant magnetic field ====
A particle moving under the influence of a constant magnetic field, undergoing cyclotron motion on a circular orbit is another important example of an accidental symmetry. The symmetry multiplets in this case are the Landau levels which are infinitely degenerate.
== Examples ==
=== The hydrogen atom ===
In atomic physics, the bound states of an electron in a hydrogen atom show us useful examples of degeneracy. In this case, the Hamiltonian commutes with the total orbital angular momentum
L
^
2
{\displaystyle {\hat {L}}^{2}}
, its component along the z-direction,
L
^
z
{\displaystyle {\hat {L}}_{z}}
, total spin angular momentum
S
^
2
{\displaystyle {\hat {S}}^{2}}
and its z-component
S
^
z
{\displaystyle {\hat {S}}_{z}}
. The quantum numbers corresponding to these operators are
ℓ
{\displaystyle \ell }
,
m
ℓ
{\displaystyle m_{\ell }}
,
s
{\displaystyle s}
(always 1/2 for an electron) and
m
s
{\displaystyle m_{s}}
respectively.
The energy levels in the hydrogen atom depend only on the principal quantum number n. For a given n, all the states corresponding to
ℓ
=
0
,
…
,
n
−
1
{\displaystyle \ell =0,\ldots ,n-1}
have the same energy and are degenerate. Similarly for given values of n and ℓ, the
(
2
ℓ
+
1
)
{\displaystyle (2\ell +1)}
, states with
m
ℓ
=
−
ℓ
,
…
,
ℓ
{\displaystyle m_{\ell }=-\ell ,\ldots ,\ell }
are degenerate. The degree of degeneracy of the energy level En is therefore
∑
ℓ
=
0
n
−
1
(
2
ℓ
+
1
)
=
n
2
,
{\displaystyle \sum _{\ell \mathop {=} 0}^{n-1}(2\ell +1)=n^{2},}
which is doubled if the spin degeneracy is included.: 267f
The degeneracy with respect to
m
ℓ
{\displaystyle m_{\ell }}
is an essential degeneracy which is present for any central potential, and arises from the absence of a preferred spatial direction. The degeneracy with respect to
ℓ
{\displaystyle \ell }
is often described as an accidental degeneracy, but it can be explained in terms of special symmetries of the Schrödinger equation which are only valid for the hydrogen atom in which the potential energy is given by Coulomb's law.: 267f
=== Isotropic three-dimensional harmonic oscillator ===
It is a spinless particle of mass m moving in three-dimensional space, subject to a central force whose absolute value is proportional to the distance of the particle from the centre of force.
F
=
−
k
r
{\displaystyle F=-kr}
It is said to be isotropic since the potential
V
(
r
)
{\displaystyle V(r)}
acting on it is rotationally invariant, i.e.,
V
(
r
)
=
1
2
m
ω
2
r
2
{\displaystyle V(r)={\tfrac {1}{2}}m\omega ^{2}r^{2}}
where
ω
{\displaystyle \omega }
is the angular frequency given by
k
/
m
{\textstyle {\sqrt {k/m}}}
.
Since the state space of such a particle is the tensor product of the state spaces associated with the individual one-dimensional wave functions, the time-independent Schrödinger equation for such a system is given by-
−
ℏ
2
2
m
(
∂
2
ψ
∂
x
2
+
∂
2
ψ
∂
y
2
+
∂
2
ψ
∂
z
2
)
+
1
2
m
ω
2
(
x
2
+
y
2
+
z
2
)
ψ
=
E
ψ
{\displaystyle -{\frac {\hbar ^{2}}{2m}}\left({\frac {\partial ^{2}\psi }{\partial x^{2}}}+{\frac {\partial ^{2}\psi }{\partial y^{2}}}+{\frac {\partial ^{2}\psi }{\partial z^{2}}}\right)+{\frac {1}{2}}{m\omega ^{2}\left(x^{2}+y^{2}+z^{2}\right)\psi }=E\psi }
So, the energy eigenvalues are
E
n
x
,
n
y
,
n
z
=
(
n
x
+
n
y
+
n
z
+
3
2
)
ℏ
ω
{\displaystyle E_{n_{x},n_{y},n_{z}}=\left(n_{x}+n_{y}+n_{z}+{\tfrac {3}{2}}\right)\hbar \omega }
or,
E
n
=
(
n
+
3
2
)
ℏ
ω
{\displaystyle E_{n}=\left(n+{\tfrac {3}{2}}\right)\hbar \omega }
where n is a non-negative integer.
So, the energy levels are degenerate and the degree of degeneracy is equal to the number of different sets
{
n
x
,
n
y
,
n
z
}
{\displaystyle \{n_{x},n_{y},n_{z}\}}
satisfying
n
x
+
n
y
+
n
z
=
n
{\displaystyle n_{x}+n_{y}+n_{z}=n}
The degeneracy of the
n
{\displaystyle n}
-th state can be found by considering the distribution of
n
{\displaystyle n}
quanta across
n
x
{\displaystyle n_{x}}
,
n
y
{\displaystyle n_{y}}
and
n
z
{\displaystyle n_{z}}
. Having 0 in
n
x
{\displaystyle n_{x}}
gives
n
+
1
{\displaystyle n+1}
possibilities for distribution across
n
y
{\displaystyle n_{y}}
and
n
z
{\displaystyle n_{z}}
. Having 1 quanta in
n
x
{\displaystyle n_{x}}
gives
n
{\displaystyle n}
possibilities across
n
y
{\displaystyle n_{y}}
and
n
z
{\displaystyle n_{z}}
and so on. This leads to the general result of
n
−
n
x
+
1
{\displaystyle n-n_{x}+1}
and summing over all
n
{\displaystyle n}
leads to the degeneracy of the
n
{\displaystyle n}
-th state,
∑
n
x
=
0
n
(
n
−
n
x
+
1
)
=
(
n
+
1
)
(
n
+
2
)
2
{\displaystyle \sum _{n_{x}=0}^{n}(n-n_{x}+1)={\frac {(n+1)(n+2)}{2}}}
For the ground state
n
=
0
{\displaystyle n=0}
, the degeneracy is
1
{\displaystyle 1}
so the state is non-degenerate. For all higher states, the degeneracy is greater than 1 so the state is degenerate.
== Removing degeneracy ==
The degeneracy in a quantum mechanical system may be removed if the underlying symmetry is broken by an external perturbation. This causes splitting in the degenerate energy levels. This is essentially a splitting of the original irreducible representations into lower-dimensional such representations of the perturbed system.
Mathematically, the splitting due to the application of a small perturbation potential can be calculated using time-independent degenerate perturbation theory. This is an approximation scheme that can be applied to find the solution to the eigenvalue equation for the Hamiltonian H of a quantum system with an applied perturbation, given the solution for the Hamiltonian H0 for the unperturbed system. It involves expanding the eigenvalues and eigenkets of the Hamiltonian H in a perturbation series.
The degenerate eigenstates with a given energy eigenvalue form a vector subspace, but not every basis of eigenstates of this space is a good starting point for perturbation theory, because typically there would not be any eigenstates of the perturbed system near them. The correct basis to choose is one that diagonalizes the perturbation Hamiltonian within the degenerate subspace.
=== Physical examples of removal of degeneracy by a perturbation ===
Some important examples of physical situations where degenerate energy levels of a quantum system are split by the application of an external perturbation are given below.
=== Symmetry breaking in two-level systems ===
A two-level system essentially refers to a physical system having two states whose energies are close together and very different from those of the other states of the system. All calculations for such a system are performed on a two-dimensional subspace of the state space.
If the ground state of a physical system is two-fold degenerate, any coupling between the two corresponding states lowers the energy of the ground state of the system, and makes it more stable.
If
E
1
{\displaystyle E_{1}}
and
E
2
{\displaystyle E_{2}}
are the energy levels of the system, such that
E
1
=
E
2
=
E
{\displaystyle E_{1}=E_{2}=E}
, and the perturbation
W
{\displaystyle W}
is represented in the two-dimensional subspace as the following 2×2 matrix
W
=
[
0
W
12
W
12
∗
0
]
.
{\displaystyle \mathbf {W} ={\begin{bmatrix}0&W_{12}\\[1ex]W_{12}^{*}&0\end{bmatrix}}.}
then the perturbed energies are
E
+
=
E
+
|
W
12
|
E
−
=
E
−
|
W
12
|
{\displaystyle {\begin{aligned}E_{+}&=E+|W_{12}|\\E_{-}&=E-|W_{12}|\end{aligned}}}
Examples of two-state systems in which the degeneracy in energy states is broken by the presence of off-diagonal terms in the Hamiltonian resulting from an internal interaction due to an inherent property of the system include:
Benzene, with two possible dispositions of the three double bonds between neighbouring Carbon atoms.
Ammonia molecule, where the Nitrogen atom can be either above or below the plane defined by the three Hydrogen atoms.
H+2 molecule, in which the electron may be localized around either of the two nuclei.
=== Fine-structure splitting ===
The corrections to the Coulomb interaction between the electron and the proton in a Hydrogen atom due to relativistic motion and spin–orbit coupling result in breaking the degeneracy in energy levels for different values of l corresponding to a single principal quantum number n.
The perturbation Hamiltonian due to relativistic correction is given by
H
r
=
−
p
4
/
8
m
3
c
2
{\displaystyle H_{r}=-p^{4}/8m^{3}c^{2}}
where
p
{\displaystyle p}
is the momentum operator and
m
{\displaystyle m}
is the mass of the electron. The first-order relativistic energy correction in the
|
n
l
m
⟩
{\displaystyle |nlm\rangle }
basis is given by
E
r
=
(
−
1
/
8
m
3
c
2
)
⟨
n
ℓ
m
|
p
4
|
n
ℓ
m
⟩
{\displaystyle E_{r}=\left(-1/8m^{3}c^{2}\right)\left\langle n\ell m\right|p^{4}\left|n\ell m\right\rangle }
Now
p
4
=
4
m
2
(
H
0
+
e
2
/
r
)
2
{\displaystyle p^{4}=4m^{2}(H^{0}+e^{2}/r)^{2}}
E
r
=
−
1
2
m
c
2
[
E
n
2
+
2
E
n
e
2
⟨
1
r
⟩
+
e
4
⟨
1
r
2
⟩
]
=
−
1
2
m
c
2
α
4
[
−
3
/
(
4
n
4
)
+
1
/
n
3
(
ℓ
+
1
/
2
)
]
{\displaystyle {\begin{aligned}E_{r}&=-{\frac {1}{2mc^{2}}}\left[E_{n}^{2}+2E_{n}e^{2}\left\langle {\frac {1}{r}}\right\rangle +e^{4}\left\langle {\frac {1}{r^{2}}}\right\rangle \right]\\&=-{\frac {1}{2}}mc^{2}\alpha ^{4}\left[-3/(4n^{4})+1/{n^{3}(\ell +1/2)}\right]\end{aligned}}}
where
α
{\displaystyle \alpha }
is the fine structure constant.
The spin–orbit interaction refers to the interaction between the intrinsic magnetic moment of the electron with the magnetic field experienced by it due to the relative motion with the proton. The interaction Hamiltonian is
H
s
o
=
−
e
m
c
m
⋅
L
r
3
=
e
2
m
2
c
2
r
3
S
⋅
L
{\displaystyle H_{so}=-{\frac {e}{mc}}{\frac {\mathbf {m} \cdot \mathbf {L} }{r^{3}}}={\frac {e^{2}}{m^{2}c^{2}r^{3}}}\mathbf {S} \cdot \mathbf {L} }
which may be written as
H
s
o
=
e
2
4
m
2
c
2
r
3
[
J
2
−
L
2
−
S
2
]
{\displaystyle H_{so}={\frac {e^{2}}{4m^{2}c^{2}r^{3}}}\left[J^{2}-L^{2}-S^{2}\right]}
The first order energy correction in the
|
j
,
m
,
ℓ
,
1
/
2
⟩
{\displaystyle |j,m,\ell ,1/2\rangle }
basis where the perturbation Hamiltonian is diagonal, is given by
E
s
o
=
ℏ
2
e
2
4
m
2
c
2
j
(
j
+
1
)
−
ℓ
(
ℓ
+
1
)
−
3
4
a
0
3
n
3
ℓ
(
ℓ
+
1
2
)
(
ℓ
+
1
)
{\displaystyle E_{so}={\frac {\hbar ^{2}e^{2}}{4m^{2}c^{2}}}{\frac {j(j+1)-\ell (\ell +1)-{\frac {3}{4}}}{a_{0}^{3}n^{3}\ell (\ell +{\frac {1}{2}})(\ell +1)}}}
where
a
0
{\displaystyle a_{0}}
is the Bohr radius.
The total fine-structure energy shift is given by
E
f
s
=
−
m
c
2
α
4
2
n
3
[
1
/
(
j
+
1
/
2
)
−
3
/
4
n
]
{\displaystyle E_{fs}=-{\frac {mc^{2}\alpha ^{4}}{2n^{3}}}\left[1/(j+1/2)-3/4n\right]}
for
j
=
ℓ
±
1
2
{\textstyle j=\ell \pm {\tfrac {1}{2}}}
.
=== Zeeman effect ===
The splitting of the energy levels of an atom when placed in an external magnetic field because of the interaction of the magnetic moment
m
→
{\displaystyle {\vec {m}}}
of the atom with the applied field is known as the Zeeman effect.
Taking into consideration the orbital and spin angular momenta,
L
{\displaystyle \mathbf {L} }
and
S
{\displaystyle \mathbf {S} }
, respectively, of a single electron in the Hydrogen atom, the perturbation Hamiltonian is given by
V
^
=
−
(
m
ℓ
+
m
s
)
⋅
B
{\displaystyle {\hat {V}}=-(\mathbf {m} _{\ell }+\mathbf {m} _{s})\cdot \mathbf {B} }
where
m
ℓ
=
−
e
L
/
2
m
{\displaystyle \mathbf {m} _{\ell }=-e\mathbf {L} /2m}
and
m
s
=
−
e
S
/
m
{\displaystyle \mathbf {m} _{s}=-e\mathbf {S} /m}
.
Thus,
V
^
=
e
2
m
(
L
+
2
S
)
⋅
B
{\displaystyle {\hat {V}}={\frac {e}{2m}}(\mathbf {L} +2\mathbf {S} )\cdot \mathbf {B} }
Now, in case of the weak-field Zeeman effect, when the applied field is weak compared to the internal field, the spin–orbit coupling dominates and
L
{\textstyle \mathbf {L} }
and
S
{\textstyle \mathbf {S} }
are not separately conserved. The good quantum numbers are n, ℓ, j and mj, and in this basis, the first order energy correction can be shown to be given by
E
z
=
−
μ
B
g
j
B
m
j
,
{\displaystyle E_{z}=-\mu _{B}g_{j}Bm_{j},}
where
μ
B
=
e
ℏ
/
2
m
{\displaystyle \mu _{B}={e\hbar }/2m}
is called the Bohr Magneton. Thus, depending on the value of
m
j
{\displaystyle m_{j}}
, each degenerate energy level splits into several levels.
In case of the strong-field Zeeman effect, when the applied field is strong enough, so that the orbital and spin angular momenta decouple, the good quantum numbers are now n, l, ml, and ms. Here, Lz and Sz are conserved, so the perturbation Hamiltonian is given by-
V
^
=
e
B
(
L
z
+
2
S
z
)
/
2
m
{\displaystyle {\hat {V}}=eB(L_{z}+2S_{z})/2m}
assuming the magnetic field to be along the z-direction. So,
V
^
=
e
B
(
m
ℓ
+
2
m
s
)
/
2
m
{\displaystyle {\hat {V}}=eB(m_{\ell }+2m_{s})/2m}
For each value of mℓ, there are two possible values of ms,
±
1
/
2
{\displaystyle \pm 1/2}
.
=== Stark effect ===
The splitting of the energy levels of an atom or molecule when subjected to an external electric field is known as the Stark effect.
For the hydrogen atom, the perturbation Hamiltonian is
H
^
s
=
−
|
e
|
E
z
{\displaystyle {\hat {H}}_{s}=-|e|Ez}
if the electric field is chosen along the z-direction.
The energy corrections due to the applied field are given by the expectation value of
H
^
s
{\displaystyle {\hat {H}}_{s}}
in the
|
n
ℓ
m
⟩
{\displaystyle |n\ell m\rangle }
basis. It can be shown by the selection rules that
⟨
n
ℓ
m
ℓ
|
z
|
n
1
ℓ
1
m
ℓ
1
⟩
≠
0
{\displaystyle \langle n\ell m_{\ell }|z|n_{1}\ell _{1}m_{\ell 1}\rangle \neq 0}
when
ℓ
=
ℓ
1
±
1
{\displaystyle \ell =\ell _{1}\pm 1}
and
m
ℓ
=
m
ℓ
1
{\displaystyle m_{\ell }=m_{\ell 1}}
.
The degeneracy is lifted only for certain states obeying the selection rules, in the first order. The first-order splitting in the energy levels for the degenerate states
|
2
,
0
,
0
⟩
{\displaystyle |2,0,0\rangle }
and
|
2
,
1
,
0
⟩
{\displaystyle |2,1,0\rangle }
, both corresponding to n = 2, is given by
Δ
E
2
,
1
,
m
ℓ
=
±
|
e
|
ℏ
2
/
(
m
e
e
2
)
E
{\displaystyle \Delta E_{2,1,m_{\ell }}=\pm |e|\hbar ^{2}/(m_{e}e^{2})E}
.
== See also ==
Density of states
== References ==
== Further reading ==
Cohen-Tannoudji, Claude; Diu, Bernard; Laloë, Franck. Quantum Mechanics. Vol. 1. Hermann. ISBN 978-2-7056-8392-4.
Shankar, Ramamurti (2013). Principles of Quantum Mechanics. Springer. ISBN 978-1-4615-7675-4.
Larson, Ron; Falvo, David C. (30 March 2009). Elementary Linear Algebra, Enhanced Edition. Cengage Learning. pp. 8–. ISBN 978-1-305-17240-1.
Hobson; Riley (27 August 2004). Mathematical Methods For Physics And Engineering (Clpe) 2Ed. Cambridge University Press. ISBN 978-0-521-61296-8.
Hemmer (2005). Kvantemekanikk: P.C. Hemmer. Tapir akademisk forlag. Tillegg 3: supplement to sections 3.1, 3.3, and 3.5. ISBN 978-82-519-2028-5.
Quantum degeneracy in two dimensional systems, Debnarayan Jana, Dept. of Physics, University College of Science and Technology
Al-Hashimi, Munir (2008). Accidental Symmetry in Quantum Physics. | Wikipedia/Degenerate_orbital |
Inverted ligand field theory (ILFT) describes a phenomenon in the bonding of coordination complexes where the lowest unoccupied molecular orbital is primarily of ligand character. This is contrary to the traditional ligand field theory or crystal field theory picture and arises from the breaking down of the assumption that in organometallic complexes, ligands are more electronegative and have frontier orbitals below those of the d orbitals of electropositive metals. Towards the right of the d-block, when approaching the transition-metal–main group boundary, the d orbitals become more core-like, making their cations more electronegative. This decreases their energies and eventually arrives at a point where they are lower in energy than the ligand frontier orbitals. Here the ligand field inverts so that the bonding orbitals are more metal-based, and antibonding orbitals more ligand-based. The relative arrangement of the d orbitals are also inverted in complexes displaying this inverted ligand field.
== History ==
The first example of an inverted ligand field was demonstrated in paper form 1995 by James Snyder. In this theoretical paper, Snyder proposed that the [Cu(CF3)4]− complexes reported by Naumann et al. and assigned a formal oxidation state of +3 at the copper would be better thought of as Cu(I). By comparing the d-orbital occupation, calculated charges and orbital population of [Cu(CF3)4]− "Cu(III)" complex and the formally Cu(I) [Cu(CH3)2]− complex, they illustrated how the former could be better described as a d10 copper complex experiencing two electron donation from the CF−3 ligands. The phenomenon, termed an inverted ligand field by Roald Hoffman, began to be described by Aullón and Alvarez as they identified this phenonmenon as being a result of relative electronegativities. Lancaster and co-workers later provided experimental evidence to support the assignment of this oxidation state. Using UV/visible/near IR spectroscopy, Cu K-edge X-ray absorption spectroscopy, and 1s2p resonant inelastic X-ray scattering in concert with density functional theory, multiplet theory, and multireference calculations, they were able to map the ground state electronic configuration. This showed that the lowest unoccupied orbital was of primarily trifluoromethyl character. This confirmed the presence of an inverted ligand field and started building experimental tools to probe this phenomenon. Since the Snyder case, many other complexes of later transition metals have been shown to display inverted ligand field through both theoretical and experimental methods.
== Probing inverted ligand fields ==
Computational and experimental techniques have been imperative for the study of inverted ligand fields, especially when used in cooperatively.
=== Computational ===
Computational methods have played a large role in understanding the nature of bonding in both molecular and solid-state systems displaying inverted ligand fields. The Hoffman group has completed many calculations to probe occurrence of inverted ligand fields in varying systems. In a study of the absorption of CO on PtBi and PtBi2 surfaces, on an octahedral [Pt(BiH3)6]4+ model with a Pt thought of having a formal +4 oxidation state, the team found that the t2g metal orbitals were higher energy that the eg orbitals. This inversion of the d orbital ordering was attributed to the bismuth based ligands being higher in energy than the metal d orbitals. In another study involving calculations on Ag(III) salt KAgF4, other Ag(II), and Ag(III) compounds, the Ag d orbitals were found to be below those of the fluoride ligand orbitals, and was confirmed by Grochala and cowrokers by core and valence spectroscopies.
The Mealli group developed the program Computer Aided Composition of Atomic Orbitals (CACAO) to provide visualised molecular orbitals analyses based on perturbation theory principles. This program successfully displayed orbital energy inversion with organometallic complexes containing electronegative metals such as Ni or Cu bound to electropositive ligand atoms such as B, Si, or Sn. In these cases the bonding was described as a ligand to metal dative bond or sigma backdonation.
Alvarez and coworkers used computational methods to illustrate ligand field inversion in the band structures of solid state materials. The group found that, contrary to the classical bonding scheme, in calculated MoNiP8 band structures the eg-type orbitals of the octahedral nickel atom were found to be the major component of an occupied band below the t2g set. Additionally, the band around the fermi level which included the Ni+ antibonding orbitals were found to be mostly of phosphorus character, a clear example if an inverted ligand field. Similar observations were made in other solid state materials like the skutterudite CoP3 structure. A consequence of the inverted ligand field in this case is that the conductivity in skutterudites is associated with the phosphorus rings rather than the metal atoms.
=== Experimental ===
X-ray absorption spectroscopy (XAS) has been a powerful tool in deducing the oxidation states of transition metals. Energy shifts in XAS are higher due to the higher effective nuclear charge of atoms in higher oxidations, presumably due to the higher binding energy for deeper, more core-like electrons.
Despite this being a very powerful technique, competing effects on the rising edge positions can make assignment difficult. It was initially thought that the weak, quadrupole-allowed pre-edge peak assigned as the Cu 1s to 3d transition could be used to distinguish between Cu(II) and Cu(III) with the features appearing at 8979 ±0.3 eV and 8981 ±0.5 eV, respectively. Ab initio calculations by Tomson, Wieghardt, and co-workers displayed that pre-peaks previously assigned as Cu(III) could be displayed by Cu(II) bearing complexes. Many groups have displayed that metal K-edge XAS transitions involving ligand-localised acceptor orbitals, as well as spectral shifts from change in coordination environment, can make metal K-edge analysis less predictable.
The most successful use of K and L-edge XAS provide valuable information on the composition of molecular orbitals and display inverted ligand fields has been done in studies that made use of computational techniques in concert with experimental techniques. This was the case of the L2[Cu2(S2)n]2+ complexes of York, Brown, and Tolman, and the Cu(CF3)4− by various groups including Hoffman, Overgaard, and Lancaster.
Another experimental tool used to probe ligand field inversion includes Electron paramagnetic resonance (ESR/EPR), which can provide information regarding the metal electronic configuration, the nature of the SOMO, and high resolution information on the ligands.
== Impact of charge and geometry ==
Changes in both charge and geometry of organometallic complexes can greatly vary the energies of molecular orbitals and can therefore dictate the likelihood of observing an inverted ligand field. Hoffman and coworkers explored the impact of these variables by calculating the atomic composition of molecular orbitals for mono- di- and trianion copper complexes. The square planar monoanion displayed the reported ligand field inversion. The "Cu(II)" which has an intermediate square planar to tetrahedral geometry also displayed this feature with the antibonding t2-derived orbital being mostly of ligand character and the x2-y2 orbital being the lowest molecular orbital of the d block. The tetrahedral trianion showed a return to the Werner-type ligand field. By modulating the geometry of the "Cu(II)" species and displaying the change in energies of MO on walsh diagrams, the group was able to show how the complex could display both a classical and inverted ligand field when in Td and SP geometry respectively. Additional calculations on the Cu(I) with non-tetrahedral geometry also displayed an inverted ligand field. This indicated the importance of not just oxidation state but geometry in determining the inversion of a ligand field.
== Consequences on bonding ==
The inversion of ligand fields has interesting implications on the nature of reactivity of organometallic complexes. This sigma non-innocence of ligands arising from inverted ligand fields could therefore be used to tune reactivity of complexes and open space in understanding the mechanisms of existing reactions.
In an analysis of the [ZnF4]2− , it was found that due to ligand field inversion displayed in this species, core ionization removes an electron from the metal-rich bonding t2 orbital, lengthening the Zn–F bonds. This is contrary to the classical ligand field where ionization would remove an electron from the antibonding t2 orbital shortening the Zn–F bonds.
The presence of electron-deficient ligands also result in an inverted ligand field. Calculations have shown that the large O 2p contribution into the LUMO/LUMO+1 in [(LTEEDCu)2(O2)]2+ should make the complex highly oxidizing as it contains electron deficient O2− ligands. Studies have corroborated this property as this complex has shown to be able to undergo C–H and C–F activation and aromatic hydroxylation.
There is evidence showing that reductive elimination on species displaying ligand field inversion do not undergo a redox event at the metal center. The C-CF3 bond formation by "Ni(IV)" complexes was completed without redox participation of the Nickel. The metal appears to remain Ni(II) throughout the reaction. The mechanism is thought to be through the attack of a masked electrophilic cation by anionic CF3. The electron deficiency here is due to the inverted ligand field.
== References == | Wikipedia/Inverted_ligand_field_theory |
The Dewar–Chatt–Duncanson model is a model in organometallic chemistry that explains the chemical bonding in transition metal alkene complexes. The model is named after Michael J. S. Dewar, Joseph Chatt and L. A. Duncanson.
The alkene donates electron density into a π-acid metal d-orbital from a σ-symmetry bonding orbital between the carbon atoms. The metal donates electrons back from a (different) filled d-orbital into the empty π* antibonding orbital. Both of these effects tend to reduce the carbon-carbon bond order, leading to an elongated C−C distance and a lowering of its vibrational frequency.
In Zeise's salt K[PtCl3(C2H4)].H2O the C−C bond length has increased to 134 picometres from 133 pm for ethylene. In the nickel compound Ni(C2H4)(PPh3)2 the value is 143 pm.
The interaction also causes carbon atoms to "rehybridise" from sp2 towards sp3, which is indicated by the bending of the hydrogen atoms on the ethylene back away from the metal. In silico calculations show that 75% of the binding energy is derived from the forward donation and 25% from backdonation. This model is a specific manifestation of the more general π backbonding model.
Similar to alkenes, alkynes adopt a similar bonding interaction, as shown in the image on the right. Not all alkyne-metal complexes utilize all four of these interactions for bonding (due to reasons like unviable d orbitals).
Main group elements can also form π-complexes with alkenes and alkynes. The β-diketiminato aluminum(I) complex Al{HC(CMeNAr)2} (Ar = 2,6-diisopropylphenyl), which bears an Al-based spx lone pair, reacts with alkenes and alkynes to give alumina(III)cyclopropanes and alumina(III)cyclopropenes in a process analogous to the formation of π-complexes by transition metals. However, in most cases, the backbonding interaction is absent in these complexes due to the lack of energetically accessible filled orbitals for backdonation, resulting in π-complexes that dissociate readily and are therefore more challenging to observe or isolate.
== References == | Wikipedia/Dewar–Chatt–Duncanson_model |
Ammonium tetrachloroaurate is an inorganic chemical compound with the chemical formula NH4AuCl4.
== Synthesis ==
Ammonium tetrachloroaurate can be obtained by reacting a saturated solution of gold(III) chloride with ammonium chloride in hydrochloric acid.
== Physical properties ==
The compound is slightly soluble in water and ethanol. It forms hydrates.
Ammonium tetrachloroaurate forms orange-yellow crystals. The hydrate has a monoclinic crystal structure with the space group C 2/ c (space group no. 15).
Ammonium tetrachloroaurate decomposes in air at temperatures from 230 to 350 °C . The decomposition reaction is endothermic.
== Uses ==
The hydrate is used to prepare Pd-Au alloy films.
Ammonium tetrachloroaurate can be used to produce gold nanoparticles.
== References == | Wikipedia/Ammonium_tetrachloroaurate |
Guanidine nitrate is the chemical compound with the formula [C(NH2)3]NO3. It is a colorless, water-soluble salt. It is produced on a large scale and finds use as precursor for nitroguanidine, fuel in pyrotechnics and gas generators. Its correct name is guanidinium nitrate, but the colloquial term guanidine nitrate is widely used.
== Production and properties ==
Although it is the salt formed by neutralizing guanidine with nitric acid, guanidine nitrate is produced industrially by the reaction of dicyandiamide (or calcium salt) and ammonium nitrate.
It has been used as a monopropellant in the Jetex engine for model airplanes. It is attractive because it has a high gas output and low flame temperature. It has a relatively high monopropellant specific impulse of 177 seconds (1.7 kN·s/kg).
Guanidine nitrate's explosive decomposition is given by the following equation:
[C(NH2)3]NO3 (s) → 3 H2O (g) + 2 N2 (g) + C (s)
== Uses ==
Guanidine nitrate is used as the gas generator in automobile airbags. It is less toxic than the mixture used in older airbags of sodium azide, potassium nitrate and silica (NaN3, KNO3, and SiO2), and it is less explosive and sensitive to moisture compared to the very cheap ammonium nitrate (NH4NO3).
== Safety ==
The compound is a hazardous substance, being an explosive and containing an oxidant (nitrate). It is also harmful to the eyes, skin, and respiratory tract.
== Notes ==
== External links ==
Jetex: Propellants
PhysChem: Guanidine Nitrate Archived 2004-05-05 at the Wayback Machine MSDS | Wikipedia/Guanidine_nitrate |
Ammonium perchlorate ("AP") is an inorganic compound with the formula NH4ClO4. It is a colorless or white solid that is soluble in water. It is a powerful oxidizer. Combined with a fuel, it can be used as a rocket propellant called ammonium perchlorate composite propellant. Its instability has involved it in accidents such as the PEPCON disaster.
== Production ==
Ammonium perchlorate (AP) is produced by reaction between ammonia and perchloric acid. This process is the main outlet for the industrial production of perchloric acid. The salt also can be produced by salt metathesis reaction of ammonium salts with sodium perchlorate. This process exploits the relatively low solubility of NH4ClO4, which is about 10% of that for sodium perchlorate.
AP crystallises as colorless rhombohedra.
== Decomposition ==
Like most ammonium salts, ammonium perchlorate decomposes before melting. Mild heating results in production of hydrogen chloride, nitrogen, oxygen, and water.
4 NH4ClO4 → 4 HCl + 2 N2 + 5 O2 + 6 H2O
The combustion of AP is quite complex and is widely studied. AP crystals decompose before melting, even though a thin liquid layer has been observed on crystal surfaces during high-pressure combustion processes. Strong heating may lead to explosions. Complete reactions leave no residue. Pure crystals cannot sustain a flame below the pressure of 2 MPa.
AP is a Class 4 oxidizer (can undergo an explosive reaction) for particle sizes over 15 micrometres and is classified as an explosive for particle sizes less than 15 micrometres.
== Applications ==
During World War I England and France used mixtures featuring ammonium perchlorate (such as "balstine") as a substitute high explosive.
The primary use of ammonium perchlorate is in making solid rocket propellants. When AP is mixed with a fuel (like a powdered aluminium and/or with an elastomeric binder), it can generate self-sustained combustion at pressures far below atmospheric pressure. It is an important oxidizer with a decades-long history of use in solid rocket propellants – space launch (including the Space Shuttle Solid Rocket Booster), military, amateur, and hobby high-power rockets, as well as in some fireworks.
Some "breakable" epoxy adhesives contain suspensions of AP. Upon heating to 300°C, the AP degrades the organic adhesive, breaking the cemented joint.
== Toxicity ==
Perchlorate itself confers little acute toxicity. For example, sodium perchlorate has an LD50 of 2–4g/kg and is eliminated rapidly after ingestion. However, chronic exposure to perchlorates, even in low concentrations, has been shown to cause various thyroid problems, as it is taken up in place of iodine.
== References ==
== Further reading ==
Schmidt, Eckart W. (2022). "Perchlorate Oxidizers". Encyclopedia of Oxidizers. De Gruyter. pp. 3383–3880. doi:10.1515/9783110750294-028. ISBN 978-3-11-075029-4. | Wikipedia/Ammonium_perchlorate |
Ammonium chlorate is an inorganic compound with the formula NH4ClO3.
It is obtained by neutralizing chloric acid with either ammonia or ammonium carbonate, or by precipitating barium, strontium or calcium chlorates with ammonium carbonate or ammonium sulfate, producing the respective carbonate or sulfate precipitate and an ammonium chlorate solution. Ammonium chlorate crystallizes in small needles, readily soluble in water.
The bitartrate method is a candidate for production and can be used if exotic chlorates are currently inaccessible or need to be synthesized. Warm solutions of potassium chlorate and ammonium bitartrate are needed. The latter can be synthesized by adding aqueous ammonia to an excess of tartaric acid. Then, a double displacement reaction will result in precipitation of ammonium chlorate.
On heating, ammonium chlorate decomposes at about 102 °C, with liberation of nitrogen, chlorine and oxygen. It is soluble in dilute aqueous alcohol, but insoluble in strong alcohol. This compound is a powerful oxidizer and should never be stored with flammable materials, as it can easily form sensitive explosive compositions.
Ammonium chlorate is a very unstable oxidizer and will decompose independently, sometimes violently, at room temperature. This results from the mixture of the reducing ammonium cation and the oxidizing chlorate anion. Even solutions are known to be unstable. Because of the dangerous nature of this salt it should only be kept in solution when needed, and never be allowed to crystallize.
== Preparation ==
Ammonium chlorate can be made by mixing stoichiometric solutions of ammonium nitrate and sodium chlorate or ammonium sulfate and barium chlorate.
== References == | Wikipedia/Ammonium_chlorate |
Ammonium laurate is a chemical compound with the chemical formula NH4C6H7O6.This is an organic ammonium salt of lauric acid.
== Synthesis ==
Ammonium laurate can be prepared by mixing dry ammonia with an aquous solution of pure lauric acid. This industrial method requires introducing ammonia gas into a lauric acid solution dissolved in a non-water-based solvent. The process is conducted under carefully regulated temperature and pressure parameters to maximize both the quantity and quality of the resulting product.
Also, ammonium laurate can be obtained by reacting lauric acid with ammonium hydroxide. This process generally begins with dissolving lauric acid in a solvent like ethanol, followed by the addition of ammonium hydroxide to the mixture.
== Physical properties ==
The compound typically appears as a white to off-white solid or powder. It is soluble in water, making it useful in various applications.
The substance is harmful when inhaled, ingested, or put in contact with the skin. It can cause skin irritation and eye damage. It can emit harmful fumes under fire conditions.
== Uses ==
The compound is used as a surfactant, wetting agent, emulsifier with foaming properties.
Also, ammonium laurate is used in the extraction and recovery of polyhydroxyalkanoates (PHAs), biodegradable polymers produced by various microorganisms.
== References == | Wikipedia/Ammonium_laurate |
Potassium chlorate is the inorganic compound with the molecular formula KClO3. In its pure form, it is a white solid. After sodium chlorate, it is the second most common chlorate in industrial use. It is a strong oxidizing agent and its most important application is in safety matches. In other applications it is mostly obsolete and has been replaced by safer alternatives in recent decades. It has been used
in fireworks, propellants and explosives,
to prepare oxygen, both in the lab and in chemical oxygen generators,
as a disinfectant, for example in dentifrices and medical mouthwashes,
in agriculture as an herbicide.
== Production ==
On the industrial scale, potassium chlorate is produced by the salt metathesis reaction of sodium chlorate and potassium chloride:
NaClO3 + KCl → NaCl + KClO3
The reaction is driven by the low solubility of potassium chlorate in water. The equilibrium of the reaction is shifted to the right hand side by the continuous precipitation of the product (Le Chatelier's Principle). The precursor sodium chlorate is produced industrially in very large quantities by electrolysis of sodium chloride, common table salt.
The direct electrolysis of KCl in aqueous solution is also used sometimes, in which elemental chlorine formed at the anode reacts with KOH in situ. The low solubility of KClO3 in water causes the salt to conveniently isolate itself from the reaction mixture by simply precipitating out of solution.
Potassium chlorate can be produced in small amounts by disproportionation in a sodium hypochlorite solution followed by metathesis reaction with potassium chloride:
3 NaOCl → 2 NaCl + NaClO3
KCl + NaClO3 → NaCl + KClO3
It can also be produced by passing chlorine gas into a hot solution of caustic potash:
3 Cl2 + 6 KOH → KClO3 + 5 KCl + 3 H2O
as seen in this video
According to X-ray crystallography, potassium chlorate is a dense salt-like structure consisting of chlorate and potassium ions in close association.
== Uses ==
Potassium chlorate was one key ingredient in early firearms percussion caps (primers). It continues in that application, where not supplanted by potassium perchlorate.
Chlorate-based propellants are more efficient than traditional gunpowder and are less susceptible to damage by water. However, they can be extremely unstable in the presence of sulfur or phosphorus and are much more expensive. Chlorate propellants must be used only in equipment designed for them; failure to follow this precaution is a common source of accidents. Potassium chlorate, often in combination with silver fulminate, is used in trick noise-makers known as "crackers", "snappers", "pop-its", "caps" or "bang-snaps", a popular type of novelty firework.
Another application of potassium chlorate is as the oxidizer in a smoke composition such as that used in smoke grenades. Since 2005, a cartridge with potassium chlorate mixed with lactose and rosin is used for generating the white smoke signaling the election of new pope by a papal conclave.
High school and college laboratories often use potassium chlorate to generate oxygen gas. It is a far cheaper source than a pressurized or cryogenic oxygen tank. Potassium chlorate readily decomposes if heated while in contact with a catalyst, typically manganese(IV) dioxide (MnO2). Thus, it may be simply placed in a test tube and heated over a burner. If the test tube is equipped with a one-holed stopper and hose, warm oxygen can be drawn off. The reaction is as follows:
2 KClO3(s) + MnO2(cat) → 3 O2(g) + 2 KCl(s)
Heating it in the absence of a catalyst converts it into potassium perchlorate:
4 KClO3 → 3 KClO4 + KCl
With further heating, potassium perchlorate decomposes to potassium chloride and oxygen:
KClO4 → KCl + 2 O2
The safe performance of this reaction requires very pure reagents and careful temperature control. Molten potassium chlorate is an extremely powerful oxidizer and spontaneously reacts with many common materials such as sugar. Explosions have resulted from liquid chlorates spattering into the latex or PVC tubes of oxygen generators and from contact between chlorates and hydrocarbon sealing greases. Impurities in potassium chlorate itself can also cause problems. When working with a new batch of potassium chlorate, it is advisable to take a small sample (~1 gram) and heat it strongly on an open glass plate. Contamination may cause this small quantity to explode, indicating that the chlorate should be discarded.
Potassium chlorate is used in chemical oxygen generators (also called chlorate candles or oxygen candles), employed as oxygen-supply systems of e.g. aircraft, space stations, and submarines, and has been responsible for at least one plane crash. A fire on the space station Mir was traced to oxygen generation candles that use a similar lithium perchlorate. The decomposition of potassium chlorate was also used to provide the oxygen supply for limelights.
Potassium chlorate is used also as a pesticide. In Finland it was sold under trade name Fegabit.
Potassium chlorate can react with sulfuric acid to form a highly reactive solution of chloric acid and potassium sulfate:
2 KClO3 + H2SO4 → 2 HClO3 + K2SO4
The solution so produced is sufficiently reactive that it spontaneously ignites if combustible material (sugar, paper, etc.) is present.
In schools, molten potassium chlorate is used in screaming jelly babies, Gummy bear, Haribo, and Trolli candy demonstration where the candy is dropped into the molten salt.
In chemical labs it is used to oxidize HCl and release small amounts of gaseous chlorine.
Militant groups in Afghanistan also use potassium chlorate extensively as a key component in the production of improvised explosive devices (IEDs). When significant effort was made to reduce the availability of ammonium nitrate fertilizer in Afghanistan, IED makers started using potassium chlorate as a cheap and effective alternative. In 2013, 60% of IEDs in Afghanistan used potassium chlorate, making it the most common ingredient used in IEDs.
Potassium chlorate was also the main ingredient in the car bomb used in the 2002 Bali bombings that killed 202 people.
Potassium chlorate is used to force the blossoming stage of the longan tree, causing it to produce fruit in warmer climates.
== Safety ==
Potassium chlorate should be handled with care. It reacts vigorously, and in some cases spontaneously ignites or explodes, when mixed with many combustible materials. It burns vigorously in combination with virtually any combustible material, even those normally only slightly flammable (including ordinary dust and lint). Mixtures of potassium chlorate and a fuel can ignite by contact with sulfuric acid, so it should be kept away from this reagent.
Sulfur should be avoided in pyrotechnic compositions containing potassium chlorate, as these mixtures are prone to spontaneous deflagration. Most sulfur contains trace quantities of sulfur-containing acids, and these can cause spontaneous ignition - "Flowers of sulfur" or "sublimed sulfur", despite the overall high purity, contains significant amounts of sulfur acids. Also, mixtures of potassium chlorate with any compound with ignition promoting properties, such as antimony(III) sulfide, are very dangerous to prepare, as they are extremely shock sensitive.
== See also ==
Chloric acid
== References ==
"Chlorate de potassium. Chlorate de sodium", Fiche toxicol. n° 217, Paris:Institut national de recherche et de sécurité, 2000. 4pp.
Continuous process for the manufacture of potassium chlorate by coupling with a sodium chlorate production plant
== External links == | Wikipedia/Potassium_chlorate |
Ammonium valerate is a chemical compound with the chemical formula CH3(CH2)3COONH4. This is an organic ammonium salt of valeric acid.
== Synthesis ==
Ammonium valerate can be prepared by reacting valeric acid and ammonium hydroxide.
== Physical properties ==
Ammonium valerate is very readily soluble in water and alcohol, and also soluble in ether.
It has the characteristic odor of valeric acid and a sharp, sweetish taste.
== Uses ==
Ammonium valerate is used as a flavoring agent in the food industry and as a reagent in chemical synthesis.
In the past it was used as a sedative with calming properties against nervous disorders.
== References == | Wikipedia/Ammonium_valerate |
Methylammonium nitrate is an explosive chemical with the molecular formula CH6N2O3, alternately CH3NH3+NO3−. It is the salt formed by the neutralization of methylamine with nitric acid. This substance is also known as methylamine nitrate and monomethylamine nitrate, not to be confused with methyl nitramine or monomethyl nitramine.
Methylammonium nitrate was first used as an explosive ingredient by the Germans during World War II. It was originally called mono-methylamine nitrate, a name that has largely stuck among chemists who formulate energetic materials.
Methylammonium nitrate is somewhat similar in explosive properties to ammonium nitrate (AN) which yields 85% of the power of nitroglycerine when the ammonium nitrate is incorporated into an explosive. The addition of the carbon-containing methyl group in methylammonium nitrate imparts better explosive properties and helps create a more favorable oxygen balance.
After World War II, methylammonium nitrate was largely ignored by explosives manufacturers, in favor of less-costly ammonium nitrate. Ammonium nitrate-fuel oil mixtures (ANFO) were sufficient for most large-diameter explosives uses.
Methylammonium nitrate saw a resurgence when E. I. du Pont de Nemours and Company (DuPont), seeking to lower the cost of its TNT-based Tovex water-gel explosives, incorporated a mixture of methylammonium nitrate with ammonium nitrate which served as a basis for DuPont's water-gels manufactured under the names "Tovex Extra" and "Pourvex Extra". Methylammonium nitrate, also known as PR-M (which stands for "Potomac River—Mono-methylamine nitrate") soon was seen as the possible path toward creating a low-cost blasting agent (water gel explosives) that might replace the explosives based on nitroglycerin (dynamites).
In late 1973, DuPont started to phase out dynamite and replace it with water-gels based on PR-M. However, PR-M proved to have unusual "mass effects". That is, if there was sufficient mass, under certain conditions, PR-M could explode without warning. On August 6, 1974, a tank car containing PR-M blew up in Wenatchee, Washington, rail yard, killing two and injuring 66 others. On July 4, 1976, a PR-M storage with 60,000 pounds (approximately 27,200Kg) of PR-M detonated at DuPont's Potomac River Works at Martinsburg, WV. Though there was no loss of life, there were many injuries and a substantial loss of property.
== References ==
== External links ==
Crystal structure of monomethylammonium nitrate
methyl ammonium nitrate (PRM) accidental detonation | Wikipedia/Methylammonium_nitrate |
Ceric ammonium nitrate (CAN) is the inorganic compound with the formula (NH4)2[Ce(NO3)6]. This orange-red, water-soluble cerium salt is a specialised oxidizing agent in organic synthesis and a standard oxidant in quantitative analysis.
== Preparation, properties, and structure ==
The anion [Ce(NO3)6]2− is generated by dissolving Ce2O3 in hot and concentrated nitric acid (HNO3).
The salt consists of the hexanitratocerate(IV) anion [Ce(NO3)6]2− and a pair of ammonium cations NH+4. The ammonium ions are not involved in the oxidising reactions of this salt. In the anion each nitrate group chelates the cerium atom in a bidentate manner as shown below:
The anion [Ce(NO3)6]2− has Th (idealized Oh) molecular symmetry. The CeO12 core defines an icosahedron.
Ce4+ is a strong one-electron oxidizing agent. In terms of its redox potential (E° ≈ 1.61 V vs. N.H.E.) it is an even stronger oxidizing agent than Cl2 (E° ≈ 1.36 V). Few shelf-stable reagents are stronger oxidants. In the redox process Ce(IV) is converted to Ce(III), a one-electron change, signaled by the fading of the solution color from orange to a pale yellow (providing that the substrate and product are not strongly colored).
== Applications in organic chemistry ==
In organic synthesis, CAN is useful as an oxidant for many functional groups (alcohols, phenols, and ethers) as well as C–H bonds, especially those that are benzylic. Alkenes undergo dinitroxylation, although the outcome is solvent-dependent. Quinones are produced from catechols and hydroquinones and even nitroalkanes are oxidized.
CAN provides an alternative to the Nef reaction; for example, for ketomacrolide synthesis where complicating side reactions usually encountered using other reagents. Oxidative halogenation can be promoted by CAN as an in situ oxidant for benzylic bromination, and the iodination of ketones and uracil derivatives.
=== For the synthesis of heterocycles ===
Catalytic amounts of aqueous CAN allow the efficient synthesis of quinoxaline derivatives. Quinoxalines are known for their applications as dyes, organic semiconductors, and DNA cleaving agents. These derivatives are also components in antibiotics such as echinomycin and actinomycin. The CAN-catalyzed three-component reaction between anilines and alkyl vinyl ethers provides an efficient entry into 2-methyl-1,2,3,4-tetrahydroquinolines and the corresponding quinolines obtained by their aromatization.
=== As a deprotection reagent ===
CAN is traditionally used to release organic ligands from metal carbonyls. In the process, the metal is oxidised, CO is evolved, and the organic ligand is released for further manipulation. For example, with the Wulff–Dötz reaction an alkyne, carbon monoxide, and a chromium carbene are combined to form a chromium half-sandwich complex and the phenol ligand can be isolated by mild CAN oxidation.
CAN is used to cleave para-methoxybenzyl and 3,4-dimethoxybenzyl ethers, which are protecting groups for alcohols. Two equivalents of CAN are required for each equivalent of para-methoxybenzyl ether. The alcohol is released, and the para-methoxybenzyl ether converts to para-methoxybenzaldehyde. The balanced equation is as follows:
2 [NH4]2[Ce(NO3)6] + H3COC6H4CH2OR + H2O → 4 NH+4 + 2 Ce3+ + 12 NO−3 + 2 H+ + H3COC6H4CHO + HOR
== Other applications ==
CAN is also a component of chrome etchant, a material that is used in the production of photomasks and liquid crystal displays. It is also an effective nitration reagent, especially for the nitration of aromatic ring systems. In acetonitrile, CAN reacts with anisole to obtain ortho-nitration products.
== References ==
== External links ==
Oxidizing Agents: Cerium Ammonium Nitrate | Wikipedia/Ceric_ammonium_nitrate |
Ammonium butyrate is a chemical compound with the chemical formula C3H7COONH4. This is an organic ammonium salt of butyric acid.
== Synthesis ==
The compound can be prepared by reacting dry ammonia gas with butyric acid in ether:
NH3 + C3H7COOH → C3H7COONH4↓
== Chemical properties ==
It can react with ammonia to form an ammine compound C3H7COONH4·xNH3 at low temperatures.
Heating ammonium butyrate with phosphorus pentoxide produces butyronitrile C3H7CN.
== Uses ==
The compound is used as an emulsifying agent for leather, oils, soaps, and for textile finishing.
Also, it can be used as a mineralizer for growing calcite single crystals.
== References == | Wikipedia/Ammonium_butyrate |
Hydroxylammonium nitrate or hydroxylamine nitrate (HAN) is an inorganic compound with the chemical formula [NH3OH]+[NO3]−. It is a salt derived from hydroxylamine and nitric acid. In its pure form, it is a colourless hygroscopic solid. It has potential to be used as a rocket propellant either as a solution in monopropellants or bipropellants. Hydroxylammonium nitrate (HAN)-based propellants are a viable and effective solution for future "green" propellant-based missions, as it offers 50% higher performance for a given propellant tank compared to commercially used hydrazine.
== Properties ==
The compound is a salt with separated hydroxyammonium and nitrate ions. Hydroxylammonium nitrate is unstable because it contains both a reducing agent (hydroxylammonium cation) and an oxidizer (nitrate), the situation being analogous to ammonium nitrate. It is usually handled as an aqueous solution with small amount of nitric acid as a stabilizer.: 1641 The solution is corrosive and toxic, and may be carcinogenic. Solid HAN is unstable, especially in the presence of trace amounts of iron(III).
== Laboratory preparatory routes ==
Catalytic reduction of nitric oxides
Double decomposition
Electrolysis
Hydrogenation of nitric acid
Ion exchange via resins
Neutralization
== Applications ==
HAN has applications as a component of rocket propellant, in both solid and liquid form. HAN and ammonium dinitramide (ADN), another energetic ionic compound, were investigated as less-toxic replacements for toxic hydrazine for monopropellant rockets where only a catalyst is needed to cause decomposition. HAN and ADN will work as monopropellants in water solution, as well as when dissolved with fuel liquids such as methanol.
HAN is used by the Network Centric Airborne Defense Element boost-phase interceptor being developed by Raytheon. As a solid propellant oxidizer, it is typically bonded with glycidyl azide polymer (GAP), hydroxyl-terminated polybutadiene (HTPB), or carboxy-terminated polybutadiene (CTPB) and requires preheating to 200-300 °C to decompose. When used as a monopropellant, the catalyst is a noble metal, similar to the other monopropellants that use silver, palladium, or iridium.
HAN also enabled the development of solid propellants that could be controlled electrically and switched on and off. Developed by DSSP for special effects and microthrusters, these were the first HAN-based propellants in space; and aboard the Naval Research Laboratory SpinSat, launched in 2014.
It was used in a fuel/oxidizer blend known as "AF-M315E" in the high thrust engines of the Green Propellant Infusion Mission, which was initially expected to be launched in 2015, and eventually launched and deployed on 25 June 2019. The specific impulse of AF-M315E is 257 s.
The aqueous solution of HAN can be added with fuel components such as methanol, glycine, TEAN (triethanolammonium nitrate), and amines to form high performance monopropellants for space propulsion systems.
China Aerospace Science and Technology Corporation (CASC) launched a demonstration of HAN-based thruster aboard a microsatellite in January 2018.
Japanese technology demonstration satellite Innovative Satellite Technology Demonstration-1, launched in January 2019, contains a demonstration thruster using HAN and operated successfully in orbit.
HAN is sometimes used in nuclear reprocessing as a reducing agent for plutonium ions.
== Bibliography ==
Donald G. Harlow et al. (1998). "Technical Report on Hydroxlyamine Nitrate". U.S. Department of Energy. DOE/EH-0555
Gösta Bengtsson et al. (2002) "The kinetics and mechanism of oxidation of hydroxylamine by iron(III)". J. Chem. Soc., Dalton Trans., 2002, 2548–2552. doi:10.1039/B201602H
Schmidt, Eckart W. (2022). "Hydroxylammonium Salts". Encyclopedia of Oxidizers. Vol. 3. De Gruyter. pp. 1589–1816. doi:10.1515/9783110750294-011. ISBN 978-3-11-075029-4.
Schmidt, Eckart W. (2023). "Hydroxylammonium Nitrate-Based Monopropellants". Encyclopedia of Monopropellants. Vol. 2. De Gruyter. pp. 807–1194. doi:10.1515/9783110751390-007. ISBN 978-3-11-075139-0.
== References == | Wikipedia/Hydroxylammonium_nitrate |
Calcium ammonium nitrate or CAN, also known as nitro-limestone or nitrochalk, is a widely used inorganic fertilizer, accounting for 4% of all nitrogen fertilizer used worldwide in 2007.
== Production ==
The term "calcium ammonium nitrate" is applied to multiple different, but closely related formulations. One variety of calcium ammonium nitrate is made by adding powdered limestone to ammonium nitrate; another, fully water-soluble version, is a mixture of calcium nitrate and ammonium nitrate, which crystallizes as a hydrated double salt: 5Ca(NO3)2•NH4NO3•10H2O. Unlike ammonium nitrate, these calcium containing formulations are not classified as oxidizers by the United States Department of Transportation.
Consumption of CAN was 3.54 million tonnes in 1973/74, 4.45 million tonnes in 1983/84, 3.58 million tonnes in 1993/94. Production of calcium ammonium nitrate consumed 3% of world ammonia production in 2003.
== Physical and chemical properties ==
Calcium ammonium nitrate is hygroscopic. Its dissolution in water is endothermic, leading to its use in some instant cold packs.
== Use ==
Most calcium ammonium nitrate is used as a fertilizer. Fertilizer grade CAN contains roughly 8% calcium and 21-27% nitrogen. CAN is preferred for use on acid soils, as it acidifies soil less than many common nitrogen fertilizers. It is also used in place of ammonium nitrate where ammonium nitrate is banned.
Calcium ammonium nitrate is used in some instant cold packs as an alternative to ammonium nitrate.
Calcium ammonium nitrate has seen use in improvised explosives. The CAN is not used directly, but is instead first converted to ammonium nitrate; "More than 85% of the IEDs used against U.S. forces in Afghanistan contain homemade explosives, and of those, about 70% are made with ammonium nitrate derived from calcium ammonium nitrate". CAN and other fertilizers were banned in the Malakand Division and in Afghanistan following reports of its use by militants to make explosives. Due to these bans, "Potassium chlorate — the stuff that makes matches catch fire — has surpassed fertilizer as the explosive of choice for insurgents."
== References == | Wikipedia/Calcium_ammonium_nitrate |
When heated, ammonium nitrate decomposes non-explosively into nitrous oxide and water vapor; however, it can be induced to decompose explosively by detonation into oxygen, nitrogen, and water vapor. Large stockpiles of the material can be a major fire risk due to their supporting oxidation, and may also detonate, as happened in the Texas City disaster of 1947 which led to major changes in the regulations for storage and handling.
There are two major classes of incidents resulting in explosions:
In the first case, the explosion happens by the shock induced detonation. The initiation happens by an explosive charge going off in the mass, by the detonation of a shell thrown into the mass, or by detonation of an explosive mixture in contact with the mass. Examples are Kriewald, Morgan, Oppau, Tessenderlo, and Traskwood.
In the second case, the explosion results from a fire that spreads into the ammonium nitrate (AN) itself (Texas City, Brest, Tianjin, Beirut) or to a mixture of an ammonium nitrate with a combustible material during the fire. The fire must be confined at least to a degree for successful transition from a fire to an explosion (a phenomenon known as "deflagration to detonation transition", or DDT). Pure, compact AN is stable and very difficult to initiate.
Ammonium nitrate decomposes in temperatures above 169 °C (336 °F). Pure AN is stable and will stop decomposing once the heat source is removed, but when catalysts are present, the reaction can become self-sustaining (known as self-sustaining decomposition, or SSD). This is a well-known hazard with some types of NPK fertilizers and is responsible for the loss of several cargo ships.
== Timeline of major incidents ==
The column AN states the amount of ammonium nitrate consumed in the disaster in metric tonnes.
== See also ==
ANFO (Ammonium Nitrate Fuel Oil)
Largest artificial non-nuclear explosions, many of which involved ammonium nitrate
== References == | Wikipedia/Ammonium_nitrate_disasters |
Ammonium stearate is a chemical compound with the chemical formula CH3(CH2)16COONH4.This is an organic ammonium salt of stearic acid.
== Synthesis ==
The compound can be prepared by reacting stearic acid and excess 28-30% NH3 solution. Also by reacting stearic acid and ammonium carbonate or ammonium hydroxide.
== Physical properties ==
The compound forms yellow-white powder.
Soluble in methanol and ethanol; slightly soluble in water, benzene, xylene, naphtha; practically insoluble in acetone.
When heated, the powder of ammonium stearate decomposes, releasing toxic fumes of NH3.
== Uses ==
The compound is used to produce vanishing creams and waterproofing cements.
== References == | Wikipedia/Ammonium_stearate |
Chlorate is the common name of the ClO−3 anion, whose chlorine atom is in the +5 oxidation state. The term can also refer to chemical compounds containing this anion, with chlorates being the salts of chloric acid. Other oxyanions of chlorine can be named "chlorate" followed by a Roman numeral in parentheses denoting the oxidation state of chlorine: e.g., the ClO−4 ion commonly called perchlorate can also be called chlorate(VII).
As predicted by valence shell electron pair repulsion theory, chlorate anions have trigonal pyramidal structures.
Chlorates are powerful oxidizers and should be kept away from organics or easily oxidized materials. Mixtures of chlorate salts with virtually any combustible material (sugar, sawdust, charcoal, organic solvents, metals, etc.) will readily deflagrate. Chlorates were once widely used in pyrotechnics for this reason, though their use has fallen due to their instability. Most pyrotechnic applications that formerly used chlorates now use the more stable perchlorates instead.
== Structure and bonding ==
The chlorate ion cannot be satisfactorily represented by just one Lewis structure, since all the Cl–O bonds are the same length (1.49 Å in potassium chlorate), and the chlorine atom is hypervalent. Instead, it is often thought of as a hybrid of multiple resonance structures:
== Preparation ==
=== Laboratory ===
Metal chlorates can be prepared by adding chlorine to hot metal hydroxides like KOH:
3 Cl2 + 6 KOH → 5 KCl + KClO3 + 3 H2O
In this reaction, chlorine undergoes disproportionation, both reduction and oxidation. Chlorine, oxidation number 0, forms chloride (Cl−; oxidation number −1) and chlorate(V) (ClO−3; oxidation number +5). The reaction of cold aqueous metal hydroxides with chlorine produces the chloride and hypochlorite (oxidation number +1) instead.
=== Industrial ===
The industrial-scale synthesis for sodium chlorate starts from an aqueous sodium chloride solution (brine) rather than chlorine gas. If the electrolysis equipment allows for the mixing of the chlorine and the sodium hydroxide, then the disproportionation reaction described above occurs. The heating of the reactants to 50–70 °C is performed by the electrical power used for electrolysis.
== Natural occurrence ==
A 2010 study has discovered the presence of natural chlorate deposits around the world, with relatively high concentrations found in arid and hyper-arid regions. The chlorate was also measured in rainfall samples with the amount of chlorate similar to perchlorate. It is suspected that chlorate and perchlorate may share a common natural formation mechanism and could be a part of the chlorine biogeochemistry cycle. From a microbial standpoint, the presence of natural chlorate could also explain why there is a variety of microorganisms capable of reducing chlorate to chloride. Further, the evolution of chlorate reduction may be an ancient phenomenon as all perchlorate reducing bacteria described to date also utilize chlorate as a terminal electron acceptor. It should be clearly stated, that currently no chlorate-dominant minerals are known. This means that the chlorate anion exists only as a substitution in the known mineral species, or – eventually – is present in the pore-filling solutions.
In 2011, a study by the Georgia Institute of Technology unveiled the presence of magnesium chlorate on the planet Mars.
== Compounds (salts) ==
Examples of chlorates include
potassium chlorate, KClO3
sodium chlorate, NaClO3
magnesium chlorate, Mg(ClO3)2
== Other oxyanions ==
If a Roman numeral in brackets follows the word "chlorate", this indicates the oxyanion contains chlorine in the indicated oxidation state, namely:
Using this convention, "chlorate" means any chlorine oxyanion. Usually, "chlorate" refers only to chlorine in the +5 oxidation state.
== Toxicity ==
Chlorates are relatively toxic, though they form generally harmless chlorides on reduction.
== References ==
== External links ==
"Chlorates" . Encyclopædia Britannica. Vol. 6 (11th ed.). 1911. p. 254. | Wikipedia/Chlorate |
Ammonium neodymium nitrate is a chemical compound with the chemical formula Nd(NH4)2(NO3)5. The compound is classified as a rare earth metal salt, belonging to nitrates.
== Synthesis ==
The compound can be prepared by the reaction of neodymium oxide, nitric acid, and ammonium nitrate.
Also, it can be made by a reaction of neodymium oxide or neodymium carbonate with ammonium nitrate, releasing water as a byproduct:
Nd2O3 + 6NH4NO3 → 2(NH4)2Nd(NO3)5 + 3H2O
== Physical properties ==
Ammonium neodymium nitrate is soluble in water.
The compound forms a tetrahydrate of the composition Nd(NH4)2(NO3)5 • 4H2O—red-violet crystals that melt in their own crystallization water at 47 °C.
== Chemical properties ==
The compound reacts with strong acids to form soluble complexes. It can release nitrogen oxides when decomposed.
== Uses ==
Ammonium neodymium nitrate is used as a precursor for the synthesis of many other neodymium compounds and also as a reagent for various chemical reactions.
== References == | Wikipedia/Ammonium_neodymium_nitrate |
Ammonium tartrate is a chemical compound with the chemical formula (NH4)2C4H4O6. This is an organic ammonium salt of tartaric acid.
== Synthesis ==
Ammonium tartrate can be prepared by the reaction of tartaric acid and ammonium carbonate.
== Physical properties ==
Ammonium tartrate forms colorless crystals that slowly release ammonia if exposed to air. Easily soluble in water, also soluble in alcohol.
Ammonium tartrate crystallizes in the monoclinic crystal system with the space group P21 (space group No. 4) with the lattice parameters a = 708 pm, b = 612 pm, c = 880 pm, β = 92.42 ° and Z = 2.
== Uses ==
The compound is used in textile industry and in medicine.
Also can be used as an analytical reagent and an intermediate in organic synthesis.
== See also ==
Sodium ammonium tartrate
== References == | Wikipedia/Ammonium_tartrate |
Biochemistry, or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology, and metabolism. Over the last decades of the 20th century, biochemistry has become successful at explaining living processes through these three disciplines. Almost all areas of the life sciences are being uncovered and developed through biochemical methodology and research. Biochemistry focuses on understanding the chemical basis that allows biological molecules to give rise to the processes that occur within living cells and between cells, in turn relating greatly to the understanding of tissues and organs as well as organism structure and function. Biochemistry is closely related to molecular biology, the study of the molecular mechanisms of biological phenomena.
Much of biochemistry deals with the structures, functions, and interactions of biological macromolecules such as proteins, nucleic acids, carbohydrates, and lipids. They provide the structure of cells and perform many of the functions associated with life. The chemistry of the cell also depends upon the reactions of small molecules and ions. These can be inorganic (for example, water and metal ions) or organic (for example, the amino acids, which are used to synthesize proteins). The mechanisms used by cells to harness energy from their environment via chemical reactions are known as metabolism. The findings of biochemistry are applied primarily in medicine, nutrition, and agriculture. In medicine, biochemists investigate the causes and cures of diseases. Nutrition studies how to maintain health and wellness and also the effects of nutritional deficiencies. In agriculture, biochemists investigate soil and fertilizers with the goal of improving crop cultivation, crop storage, and pest control. In recent decades, biochemical principles and methods have been combined with problem-solving approaches from engineering to manipulate living systems in order to produce useful tools for research, industrial processes, and diagnosis and control of disease—the discipline of biotechnology.
== History ==
At its most comprehensive definition, biochemistry can be seen as a study of the components and composition of living things and how they come together to become life. In this sense, the history of biochemistry may therefore go back as far as the ancient Greeks. However, biochemistry as a specific scientific discipline began sometime in the 19th century, or a little earlier, depending on which aspect of biochemistry is being focused on. Some argued that the beginning of biochemistry may have been the discovery of the first enzyme, diastase (now called amylase), in 1833 by Anselme Payen, while others considered Eduard Buchner's first demonstration of a complex biochemical process alcoholic fermentation in cell-free extracts in 1897 to be the birth of biochemistry. Some might also point as its beginning to the influential 1842 work by Justus von Liebig, Animal chemistry, or, Organic chemistry in its applications to physiology and pathology, which presented a chemical theory of metabolism, or even earlier to the 18th century studies on fermentation and respiration by Antoine Lavoisier. Many other pioneers in the field who helped to uncover the layers of complexity of biochemistry have been proclaimed founders of modern biochemistry. Emil Fischer, who studied the chemistry of proteins, and F. Gowland Hopkins, who studied enzymes and the dynamic nature of biochemistry, represent two examples of early biochemists.
The term "biochemistry" was first used when Vinzenz Kletzinsky (1826–1882) had his "Compendium der Biochemie" printed in Vienna in 1858; it derived from a combination of biology and chemistry. In 1877, Felix Hoppe-Seyler used the term (biochemie in German) as a synonym for physiological chemistry in the foreword to the first issue of Zeitschrift für Physiologische Chemie (Journal of Physiological Chemistry) where he argued for the setting up of institutes dedicated to this field of study. The German chemist Carl Neuberg however is often cited to have coined the word in 1903, while some credited it to Franz Hofmeister.
It was once generally believed that life and its materials had some essential property or substance (often referred to as the "vital principle") distinct from any found in non-living matter, and it was thought that only living beings could produce the molecules of life. In 1828, Friedrich Wöhler published a paper on his serendipitous urea synthesis from potassium cyanate and ammonium sulfate; some regarded that as a direct overthrow of vitalism and the establishment of organic chemistry. However, the Wöhler synthesis has sparked controversy as some reject the death of vitalism at his hands. Since then, biochemistry has advanced, especially since the mid-20th century, with the development of new techniques such as chromatography, X-ray diffraction, dual polarisation interferometry, NMR spectroscopy, radioisotopic labeling, electron microscopy and molecular dynamics simulations. These techniques allowed for the discovery and detailed analysis of many molecules and metabolic pathways of the cell, such as glycolysis and the Krebs cycle (citric acid cycle), and led to an understanding of biochemistry on a molecular level.
Another significant historic event in biochemistry is the discovery of the gene, and its role in the transfer of information in the cell. In the 1950s, James D. Watson, Francis Crick, Rosalind Franklin and Maurice Wilkins were instrumental in solving DNA structure and suggesting its relationship with the genetic transfer of information. In 1958, George Beadle and Edward Tatum received the Nobel Prize for work in fungi showing that one gene produces one enzyme. In 1988, Colin Pitchfork was the first person convicted of murder with DNA evidence, which led to the growth of forensic science. More recently, Andrew Z. Fire and Craig C. Mello received the 2006 Nobel Prize for discovering the role of RNA interference (RNAi) in the silencing of gene expression.
== Starting materials: the chemical elements of life ==
Around two dozen chemical elements are essential to various kinds of biological life. Most rare elements on Earth are not needed by life (exceptions being selenium and iodine), while a few common ones (aluminium and titanium) are not used. Most organisms share element needs, but there are a few differences between plants and animals. For example, ocean algae use bromine, but land plants and animals do not seem to need any. All animals require sodium, but is not an essential element for plants. Plants need boron and silicon, but animals may not (or may need ultra-small amounts).
Just six elements—carbon, hydrogen, nitrogen, oxygen, calcium and phosphorus—make up almost 99% of the mass of living cells, including those in the human body (see composition of the human body for a complete list). In addition to the six major elements that compose most of the human body, humans require smaller amounts of possibly 18 more.
== Biomolecules ==
The 4 main classes of molecules in biochemistry (often called biomolecules) are carbohydrates, lipids, proteins, and nucleic acids. Many biological molecules are polymers: in this terminology, monomers are relatively small macromolecules that are linked together to create large macromolecules known as polymers. When monomers are linked together to synthesize a biological polymer, they undergo a process called dehydration synthesis. Different macromolecules can assemble in larger complexes, often needed for biological activity.
=== Carbohydrates ===
Two of the main functions of carbohydrates are energy storage and providing structure. One of the common sugars known as glucose is a carbohydrate, but not all carbohydrates are sugars. There are more carbohydrates on Earth than any other known type of biomolecule; they are used to store energy and genetic information, as well as play important roles in cell to cell interactions and communications.
The simplest type of carbohydrate is a monosaccharide, which among other properties contains carbon, hydrogen, and oxygen, mostly in a ratio of 1:2:1 (generalized formula CnH2nOn, where n is at least 3). Glucose (C6H12O6) is one of the most important carbohydrates; others include fructose (C6H12O6), the sugar commonly associated with the sweet taste of fruits, and deoxyribose (C5H10O4), a component of DNA. A monosaccharide can switch between acyclic (open-chain) form and a cyclic form. The open-chain form can be turned into a ring of carbon atoms bridged by an oxygen atom created from the carbonyl group of one end and the hydroxyl group of another. The cyclic molecule has a hemiacetal or hemiketal group, depending on whether the linear form was an aldose or a ketose.
In these cyclic forms, the ring usually has 5 or 6 atoms. These forms are called furanoses and pyranoses, respectively—by analogy with furan and pyran, the simplest compounds with the same carbon-oxygen ring (although they lack the carbon-carbon double bonds of these two molecules). For example, the aldohexose glucose may form a hemiacetal linkage between the hydroxyl on carbon 1 and the oxygen on carbon 4, yielding a molecule with a 5-membered ring, called glucofuranose. The same reaction can take place between carbons 1 and 5 to form a molecule with a 6-membered ring, called glucopyranose. Cyclic forms with a 7-atom ring called heptoses are rare.
Two monosaccharides can be joined by a glycosidic or ester bond into a disaccharide through a dehydration reaction during which a molecule of water is released. The reverse reaction in which the glycosidic bond of a disaccharide is broken into two monosaccharides is termed hydrolysis. The best-known disaccharide is sucrose or ordinary sugar, which consists of a glucose molecule and a fructose molecule joined. Another important disaccharide is lactose found in milk, consisting of a glucose molecule and a galactose molecule. Lactose may be hydrolysed by lactase, and deficiency in this enzyme results in lactose intolerance.
When a few (around three to six) monosaccharides are joined, it is called an oligosaccharide (oligo- meaning "few"). These molecules tend to be used as markers and signals, as well as having some other uses. Many monosaccharides joined form a polysaccharide. They can be joined in one long linear chain, or they may be branched. Two of the most common polysaccharides are cellulose and glycogen, both consisting of repeating glucose monomers. Cellulose is an important structural component of plant's cell walls and glycogen is used as a form of energy storage in animals.
Sugar can be characterized by having reducing or non-reducing ends. A reducing end of a carbohydrate is a carbon atom that can be in equilibrium with the open-chain aldehyde (aldose) or keto form (ketose). If the joining of monomers takes place at such a carbon atom, the free hydroxy group of the pyranose or furanose form is exchanged with an OH-side-chain of another sugar, yielding a full acetal. This prevents opening of the chain to the aldehyde or keto form and renders the modified residue non-reducing. Lactose contains a reducing end at its glucose moiety, whereas the galactose moiety forms a full acetal with the C4-OH group of glucose. Saccharose does not have a reducing end because of full acetal formation between the aldehyde carbon of glucose (C1) and the keto carbon of fructose (C2).
=== Lipids ===
Lipids comprise a diverse range of molecules and to some extent is a catchall for relatively water-insoluble or nonpolar compounds of biological origin, including waxes, fatty acids, fatty-acid derived phospholipids, sphingolipids, glycolipids, and terpenoids (e.g., retinoids and steroids). Some lipids are linear, open-chain aliphatic molecules, while others have ring structures. Some are aromatic (with a cyclic [ring] and planar [flat] structure) while others are not. Some are flexible, while others are rigid.
Lipids are usually made from one molecule of glycerol combined with other molecules. In triglycerides, the main group of bulk lipids, there is one molecule of glycerol and three fatty acids. Fatty acids are considered the monomer in that case, and may be saturated (no double bonds in the carbon chain) or unsaturated (one or more double bonds in the carbon chain).
Most lipids have some polar character and are largely nonpolar. In general, the bulk of their structure is nonpolar or hydrophobic ("water-fearing"), meaning that it does not interact well with polar solvents like water. Another part of their structure is polar or hydrophilic ("water-loving") and will tend to associate with polar solvents like water. This makes them amphiphilic molecules (having both hydrophobic and hydrophilic portions). In the case of cholesterol, the polar group is a mere –OH (hydroxyl or alcohol).
In the case of phospholipids, the polar groups are considerably larger and more polar, as described below.
Lipids are an integral part of our daily diet. Most oils and milk products that we use for cooking and eating like butter, cheese, ghee etc. are composed of fats. Vegetable oils are rich in various polyunsaturated fatty acids (PUFA). Lipid-containing foods undergo digestion within the body and are broken into fatty acids and glycerol, the final degradation products of fats and lipids. Lipids, especially phospholipids, are also used in various pharmaceutical products, either as co-solubilizers (e.g. in parenteral infusions) or else as drug carrier components (e.g. in a liposome or transfersome).
=== Proteins ===
Proteins are very large molecules—macro-biopolymers—made from monomers called amino acids. An amino acid consists of an alpha carbon atom attached to an amino group, –NH2, a carboxylic acid group, –COOH (although these exist as –NH3+ and –COO− under physiologic conditions), a simple hydrogen atom, and a side chain commonly denoted as "–R". The side chain "R" is different for each amino acid of which there are 20 standard ones. It is this "R" group that makes each amino acid different, and the properties of the side chains greatly influence the overall three-dimensional conformation of a protein. Some amino acids have functions by themselves or in a modified form; for instance, glutamate functions as an important neurotransmitter. Amino acids can be joined via a peptide bond. In this dehydration synthesis, a water molecule is removed and the peptide bond connects the nitrogen of one amino acid's amino group to the carbon of the other's carboxylic acid group. The resulting molecule is called a dipeptide, and short stretches of amino acids (usually, fewer than thirty) are called peptides or polypeptides. Longer stretches merit the title proteins. As an example, the important blood serum protein albumin contains 585 amino acid residues.
Proteins can have structural and/or functional roles. For instance, movements of the proteins actin and myosin ultimately are responsible for the contraction of skeletal muscle. One property many proteins have is that they specifically bind to a certain molecule or class of molecules—they may be extremely selective in what they bind. Antibodies are an example of proteins that attach to one specific type of molecule. Antibodies are composed of heavy and light chains. Two heavy chains would be linked to two light chains through disulfide linkages between their amino acids. Antibodies are specific through variation based on differences in the N-terminal domain.
The enzyme-linked immunosorbent assay (ELISA), which uses antibodies, is one of the most sensitive tests modern medicine uses to detect various biomolecules. Probably the most important proteins, however, are the enzymes. Virtually every reaction in a living cell requires an enzyme to lower the activation energy of the reaction. These molecules recognize specific reactant molecules called substrates; they then catalyze the reaction between them. By lowering the activation energy, the enzyme speeds up that reaction by a rate of 1011 or more; a reaction that would normally take over 3,000 years to complete spontaneously might take less than a second with an enzyme. The enzyme itself is not used up in the process and is free to catalyze the same reaction with a new set of substrates. Using various modifiers, the activity of the enzyme can be regulated, enabling control of the biochemistry of the cell as a whole.
The structure of proteins is traditionally described in a hierarchy of four levels. The primary structure of a protein consists of its linear sequence of amino acids; for instance, "alanine-glycine-tryptophan-serine-glutamate-asparagine-glycine-lysine-...". Secondary structure is concerned with local morphology (morphology being the study of structure). Some combinations of amino acids will tend to curl up in a coil called an α-helix or into a sheet called a β-sheet; some α-helixes can be seen in the hemoglobin schematic above. Tertiary structure is the entire three-dimensional shape of the protein. This shape is determined by the sequence of amino acids. In fact, a single change can change the entire structure. The alpha chain of hemoglobin contains 146 amino acid residues; substitution of the glutamate residue at position 6 with a valine residue changes the behavior of hemoglobin so much that it results in sickle-cell disease. Finally, quaternary structure is concerned with the structure of a protein with multiple peptide subunits, like hemoglobin with its four subunits. Not all proteins have more than one subunit.
Ingested proteins are usually broken up into single amino acids or dipeptides in the small intestine and then absorbed. They can then be joined to form new proteins. Intermediate products of glycolysis, the citric acid cycle, and the pentose phosphate pathway can be used to form all twenty amino acids, and most bacteria and plants possess all the necessary enzymes to synthesize them. Humans and other mammals, however, can synthesize only half of them. They cannot synthesize isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Because they must be ingested, these are the essential amino acids. Mammals do possess the enzymes to synthesize alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, and tyrosine, the nonessential amino acids. While they can synthesize arginine and histidine, they cannot produce it in sufficient amounts for young, growing animals, and so these are often considered essential amino acids.
If the amino group is removed from an amino acid, it leaves behind a carbon skeleton called an α-keto acid. Enzymes called transaminases can easily transfer the amino group from one amino acid (making it an α-keto acid) to another α-keto acid (making it an amino acid). This is important in the biosynthesis of amino acids, as for many of the pathways, intermediates from other biochemical pathways are converted to the α-keto acid skeleton, and then an amino group is added, often via transamination. The amino acids may then be linked together to form a protein.
A similar process is used to break down proteins. It is first hydrolyzed into its component amino acids. Free ammonia (NH3), existing as the ammonium ion (NH4+) in blood, is toxic to life forms. A suitable method for excreting it must therefore exist. Different tactics have evolved in different animals, depending on the animals' needs. Unicellular organisms release the ammonia into the environment. Likewise, bony fish can release ammonia into the water where it is quickly diluted. In general, mammals convert ammonia into urea, via the urea cycle.
In order to determine whether two proteins are related, or in other words to decide whether they are homologous or not, scientists use sequence-comparison methods. Methods like sequence alignments and structural alignments are powerful tools that help scientists identify homologies between related molecules. The relevance of finding homologies among proteins goes beyond forming an evolutionary pattern of protein families. By finding how similar two protein sequences are, we acquire knowledge about their structure and therefore their function.
=== Nucleic acids ===
Nucleic acids, so-called because of their prevalence in cellular nuclei, is the generic name of the family of biopolymers. They are complex, high-molecular-weight biochemical macromolecules that can convey genetic information in all living cells and viruses. The monomers are called nucleotides, and each consists of three components: a nitrogenous heterocyclic base (either a purine or a pyrimidine), a pentose sugar, and a phosphate group.
The most common nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). The phosphate group and the sugar of each nucleotide bond with each other to form the backbone of the nucleic acid, while the sequence of nitrogenous bases stores the information. The most common nitrogenous bases are adenine, cytosine, guanine, thymine, and uracil. The nitrogenous bases of each strand of a nucleic acid will form hydrogen bonds with certain other nitrogenous bases in a complementary strand of nucleic acid. Adenine binds with thymine and uracil, thymine binds only with adenine, and cytosine and guanine can bind only with one another. Adenine, thymine, and uracil contain two hydrogen bonds, while hydrogen bonds formed between cytosine and guanine are three.
Aside from the genetic material of the cell, nucleic acids often play a role as second messengers, as well as forming the base molecule for adenosine triphosphate (ATP), the primary energy-carrier molecule found in all living organisms. Also, the nitrogenous bases possible in the two nucleic acids are different: adenine, cytosine, and guanine occur in both RNA and DNA, while thymine occurs only in DNA and uracil occurs in RNA.
== Metabolism ==
=== Carbohydrates as energy source ===
Glucose is an energy source in most life forms. For instance, polysaccharides are broken down into their monomers by enzymes (glycogen phosphorylase removes glucose residues from glycogen, a polysaccharide). Disaccharides like lactose or sucrose are cleaved into their two component monosaccharides.
==== Glycolysis (anaerobic) ====
Glucose is mainly metabolized by a very important ten-step pathway called glycolysis, the net result of which is to break down one molecule of glucose into two molecules of pyruvate. This also produces a net two molecules of ATP, the energy currency of cells, along with two reducing equivalents of converting NAD+ (nicotinamide adenine dinucleotide: oxidized form) to NADH (nicotinamide adenine dinucleotide: reduced form). This does not require oxygen; if no oxygen is available (or the cell cannot use oxygen), the NAD is restored by converting the pyruvate to lactate (lactic acid) (e.g. in humans) or to ethanol plus carbon dioxide (e.g. in yeast). Other monosaccharides like galactose and fructose can be converted into intermediates of the glycolytic pathway.
==== Aerobic ====
In aerobic cells with sufficient oxygen, as in most human cells, the pyruvate is further metabolized. It is irreversibly converted to acetyl-CoA, giving off one carbon atom as the waste product carbon dioxide, generating another reducing equivalent as NADH. The two molecules acetyl-CoA (from one molecule of glucose) then enter the citric acid cycle, producing two molecules of ATP, six more NADH molecules and two reduced (ubi)quinones (via FADH2 as enzyme-bound cofactor), and releasing the remaining carbon atoms as carbon dioxide. The produced NADH and quinol molecules then feed into the enzyme complexes of the respiratory chain, an electron transport system transferring the electrons ultimately to oxygen and conserving the released energy in the form of a proton gradient over a membrane (inner mitochondrial membrane in eukaryotes). Thus, oxygen is reduced to water and the original electron acceptors NAD+ and quinone are regenerated. This is why humans breathe in oxygen and breathe out carbon dioxide. The energy released from transferring the electrons from high-energy states in NADH and quinol is conserved first as proton gradient and converted to ATP via ATP synthase. This generates an additional 28 molecules of ATP (24 from the 8 NADH + 4 from the 2 quinols), totaling to 32 molecules of ATP conserved per degraded glucose (two from glycolysis + two from the citrate cycle). It is clear that using oxygen to completely oxidize glucose provides an organism with far more energy than any oxygen-independent metabolic feature, and this is thought to be the reason why complex life appeared only after Earth's atmosphere accumulated large amounts of oxygen.
==== Gluconeogenesis ====
In vertebrates, vigorously contracting skeletal muscles (during weightlifting or sprinting, for example) do not receive enough oxygen to meet the energy demand, and so they shift to anaerobic metabolism, converting glucose to lactate.
The combination of glucose from noncarbohydrates origin, such as fat and proteins. This only happens when glycogen supplies in the liver are worn out. The pathway is a crucial reversal of glycolysis from pyruvate to glucose and can use many sources like amino acids, glycerol and Krebs Cycle. Large scale protein and fat catabolism usually occur when those suffer from starvation or certain endocrine disorders. The liver regenerates the glucose, using a process called gluconeogenesis. This process is not quite the opposite of glycolysis, and actually requires three times the amount of energy gained from glycolysis (six molecules of ATP are used, compared to the two gained in glycolysis). Analogous to the above reactions, the glucose produced can then undergo glycolysis in tissues that need energy, be stored as glycogen (or starch in plants), or be converted to other monosaccharides or joined into di- or oligosaccharides. The combined pathways of glycolysis during exercise, lactate's crossing via the bloodstream to the liver, subsequent gluconeogenesis and release of glucose into the bloodstream is called the Cori cycle.
== Relationship to other "molecular-scale" biological sciences ==
Researchers in biochemistry use specific techniques native to biochemistry, but increasingly combine these with techniques and ideas developed in the fields of genetics, molecular biology, and biophysics. There is not a defined line between these disciplines. Biochemistry studies the chemistry required for biological activity of molecules, molecular biology studies their biological activity, genetics studies their heredity, which happens to be carried by their genome. This is shown in the following schematic that depicts one possible view of the relationships between the fields:
Biochemistry is the study of the chemical substances and vital processes occurring in live organisms. Biochemists focus heavily on the role, function, and structure of biomolecules. The study of the chemistry behind biological processes and the synthesis of biologically active molecules are applications of biochemistry. Biochemistry studies life at the atomic and molecular level.
Genetics is the study of the effect of genetic differences in organisms. This can often be inferred by the absence of a normal component (e.g. one gene). The study of "mutants" – organisms that lack one or more functional components with respect to the so-called "wild type" or normal phenotype. Genetic interactions (epistasis) can often confound simple interpretations of such "knockout" studies.
Molecular biology is the study of molecular underpinnings of the biological phenomena, focusing on molecular synthesis, modification, mechanisms and interactions. The central dogma of molecular biology, where genetic material is transcribed into RNA and then translated into protein, despite being oversimplified, still provides a good starting point for understanding the field. This concept has been revised in light of emerging novel roles for RNA.
Chemical biology seeks to develop new tools based on small molecules that allow minimal perturbation of biological systems while providing detailed information about their function. Further, chemical biology employs biological systems to create non-natural hybrids between biomolecules and synthetic devices (for example emptied viral capsids that can deliver gene therapy or drug molecules).
== See also ==
=== Lists ===
=== See also ===
== Notes ==
== References ==
=== Cited literature ===
== Further reading ==
== External links ==
"Biochemical Society".
The Virtual Library of Biochemistry, Molecular Biology and Cell Biology
Biochemistry, 5th ed. Full text of Berg, Tymoczko, and Stryer, courtesy of NCBI.
SystemsX.ch – The Swiss Initiative in Systems Biology
Full text of Biochemistry by Kevin and Indira, an introductory biochemistry textbook. | Wikipedia/biochemistry |
In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds.
Some polyunsaturated fatty acids are essentials. Polyunsaturated fatty acids are precursors to and are derived from polyunsaturated fats, which include drying oils.
== Nomenclature ==
The position of the carbon-carbon double bonds in carboxylic acid chains in fats is designated by Greek letters. The carbon atom closest to the carboxyl group is the alpha carbon, the next carbon is the beta carbon and so on. In fatty acids the carbon atom of the methyl group at the end of the hydrocarbon chain is called the omega carbon because omega is the last letter of the Greek alphabet. Omega-3 fatty acids have a double bond three carbons away from the methyl carbon, whereas omega-6 fatty acids have a double bond six carbons away from the methyl carbon. The illustration below shows the omega-6 fatty acid, linoleic acid.
Polyunsaturated fatty acids can be classified in various groups by their chemical structure:
methylene-interrupted polyenes
conjugated fatty acids
other PUFAs
Based on the length of their carbon backbone, they are sometimes classified in two groups: All feature pentadiene groups.
short chain polyunsaturated fatty acids (SC-PUFA), with 18 carbon atoms. These are more common. Key members include linoleic acid, α-linolenic acid, and arachidonic acid.
long-chain polyunsaturated fatty acids (LC-PUFA) with 20 or more carbon atoms
== Production ==
PUFAs with 18 carbon atoms, which are the most common variety, are not produced by mammals. Since they have important dietary functions, their biosynthesis has received much attention. Plants produce PUFAs from oleic acid. Key enzymes are called fatty acid desaturases, which introduce additional double bonds. Desaturases convert oleic acid into linoleic acid the precursor to alpha-linolenic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid.
Industrial PUFAs are generally obtained by hydrolysis of fats that contain PUFAs. The process is complicated by the sensitive nature of PUFAs, leading to side reactions and colorization. Thus, steam hydrolysis often fails for this reason. Alkaline hydrolysis of fats followed by acidification is expensive. Lipases, a family of enzymes, show potential as mild and green catalysts for the production of PUFAs from triglycerides.
In general, outside of dietary contexts, PUFAs are undesirable components of vegetable oils, so there is great interest in their removal from, say, olive oil. One technology for lowering the PUFA contact is by selective formation of derivatives with ureas.
== Reactions ==
From the perspective of chemical analysis, PUFA's have high iodine numbers. These high values are simply a reflection of the fact that PUFAs are polyunsaturated. Hydrogenation of PUFAs gives less unsaturated derivatives. For unsaturated products from partial hydrogenation often contain some trans isomers. The trans monounsaturated C20 species elaidic acid can be prepared in this way.
=== Peroxidation ===
Polyunsaturated fatty acids are susceptible to lipid peroxidation, far more so than monounsaturated or saturated analogues. The basis for this reactivity is the weakness of doubly allylic C-H bonds. They are drying oils, i.e. film-forming liquids suitable as painting. One practical consequence is that polyunsaturated fatty acids have poor shelf life, owing to their tendency toward autoxidation, leading, in the case of edibles, to rancidification. Metals accelerate the degradation. A range of reactions with oxygen occur. Products include fatty acid hydroperoxides, epoxy-hydroxy polyunsaturated fatty acids, jasmonates, divinylether fatty acids, and leaf aldehydes. Some of these derivatives are signalling molecules, some are used in plant defense (antifeedants), some are precursors to other metabolites that are used by the plant.
== Types ==
=== Methylene-interrupted polyenes ===
These fatty acids have 2 or more cis double bonds that are separated from each other by a single methylene bridge (−CH2−). This form is also sometimes called a divinylmethane pattern.
The essential fatty acids are all omega-3 and -6 methylene-interrupted fatty acids. See more at Essential fatty acids—Nomenclature
==== Omega-3 ====
==== Omega-6 ====
=== Conjugated fatty acids ===
=== Other polyunsaturated fatty acids ===
== Function and effects ==
The biological effects of the ω-3 and ω-6 fatty acids are largely mediated by their mutual interactions, see Essential fatty acid interactions for detail.
== Health ==
=== Potential benefits ===
Because of their effects in the diet, unsaturated fats (monounsaturated and polyunsaturated) are often referred to as good fats; while saturated fats are sometimes referred to as bad fats. Some fat is needed in the diet, but it is usually considered that fats should not be consumed excessively, unsaturated fats should be preferred, and saturated fats in particular should be limited.
In preliminary research, omega-3 fatty acids in algal oil, fish oil, fish and seafood have been shown to lower the risk of heart attacks. Other preliminary research indicates that omega-6 fatty acids in sunflower oil and safflower oil may also reduce the risk of cardiovascular disease.
Among omega-3 fatty acids, neither long-chain nor short-chain forms were consistently associated with breast cancer risk. High levels of docosahexaenoic acid (DHA), however, the most abundant omega-3 polyunsaturated fatty acid in erythrocyte (red blood cell) membranes, were associated with a reduced risk of breast cancer. DHA is vital for the grey matter structure of the human brain, as well as retinal stimulation and neurotransmission.
Contrary to conventional advice, an evaluation of evidence from 1966–1973 pertaining to the health impacts of replacing dietary saturated fat with linoleic acid found that participants in the group doing so had increased rates of death from all causes, coronary heart disease, and cardiovascular disease. Although this evaluation was disputed by many scientists, it fueled debate over worldwide dietary advice to substitute polyunsaturated fats for saturated fats.
Taking isotope-reinforced polyunsaturated fatty acids, for example deuterated linoleic acid where two atoms of hydrogen substituted with its heavy isotope deuterium, with food (heavy isotope diet) can suppress lipid peroxidation and prevent or treat the associated diseases.
=== Pregnancy ===
Polyunsaturated fat supplementation does not decrease the incidence of pregnancy-related disorders, such as hypertension or preeclampsia, but may increase the length of gestation slightly and decreased the incidence of early premature births.
Expert panels in the United States and Europe recommend that pregnant and lactating women consume higher amounts of polyunsaturated fats than the general population to enhance the DHA status of the fetus and newborn.
=== Cancer ===
Results from observational clinical trials on polyunsaturated fat intake and cancer have been inconsistent and vary by numerous factors of cancer incidence, including gender and genetic risk. Some studies have shown associations between higher intakes and/or blood levels of polyunsaturated fat omega-3s and a decreased risk of certain cancers, including breast and colorectal cancer, while other studies found no associations with cancer risk.
== Dietary sources ==
Polyunsaturated fat can be found mostly in nuts, seeds, fish, seed oils, and oysters. "Unsaturated" refers to the fact that the molecules contain less than the maximum amount of hydrogen (if there were no double bonds). These materials exist as cis or trans isomers depending on the geometry of the double bond.
== Non-dietary applications ==
PUFA's are significant components of alkyd resins, which are used in coatings.
== References ==
== Sources ==
Cyberlipid. "Polyenoic Fatty Acids". Archived from the original on 2018-09-30. Retrieved 2007-01-17.
Gunstone, Frank D. "Lipid Glossary 2" (PDF). Archived from the original (PDF) on 2006-08-13. Retrieved 2007-01-17.
Adlof, R. O. & Gunstone, F. D. (2003-09-17). "Common (non-systematic) Names for Fatty Acids". Archived from the original on 2006-12-06. Retrieved 2007-01-24.
Heinz; Roughan, PG (1983). "Similarities and Differences in Lipid Metabolism of Chloroplasts Isolated from 18:3 and 16:3 Plants". Plant Physiol. 72 (2): 273–279. doi:10.1104/pp.72.2.273. PMC 1066223. PMID 16662992. | Wikipedia/Polyunsaturated_fatty_acid |
An industrial park, also known as industrial estate or trading estate, is an area zoned and planned for the purpose of industrial development. An industrial park can be thought of as a more heavyweight version of a business park or office park, which has offices and light industry, rather than heavy industry. Industrial parks are notable for being relatively simple to build; they often feature speedily erected single-space steel sheds, occasionally in bright colours.
== Benefits ==
Industrial parks are usually located on the edges of, or outside, the main residential area of a city, and are normally provided with good transportation access, including road and rail. One such example is the large number of industrial estates located along the River Thames in the Thames Gateway area of London. Industrial parks are usually located close to transport facilities, especially where more than one transport modes coincide, including highways, railroads, airports and ports. Another common feature of a North American industrial park is a water tower, which helps to hold enough water to meet the park's demands and for firefighting purposes, and also advertises the industrial park and locality, as usually the community's name and logo are painted onto its surface.
This idea of setting land aside through this type of zoning has several purposes:
By concentrating dedicated infrastructure in a delimited area, to reduce the per-business cost of that infrastructure. Such infrastructure includes roadways, railroad sidings, ports, high-power electric supplies (often including three-phase electric power), high-end communications cables, large-volume water supplies, and high-volume gas lines.
To attract new business by providing an integrated infrastructure in one location.
Eligibility of Industrial Parks for benefits.
To set apart industrial uses from urban areas to try to reduce the environmental and social impact of the industrial uses.
To provide for localized environmental controls that are specific to the needs of an industrial area.
== Benchmarking ==
Benchmarking helps to rank industrial parks based on various criteria, including performance, investment, environmental protection, social responsibility, and governance (ESG).
For the manufacturing companies located in industrial parks, the performance of industrial park operators is important, as the costs for infrastructure and services charged by the industrial park operator is a serious factor for the competitiveness of the manufacturing companies.
== Criticism ==
Different industrial parks fulfill these criteria to differing degrees. Many small communities have established industrial parks with only access to a nearby highway, and with only the basic utilities and roadways. Public transportation options may be limited or non-existent.
Industrial parks in developing countries such as Pakistan face a myriad of additional difficulties. This includes the availability of a skilled workforce and the clustering together of radically different industrial sectors (pharmaceuticals and heavy engineering, for example), which often leads to unfavorable outcomes for quality centered industries.
== Variations ==
An industrial park specializing in biotechnology is called a biotechnology industrial park. It may also be known as a bio-industrial park or eco-industrial cluster.
Flatted factories exist in cities like Singapore and Hong Kong, where land is scarce. These are typically similar to flats, but house individual industries instead. Flatted factories have cargo lifts and roads that serve each level, providing access to each factory lot.
== Countries ==
=== India ===
India was one of the first countries in Asia to recognize the effectiveness of the Export Processing Zone (EPZ) model in promoting exports, with Asia's first EPZ set up in Kandla in 1965. In order to overcome the shortcomings experienced on account of the multiplicity of controls and clearances; absence of world-class infrastructure, and an unstable fiscal regime and with a view to attract larger foreign investments in India, the Special Economic Zones (SEZs) Policy was announced in April 2000. A special economic zone (SEZ) is a geographical region that has economic laws that are more liberal than a country's domestic economic laws. India has specific laws for its SEZs. The category 'SEZ' covers a broad range of more specific zone types, including free-trade zones (FTZ), export processing zones (EPZ), free zones (FZ), industrial estates (IE), free ports, urban enterprise zones and others. Usually, the goal of a structure is to increase foreign direct investment by foreign investors, typically an international business or a Multi National Corporation (MNC).
Notable SEZs in India
DGDC SEZ, Surat (SURSEZ)
Dholera SEZ, Gujarat
Divi's Laboratories Limited Chippada Village, Visakhapatnam, Andhra Pradesh Pharmaceuticals
DLF Cyber City, Gurgaon Gurgaon, Haryana IT/ITES
HCL ELCOT SEZ – Sholingnalur, Chennai
HCL IT city, Lucknow, Uttar Pradesh IT & Start-Up
Infosys Technologies SEZ Mangaluru Bengaluru, Karnataka IT/ITES
Jindal Steel and Power, Choudwar
Kandla SEZ, Gandhidham, Gujarat{KASEZ}
POSCO India SEZ, Paradeep
Mundra Port & Special Economic Zone, Multi Product
Maharashtra Industrial Development Corporation Ltd., Pune - IT/ITES
Reliance Jamnagar Infrastructure Ltd. Jamnagar Multi Product
Zydus Infrastructure Pvt. Ltd. Sanand, Ahmedabad Pharmaceutical
Larsen & Toubro Limited's IT/ ITeS SEZ at Surat, Gujarat
Calica Group's "3rd eye voice" IT/ITES SEZ, Ahmedabad
Gallops Engineering SEZ, Moraiyya, Near Changodar, Ahmedabad
Vatva Ahmedabad
Infocity IT Park, IT/ITES, Gandhinagar, Gujarat
GIFT SEZ, GIFT CITY, Gandhinagar, Gujarat
DAHEJ SEZ 1 and 2, Tal Vagra, Bharuch
TCS Garima Park IT/ITES SEZ, Gandhinagar
WIPRO Limited Doddakannelli Village, Varthur Hobli, Electronic City, Bengaluru IT
=== Turkey ===
An organized industrial zone (Turkish: Organize Sanayi Bölgesi) is a kind of special economic zone in Turkey. These zones were legislated for between 2000 and 2007, and may bring together related (OIZs for function) industries or just be a special zone for many industries (mixed OIZs).
Not every industry is allowed to operate in organized industrial zones.
== See also ==
Eco-industrial park
Cyberpark
Energy park
Free trade zone
Industrial district
Industrial railway
Mill town
Megasite
== References ==
== External links == | Wikipedia/Biotechnology_industrial_park |
1,3-Bisphosphoglyceric acid (1,3-Bisphosphoglycerate or 1,3BPG) is a 3-carbon organic molecule present in most, if not all, living organisms. It primarily exists as a metabolic intermediate in both glycolysis during respiration and the Calvin cycle during photosynthesis. 1,3BPG is a transitional stage between glycerate 3-phosphate and glyceraldehyde 3-phosphate during the fixation/reduction of CO2. 1,3BPG is also a precursor to 2,3-bisphosphoglycerate which in turn is a reaction intermediate in the glycolytic pathway.
== Biological structure and role ==
1,3-Bisphosphoglycerate is the conjugate base of 1,3-bisphosphoglyceric acid. It is phosphorylated at the number 1 and 3 carbons. The result of this phosphorylation gives 1,3BPG important biological properties such as the ability to phosphorylate ADP to form the energy storage molecule ATP.
=== In glycolysis ===
Compound C00118 at KEGG Pathway Database. Enzyme 1.2.1.12 at KEGG Pathway Database. Compound C00236 at KEGG Pathway Database. Enzyme 2.7.2.3 at KEGG Pathway Database. Compound C00197 at KEGG Pathway Database.
As previously mentioned 1,3BPG is a metabolic intermediate in the glycolytic pathway. It is created by the exergonic oxidation of the aldehyde in G3P. The result of this oxidation is the conversion of the aldehyde group into a carboxylic acid group which drives the formation of an acyl phosphate bond. This is incidentally the only step in the glycolytic pathway in which NAD+ is converted into NADH. The formation reaction of 1,3BPG requires the presence of an enzyme called glyceraldehyde-3-phosphate dehydrogenase.
The high-energy acyl phosphate bond of 1,3BPG is important in respiration as it assists in the formation of ATP. The molecule of ATP created during the following reaction is the first molecule produced during respiration. The reaction occurs as follows;
1,3-bisphosphoglycerate + ADP ⇌ 3-phosphoglycerate + ATP
The transfer of an inorganic phosphate from the carboxyl group on 1,3BPG to ADP to form ATP is reversible due to a low ΔG. This is as a result of one acyl phosphate bond being cleaved whilst another is created. This reaction is not naturally spontaneous and requires the presence of a catalyst. This role is performed by the enzyme phosphoglycerate kinase. During the reaction phosphoglycerate kinase undergoes a substrate induced conformational change similar to another metabolic enzyme called hexokinase.
Because two molecules of glyceraldehyde-3-phosphate are formed during glycolysis from one molecule of glucose, 1,3BPG can be said to be responsible for two of the ten molecules of ATP produced during the entire process. Glycolysis also uses two molecules of ATP in its initial stages as a committed and irreversible step. For this reason glycolysis is not reversible and has a net produce of 2 molecules of ATP and two of NADH. The two molecules of NADH themselves go on to produce approximately 3 molecules of ATP each.
Click on genes, proteins and metabolites below to link to respective articles.
=== In the Calvin cycle ===
1,3-BPG has a very similar role in the Calvin cycle to its role in the glycolytic pathway. For this reason both reactions are said to be analogous. However the reaction pathway is effectively reversed. The only other major difference between the two reactions is that NADPH is used as an electron donor in the calvin cycle whilst NAD+ is used as an electron acceptor in glycolysis. In this reaction cycle 1,3BPG originates from 3-phosphoglycerate and is made into glyceraldehyde 3-phosphate by the action of specific enzymes.
Contrary to the similar reactions of the glycolytic pathway, 1,3BPG in the Calvin cycle does not produce ATP but instead uses it. For this reason it can be considered to be an irreversible and committed step in the cycle. The outcome of this section of the cycle is an inorganic phosphate is removed from 1,3BPG as a hydrogen ion and two electrons are added to the compound+.
In complete reverse of the glycolytic pathway reaction, the enzyme phosphoglycerate kinase catalyses the reduction of the carboxyl group of 1,3BPG to form an aldehyde instead. This reaction also releases an inorganic phosphate molecule which is subsequently used as energy for the donation of electrons from the conversion of NADPH to NADP+. Overseeing this latter stage of the reaction is the enzyme glyceraldehyde-phosphate dehydrogenase.
=== In oxygen transfer ===
During normal metabolism in human erythrocytes, ≈19% of the 1,3BPG produced does not go any further in the glycolytic pathway. It is instead shunted through the Luebering–Rapoport pathway involving the reduction of ATP in the red blood cells. During this alternate pathway it is made into a similar molecule called 2,3-bisphosphoglyceric acid (2,3BPG). 2,3BPG is used as a mechanism to oversee the efficient release of oxygen from hemoglobin. Levels of this 1,3BPG will raise in a patient's blood when oxygen levels are low as this is one of the mechanisms of acclimatization. Low oxygen levels trigger a rise in 1,3BPG levels which in turn raises the level of 2,3BPG which alters the efficiency of oxygen dissociation from hemoglobin.
== References ==
Alberts, Bruce; et al. (2001). Molecular Biology of the Cell. New York: Garland Science. ISBN 0-8153-4072-9.
Germann, William J.; Stanfield, Cindy L. (2002). Principles of Human Physiology. San Francisco: Benjamin Cummings. ISBN 0-8053-6056-5.
Stryer, Lubert; et al. (2002). Biochemistry (5th ed.). New York: W. H. Freeman. ISBN 0-7167-4684-0.
== External links ==
1,3BPG in Glycolysis and Fermentation
Medical Dictionary reference for 1,3BPG
1,3BPG enzyme mechanisms Archived 2013-04-14 at archive.today | Wikipedia/1,3-bisphosphoglycerate |
Sickle cell disease (SCD), also simply called sickle cell, is a group of inherited haemoglobin-related blood disorders. The most common type is known as sickle cell anemia. Sickle cell anemia results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells. This leads to the red blood cells adopting an abnormal sickle-like shape under certain circumstances; with this shape, they are unable to deform as they pass through capillaries, causing blockages. Problems in sickle cell disease typically begin around 5 to 6 months of age. A number of health problems may develop, such as attacks of pain (known as a sickle cell crisis) in joints, anemia, swelling in the hands and feet, bacterial infections, dizziness and stroke. The probability of severe symptoms, including long-term pain, increases with age. Without treatment, people with SCD rarely reach adulthood but with good healthcare, median life expectancy is between 58 and 66 years. All of the major organs are affected by sickle cell disease. The liver, heart, kidneys, gallbladder, eyes, bones, and joints can be damaged from the abnormal functions of the sickle cells and their inability to effectively flow through the small blood vessels.
Sickle cell disease occurs when a person inherits two abnormal copies of the β-globin gene that makes haemoglobin, one from each parent. Several subtypes exist, depending on the exact mutation in each haemoglobin gene. An attack can be set off by temperature changes, stress, dehydration, and high altitude. A person with a single abnormal copy does not usually have symptoms and is said to have sickle cell trait. Such people are also referred to as carriers. Diagnosis is by a blood test, and some countries test all babies at birth for the disease. Diagnosis is also possible during pregnancy.
The care of people with sickle cell disease may include infection prevention with vaccination and antibiotics, high fluid intake, folic acid supplementation, and pain medication. Other measures may include blood transfusion and the medication hydroxycarbamide (hydroxyurea). In 2023, new gene therapies were approved involving the genetic modification and replacement of blood forming stem cells in the bone marrow.
As of 2021, SCD is estimated to affect about 7.7 million people worldwide, directly causing an estimated 34,000 annual deaths and a contributory factor to a further 376,000 deaths. About 80% of sickle cell disease cases are believed to occur in Sub-Saharan Africa. It also occurs to a lesser degree among people in parts of India, Southern Europe, West Asia, North Africa and among people of African origin (sub-Saharan) living in other parts of the world. The condition was first described in the medical literature by American physician James B. Herrick in 1910. In 1949, its genetic transmission was determined by E. A. Beet and J. V. Neel. In 1954, it was established that carriers of the abnormal gene are protected to some degree against malaria.
== Signs and symptoms ==
Signs of sickle cell disease usually begin in early childhood. The severity of symptoms can vary from person to person, as can the frequency of crisis events. Sickle cell disease may lead to various acute and chronic complications, several of which have a high mortality rate.
=== First events ===
When SCD presents within the first year of life, the most common problem is an episode of pain and swelling in the child's hands and feet, known as dactylitis or "hand-foot syndrome." Pallor, jaundice, and fatigue can also be early signs due to anaemia resulting from sickle cell disease.
In children older than 2 years, the most common initial presentation is a painful episode of a generalized or variable nature, while a slightly less common presentation involves acute chest pain. Dactylitis is rare or almost never occurs in children over the age of 2.
=== Critical events ===
==== Vaso-occlusive crisis ====
Also termed "sickle cell crisis" or "sickling crisis", the vaso-occlusive crisis (VOC) manifests principally as extreme pain, most often affecting the chest, back, legs and/or arms. The underlying cause is sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organ, resulting in ischaemia, pain, necrosis, and often organ damage. The frequency, severity, and duration of these crises vary considerably. Milder crises can be managed with nonsteroidal anti-inflammatory drugs. For more severe crises, patients may require inpatient management for intravenous opioids. Vaso-occlusive crisis involving organs such as the penis or lungs are considered an emergency and treated with red blood cell transfusions.
A VOC can be triggered by anything which causes blood vessels to constrict; this includes physical or mental stress, cold, and dehydration. "After HbS deoxygenates in the capillaries, it takes some time (seconds) for HbS polymerization and the subsequent flexible-to-rigid transformation. If the transit time of RBC through the microvasculature is longer than the polymerization time, sickled RBC will lodge in the microvasculature."
==== Splenic sequestration crisis ====
The spleen is especially prone to damage in SCD due to its role as a blood filter. A splenic sequestration crisis, also known as a spleen crisis, is a medical emergency that occurs when sickled red blood cells block the spleen's filter mechanism, causing the spleen to swell and fill with blood. The accumulation of red blood cells in the spleen results in a sudden drop in circulating hemoglobin and potentially life-threatening anemia. Symptoms include pain on the left side, swollen spleen (which can be detected by palpation), fatigue, dizziness, irritability, rapid heartbeat, or pale skin. It most commonly affects young children, the median age of first occurrence is 1.4 years. By the age of 5 years repeated instances of sequestration cause scarring and eventual atrophy of the spleen.
Treatment is supportive, with blood transfusion if hemoglobin levels fall too low. Full or partial splenectomy may be necessary. Long term consequences of a loss of spleen function are increased susceptibility to bacterial infections.
==== Acute chest syndrome ====
Acute chest syndrome is caused by a VOC which affects the lungs, possibly triggered by infection or by emboli which have circulated from other organs. Symptoms include wheezing, chest pain, fever, pulmonary infiltrate (visible on x-ray), and hypoxemia. After sickling crisis (see above) it is the second-most common cause of hospitalization and it accounts for about 25% of deaths in patients with SCD. Most cases present with vaso-occlusive crises, and then develop acute chest syndrome.
==== Aplastic crisis ====
Aplastic crises are instances of an acute worsening of the patient's baseline anaemia, producing pale appearance, fast heart rate, and fatigue. This crisis is normally triggered by parvovirus B19, which directly affects production of red blood cells by invading the red cell precursors and multiplying in and destroying them. Parvovirus infection almost completely prevents red blood cell production for two to three days (red cell aplasia). In normal individuals, this is of little consequence, but the shortened red cell life of SCD patients results in an abrupt, life-threatening situation. Reticulocyte count drops dramatically during the disease (causing reticulocytopenia), red cell production lapses, and the rapid destruction of existing red cells leads to acute and severe anemia. This crisis takes four to seven days to resolve. Most patients can be managed supportively; some need a blood transfusion.
=== Complications ===
Sickle cell anaemia can lead to various complications including:
Increased risk of severe bacterial infections is due to loss of functioning spleen tissue. These infections are typically caused by bacteria such as Streptococcus pneumoniae and Haemophilus influenzae. Daily penicillin prophylaxis is the most commonly used treatment during childhood, with some haematologists continuing treatment indefinitely. Patients benefit from routine vaccination for S. pneumoniae.
Stroke can result from blockage of blood vessels in the brain, causing numbness, confusion, or weakness which may be long lasting. Silent stroke causes no immediate symptoms, but is associated with damage to the brain. Silent stroke is probably five times as common as symptomatic stroke. About 10–15% of children with SCD have strokes, with silent strokes predominating in the younger patients.
Cholelithiasis (gallstones) and cholecystitis may result from excessive bilirubin production and precipitation due to prolonged haemolysis.
Avascular necrosis (aseptic bone necrosis) of the hip and other major joints may occur as a result of ischaemia.
Priapism and infarction of the penis
Osteomyelitis (bacterial bone infection) as a result of damage to the spleen, commonly caused by either Staphylococcus aureus or species of Salmonella.
Chronic kidney failure due to sickle-cell nephropathy manifests itself with hypertension, protein loss in the urine, loss of red blood cells in urine and worsened anaemia. If it progresses to end-stage kidney failure, it carries a poor prognosis.
Leg ulcers are relatively common in SCD and can be disabling.
In eyes, background retinopathy, proliferative retinopathy, vitreous haemorrhages, and retinal detachments can result in blindness. Regular annual eye checks are recommended.
During pregnancy, intrauterine growth restriction, spontaneous abortion, and pre-eclampsia
Chronic pain: Even in the absence of acute vaso-occlusive pain, many patients have unreported chronic pain.
Pulmonary hypertension (increased pressure on the pulmonary artery) can lead to strain on the right ventricle and a risk of heart failure; typical symptoms are shortness of breath, decreased exercise tolerance, and episodes of syncope. 21% of children and 30% of adults have evidence of pulmonary hypertension when tested; this is associated with reduced walking distance and increased mortality.
Cardiomyopathy and left ventricular diastolic dysfunction caused by fibrosis or scarring of cardiac tissues. This also contributes to pulmonary hypertension, decreased exercise capacity, and arrhythmias.
== Genetics ==
Hemoglobin is an oxygen-binding protein, found in erythrocytes, which transports oxygen from the lungs (or in the fetus, from the placenta) to the tissues. Each molecule of hemoglobin comprises 4 protein subunits, referred to as globins. Normally, humans have:-
hemoglobin F (Fetal hemoglobin, HbF), consisting of two alpha (α-globin) and two gamma (γ-globin) chains. This dominates during development of the fetus and until about 6 weeks of age. Afterwards, haemoglobin A dominates throughout life.
hemoglobin A, (Adult hemoglobin, HbA) which consists of two alpha and two beta (β-globin) chains. This is the most common human hemoglobin tetramer, accounting for over 97% of the total red blood cell hemoglobin in normal adults.
hemoglobin A2, (HbA2) is a second form of adult hemoglobin and is composed of two alpha and two delta (δ-globin) chains. This hemoglobin typically makes up 1–3% of hemoglobin in adults.
β-globin is encoded by the HBB gene on human chromosome 11; mutations in this gene produce variants of the protein which are implicated with abnormal hemoglobins. The mutation which causes sickle cell disease results in an abnormal hemoglobin known as hemoglobin S (HbS), which replaces HbA in adults. The human genome contains a pair of genes for β-globin; in people with sickle cell disease, both genes are affected and the erythropoietic cells in the bone marrow will only create HbS. In people with sickle cell trait, only one gene is abnormal; erythropoiesis generates a mixture of normal HbA and sickle HbS. The person has very few if any symptoms of sickle cell disease but carries the gene and can pass it on to their children.
Sickle cell disease has an autosomal recessive pattern of inheritance from parents. Both copies of the affected gene must carry the same mutation (homozygous condition) for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry one mutated gene and one normal gene (heterozygous condition) and are referred to as genetic carriers; they may not have any symptoms. When both parents have the sickle cell trait, any given child has a 25% chance of sickle cell disease; a 25% chance of no sickle cell alleles, and a 50% chance of the heterozygous condition (see diagram).
There are several different haplotypes of the sickle cell gene mutation, indicating that it probably arose spontaneously in different geographic areas. The variants are known as Cameroon, Senegal, Benin, Bantu, and Saudi-Asian. These are clinically important because some are associated with higher HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have milder disease.
The gene defect is a single nucleotide mutation of the β-globin gene, which results in glutamate being substituted by valine at position 6 of the β-globin chain. Hemoglobin S with this mutation is referred to as HbS, as opposed to the normal adult HbA. Under conditions of normal oxygen concentration this causes no apparent effects on the structure of haemoglobin or its ability to transport oxygen around the body. However, the deoxy form of HbS has an exposed hydrophobic patch which causes HbS molecules to join to form long inflexible chains. Under conditions of low oxygen concentration in the bloodstream, such as exercise, stress, altitude or dehydration, HbS polymerization forms fibrous precipitates within the red blood cell. In people homozygous for the sickle cell mutation, the presence of long-chain polymers of HbS distort the shape of the red blood cell from a smooth, doughnut-like shape to the sickle shape, making it fragile and susceptible to blocking or breaking within capillaries.
In people heterozygous for HbS (carriers of sickle cell disease), the polymerisation problems are minor because the normal allele can produce half of the haemoglobin. Sickle cell carriers have symptoms only if they are deprived of oxygen (for example, at altitude) or while severely dehydrated.
=== Malaria ===
SCD is most prevalent in areas which have historically been associated with endemic malaria. The sickle cell trait provides a carrier with a survival advantage against malaria fatality over people with normal hemoglobin in regions where malaria is endemic.
Infection with the malaria parasite affects asymptomatic carriers of the abnormal hemoglobin gene differently from patients with full SCD. Carriers (heterozygous for the gene) who catch malaria are less likely to suffer from severe symptoms than people with normal hemogolobin. SCD patients (homozygous for the gene) are similarly less likely to become infected with malaria; however once infected they are more likely to develop severe and life-threatening anemia.
The impact of sickle cell anemia on malaria immunity illustrates some evolutionary trade-offs that have occurred because of endemic malaria. Although the shorter life expectancy for those with the homozygous condition would tend to disfavour the trait's survival, the trait is preserved in malaria-prone regions because of the benefits provided by the heterozygous form; an example of natural selection.
Due to the adaptive advantage of the heterozygote, the disease is still prevalent, especially among people with recent ancestry in malaria-stricken areas, such as Africa, the Mediterranean, India, and the Middle East. Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century, with the exception of rare sporadic cases.
The malaria parasite has a complex lifecycle and spends part of it in red blood cells. There are two mechanisms which protect sickle cell carriers from malaria. One is that the parasite is hindered from growing and reproducing in a carrier's red blood cells; another is that a carrier's red cells show signs of damage when infected, and are detected and destroyed as they pass through the spleen.
== Pathophysiology ==
Under conditions of low oxygen concentration, HBS polymerises to form long strands within the red blood cell (RBC). These strands distort the shape of the cell and after a few seconds cause it to adopt an abnormal, inflexible sickle-like shape. This process reverses when oxygen concentration is raised and the cells resume their normal biconcave disc shape. If sickling takes place in the venous system, after blood has passed through the capillaries, it has no effect on the organs and the RBCs can unsickle when they become oxygenated in the lungs. Repeated switching between sickle and normal shapes damages the membrane of the RBC so that it eventually becomes permanently sickled.
Normal red blood cells are quite elastic and have a biconcave disc shape, which allows the cells to deform to pass through capillaries. In sickle cell disease, low oxygen tension promotes red blood cell sickling and repeated episodes of sickling damage the cell membrane and decrease the cell's elasticity. These cells fail to return to normal shape when normal oxygen tension is restored. As a consequence, these rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel occlusion and ischaemia.
Cells which have become sickled are detected as they pass through the spleen and are destroyed. In young children with SCD, the accumulation of sickled cells in the spleen can result in splenic sequestration crisis. In this, the spleen becomes engorged with blood, depriving the general circulation of blood cells and leading to severe anemia. The spleen initially becomes noticeably swollen but the lack of a healthy blood flow through the organ culminates in scarring of the spleen tissues and eventually death of the organ, generally before the age of 5 years.
The actual anaemia of the illness is caused by haemolysis, the destruction of the red cells, because of their shape. Although the bone marrow attempts to compensate by creating new red cells, it does not match the rate of destruction. Healthy red blood cells typically function for 90–120 days, but sickled cells only last 10–20 days.
The rapid breakdown of RBC's in SCD results in the release of free heme into the bloodstream exceeding the capacity of the body's protective mechanisms. Although heme is an essential component of hemoglobin, it is also a potent oxidative molecule. Free heme is also an alarmin - a signal of tissue damage or infection, which triggers defensive responses in the body and increases the risk of inflammation and vaso-occlusive events.
== Diagnosis ==
=== Prenatal and newborn screening ===
Checking for SCD begins during pregnancy, with a prenatal screening questionnaire which includes, among other things, a consideration of health issues in the child's parents and close relatives. During pregnancy, genetic testing can be done on either a blood sample from the fetus or a sample of amniotic fluid. During the first trimester of pregnancy, chorionic villus sampling (CVS) is also a technique used for SCD prenatal diagnosis. A routine heel prick test, in which a small sample of blood is collected a few days after birth, is used to check conclusively for SCD as well as other inherited conditions.
=== Tests ===
Where SCD is suspected, a number of tests can be used. Often a simpler, cheaper test is applied first with a more complex test such as DNA analysis used to confirm a positive result.
Two tests which are specific for SCD:
A blood smear is a thin layer of blood smeared on a glass microscope slide and then stained in such a way as to allow the various blood cells to be examined microscopically. This technique can be used to visually detect sickled cells, however it does not detect sickle carriers.
A solubility test relies on the fact that HbS is less soluble than normal hemoglobin (HbA); it is highly reliable but does not distinguish between full SCD and carrier status.
Tests which can be used for SCD as well as for other hemoglobinopathies:
Hemoglobin electrophoresis is a test that can detect different types of hemoglobin. Hemoglobin is extracted from the red cells, then introduced into a porous gel and subjected to an electrical field. This separates the normal and abnormal types of hemoglobin which can then be identified and quantified.
Isoelectric focusing (IEF) is a technique that can be used to diagnose sickle cell disease and other hemoglobinopathies. The technique separates molecules based on their isoelectric point, or the pH at which they have no net electrical charge. IEF uses an electric charge to separate and identify different types of hemoglobin, which become focused into sharp stationary bands. The technique can distinguish many types of abnormal hemoglobin.
High-performance liquid chromatography (HPLC) is reliable, fully automated, and able to distinguish most types of sickle cell disease including heterozygous, The method separates and quantifies hemoglobin fractions by measuring their rate of flow through a column of absorbent material.
DNA analysis using polymerase chain reaction (PCR), to amplify small samples of DNA. Variants of PCR used to diagnose SCD include Amplification-refractory mutation system (ARMS) and Allele-Specific Recombinase Polymerase Amplification. These tests can identify subtypes of SCD as well as combination hemoglobinopathies.
== Genetic counseling ==
Genetic counselling is the process by which people with a hereditary disorder are advised of the probability of transmitting it and the ways in which this may be prevented or ameliorated.
People who are known carriers of the disease or at risk of having a child with sickle cell anemia may undergo genetic counseling. Genetic counselors work with families to discuss the benefits, limitations, and logistics of genetic testing options as well as the potential impact of testing and test results on the individual. Counselling is best given before a child is conceived, and a number of possible courses could be suggested. These include adoption, the use of eggs or sperm from a healthy donor, and in-vitro fertilisation (IVF) when combined with pre-implantation genetic diagnosis of the embryos.
== Treatment ==
=== Management ===
There are a number of precautions which can help reduce the risk of developing a sickling crisis. Lifestyle behaviours include maintaining good hydration and avoiding physical stress or exhaustion. Since sickling can be triggered by low oxygen levels, people with SCD should avoid high altitudes such as high mountains or flying in unpressurised aircraft. People with SCD should avoid alcohol and smoking, as alcohol can cause dehydration and smoking can trigger acute chest syndrome. Stress can also trigger a sickle cell crisis, so relaxation techniques like breathing exercises can help.
Pneumococcal infection is a leading cause of death among children with SCD; penicillin is recommended daily during the first 5 years of life in order to minimise the risk of infection.
Dietary supplementation of folic acid is sometimes recommended, on the basis that it facilitates the creation of new red blood cells and may reduce anemia. A Cochrane review of its use in 2016 found "the effect of supplementation on anaemia and any symptoms of anaemia remains unclear" due to a lack of medical evidence.
People with SCD are recommended to receive all vaccinations which are recommended by health authorities in order to avoid serious infection which might trigger a sickling crisis.
Hydroxyurea was the first approved drug for the treatment of SCD, which has been shown to decrease the number and severity of attacks and possibly increase survival time. This is achieved, in part, by reactivating fetal haemoglobin production in place of the haemoglobin S that causes sickling. Hydroxyurea lowers the expression of adhesion molecules on endothelial and red blood cells, which lowers the chance of small vessel blockages. Additionally, it encourages the release of nitric oxide, which enhances blood flow and inhibits the formation of clots. Hydroxyurea had previously been used as a chemotherapy agent, and some concern exists that long-term use may be harmful. A Cochrane review in 2022 found a weak evidence base for its use in SCD.
Voxelotor was received accelerated approval as a treatment for SCD in the United States in 2019, and was approved by the European Medicines Agency (EMA) in 2021. In trials, it had been shown to have disease-modifying potential by increasing hemoglobin levels and decreasing hemolysis indicators However, following an increased risk of vaso-occlusive seizures and death observed in registries and clinical trials, the manufacturer, Pfizer, withdrew it from the market worldwide.
=== Blood transfusion ===
A simple blood transfusion can be used to treat SCD when hemoglobin levels drop too low, or to prepare for an operation or pregnancy. It can also be used to protect against long-term complications, or to reduce the risk of stroke. The simple, or top-up transfusion is a procedure in which healthy blood cells from a donor are infused into the patient's bloodstream. This benefits by alleviating anemia and increasing oxygen levels in the tissues, reducing the risk of sickling and relieving sickling symptoms. A simple transfusion can be used to treat SCD when hemoglobin levels drop too low, or to prepare for an operation or pregnancy. It can also be used to protect against long-term complications, or to reduce the risk of stroke.
An exchange transfusion is a procedure in which blood is removed from the body, then processed to extract sickled cells, which are replaced by healthy red blood cells from a donor. The treated blood, including white cells and plasma, is then returned to the patient. Exchange transfusions are likely to be needed in an emergency, in severe cases of SCD, or to support a mother during pregnancy.
=== Stroke prevention ===
Transcranial Doppler ultrasound (TCD) can detect children with sickle cell that have a high risk for stroke. The ultrasound test detects blood vessels partially obstructed by sickle cells by measuring the rate of blood into the brain, as blood flow velocity is inversely related to arterial diameter, and consequently, high blood-flow velocity is correlated with narrowing of the arteries.
In children, preventive RBC transfusion therapy has been shown to reduce the risk of first stroke or silent stroke when transcranial Doppler ultrasonography shows abnormal cerebral blood flow. In those who have sustained a prior stroke event, it also reduces the risk of recurrent stroke and additional silent strokes.
=== Vaso-occlusive crisis ===
Most people with sickle cell disease have intensely painful episodes called vaso-occlusive crises (VOC). However, the frequency, severity, and duration of these crises vary tremendously. In a VOC, the circulation of blood vessels is obstructed by sickled red blood cells, causing ischemic injuries to the tissues, inflammation and pain. Recurrent episodes may cause irreversible organ damage.
The most common and obvious symptom of a VOC is pain, which may be felt anywhere in the body but most commonly in the limbs and back. The degree of pain varies from mild to severe. Home treatment options include bedrest and hydration, and pain control using over-the-counter medication such as paracetamol or ibuprofen. More severe cases may require prescription opioids such as codeine or morphine for pain control.
In 2019, crizanlizumab, a monoclonal antibody targeting P-selectin, was approved in the United States to reduce the frequency of vaso-occlusive crisis in those 16 years and older. It had also been approved in the UK and Europe, but in both cases authorisation was subsequently withdrawn because of poor evidence of its effectiveness.
=== Acute chest syndrome ===
Acute chest syndrome is caused by vaso-occlusion occurring in the lungs. As with a VOC, treatment includes pain control and hydration. Antibiotics are required because there is a severe risk of pulmonary infection, and oxygen supplementation for hypoxia. Blood transfusion may also be required, or exchange transfusion in severe cases.
=== Treating avascular necrosis ===
When treating avascular necrosis of the bone in people with sickle cell disease, the aim of treatment is to reduce or stop the pain and maintain joint mobility. Treatment options include resting the joint, physical therapy, pain-relief medicine, joint-replacement surgery, or bone grafting.
=== Psychological therapy ===
Psychological therapies such as patient education, cognitive therapy, behavioural therapy, and psychodynamic psychotherapy, that aim to complement current medical treatments, require further research to determine their effectiveness.
== Stem cell treatments ==
Hematopoietic stem cells (HSC) are cells in the bone marrow that can develop into all types of blood cells, including red blood cells, white blood cells, and platelets. There are two possible ways to treat SCD and some other hemoglobinopathies by targeting HSCs. Since 1991, a small number of patients have received bone marrow transplants from healthy matched donors, although this procedure has a high level of risk. More recently, it has become possible to use CRISPR gene editing technology to modify the patient's own HSCs in a way that reduces or eliminates the production of sickle hemoglobin HbS and replaces it with a non-sickling form of hemoglobin.
All stem cell treatments must involve myeloablation of the patients' bone marrow in order to remove HSCs containing the faulty gene. This requires high doses of chemotherapy agents with side effects such as sickness and tiredness. A long hospital stay is necessary after infusion of the replacement HSCs while the cells take up residence in the bone marrow and start to make red blood cells with the stable form of haemoglobin.
=== Gene therapy ===
Gene therapy was first trialled in 2014 on a single patient, and followed by clinical trials in which a number of patients were successfully treated. In 2023, both exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) were approved for the treatment of sickle cell disease. Kendric Cromer in October 2024 became the first commercial case in the USA to receive gene therapy and was discharged from Children's National Hospital. The one-off gene-editing therapy, Casgevy, also known as Exa-cel, is to be offered to patients on the National Health Service (NHS) in England as from 2025.
Both Casgevy and Lyfgenia work by first harvesting the patient's HSCs, then using CRISPR gene editing to modify their DNA in the laboratory. In parallel with this, the person with sickle cell disease's bone marrow is put through a myeloablation procedure to destroy the remaining HSCs. The treated cells are then infused back into the patient where they colonise the bone marrow and eventually resume production of blood cells. Casgevy works by editing the BCL11A gene, which normally inhibits the production of hemoglobin F (fetal hemoglobin) in adults. The edit has the effect of increasing production of HbF, which is not prone to sickling. Lyfgenia introduces a new gene for T87Q-globin which coexists with the sickling beta-globin but reduces the incidence of sickling.
=== Hematopoietic stem cell transplantation ===
Hematopoietic stem cell transplantation (HSCT) involves replacing the dysfunctional stem cells from a person with sickle cell disease with healthy cells from a well-matched donor. Finding a well matched donor is essential to the process' success. Different types of donors may be suitable and include umbilical cord blood, human leukocyte antigen (HLA) matched relatives, or HLA matched donors that are not related to the person being treated. Risks associated with HSCT can include graft-versus host disease, failure of the graft, and other toxicity related to the transplant.
== Prognosis ==
Sickle cell disease is most prevalent in sub-saharan Africa. In areas without healthcare infrastructure, it is estimated that between 50% and 90% of children born with the disease die before the age of 5 years.
In contrast, life expectancy in the United States in 2010–2020 was 43 years and in the UK 67 years.
== Epidemiology ==
The HbS gene can be found in every ethnic group. The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, tribal regions of India, and the Middle East. About 80% of sickle cell disease cases are believed to occur in Sub-Saharan Africa. Migration of substantial populations from these high-prevalence areas to low-prevalence countries in Europe has dramatically increased in recent decades and in some European countries, sickle cell disease has now overtaken more familiar genetic conditions such as haemophilia and cystic fibrosis. In 2015, it resulted in about 114,800 deaths.
Sickle cell disease occurs more commonly among people whose ancestors lived in tropical and subtropical sub-Saharan regions where malaria is or was common. Where malaria is common, carrying a single sickle cell allele (trait) confers a heterozygote advantage; humans with one of the two alleles of sickle cell disease show less severe symptoms when infected with malaria.
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
=== Africa ===
Three-quarters of sickle cell cases occur in Africa. A WHO report dated 2006 estimated that around 2% of newborns in Nigeria were affected by sickle cell anaemia, giving a total of 150,000 affected children born every year in Nigeria alone. The carrier frequency ranges between 10 and 40% across equatorial Africa, decreasing to 1–2% on the North African coast and <1% in South Africa. In the West African countries of Ghana and Nigeria, the frequencies can vary from 15 to 30%. In the whole of Nigeria, 24% of the population carries the gene, and 20 per 1000 newborns are born with the disease, or 150 000 annually.
Uganda has the fifth-highest sickle cell disease burden in Africa. One study indicates that 20 000 babies per year, or 0.7% of the total, are born with sickle cell disease, and 13.3% carry the trait. In Uganda, carrier frequency of the trait varies strongly across tribal lines: among the Baamba, it reaches 45%.
=== United States ===
The number of people with the disease in the United States is about 100,000 (one in 3,300), mostly affecting Americans of sub-Saharan African descent. In the United States, about one out of 365 African-American children and one in every 16,300 Hispanic-American children have sickle cell anaemia. The life expectancy for men with SCD is approximately 42 years of age while women live approximately six years longer. An additional 2 million are carriers of the sickle cell trait. Most infants with SCD born in the United States are identified by routine neonatal screening. As of 2016 all 50 states include screening for sickle cell disease as part of their newborn screen. The newborn's blood is sampled through a heel-prick and is sent to a lab for testing. The baby must have been eating for a minimum of 24 hours before the heel-prick test can be done. Some states also require a second blood test to be done when the baby is two weeks old to ensure the results.
Sickle cell anemia is the most common genetic disorder among African Americans. Approximately 8% are carriers and 1 in 375 are born with the disease. Patient advocates for sickle cell disease have complained that it gets less government and private research funding than similar rare diseases such as cystic fibrosis, with researcher Elliott Vichinsky saying this shows racial discrimination or the role of wealth in health care advocacy. Overall, without considering race, approximately 1.5% of infants born in the United States are carriers of at least one copy of the mutant (disease-causing) gene.
=== France ===
As a result of population growth in African-Caribbean regions of overseas France and immigration from North and sub-Saharan Africa to mainland France, sickle cell disease has become a major health problem in France. SCD has become the most common genetic disease in the country, with an overall birth prevalence of one in 2,415 in mainland France, ahead of phenylketonuria (one in 10,862), congenital hypothyroidism (one in 3,132), congenital adrenal hyperplasia (one in 19,008) and cystic fibrosis (one in 5,014) for the same reference period.
Since 2000, neonatal screening of SCD has been performed at the national level for all newborns defined as being "at-risk" for SCD based on ethnic origin (defined as those born to parents originating from sub-Saharan Africa, North Africa, the Mediterranean area (South Italy, Greece, and Turkey), the Arabic peninsula, the French overseas islands, and the Indian subcontinent).
=== United Kingdom ===
In the United Kingdom, between 12,000 and 15,000 people are thought to have sickle cell disease with an estimated 250,000 carriers of the condition in England alone. As the number of carriers is only estimated, all newborn babies in the UK receive a routine blood test to screen for the condition. Due to many adults in high-risk groups not knowing if they are carriers, pregnant women and both partners in a couple are offered screening so they can get counselling if they have the sickle cell trait. In addition, blood donors from those in high-risk groups are also screened to confirm whether they are carriers and whether their blood filters properly. Donors who are found to be carriers are informed and their blood, while often used for those of the same ethnic group, is not used for those with sickle cell disease who require a blood transfusion.
=== West Asia ===
In Saudi Arabia, about 4.2% of the population carry the sickle cell trait and 0.26% have sickle cell disease. The highest prevalence is in the Eastern province, where approximately 17% of the population carry the gene and 1.2% have sickle cell disease.
In 2005, Saudi Arabia introduced a mandatory premarital test including HB electrophoresis, which aimed to decrease the incidence of SCD and thalassemia.
In Bahrain, a study published in 1998 that covered about 56,000 people in hospitals in Bahrain found that 2% of newborns have sickle cell disease, 18% of the surveyed people have the sickle cell trait, and 24% were carriers of the gene mutation causing the disease. The country began screening of all pregnant women in 1992, and newborns started being tested if the mother was a carrier. In 2004, a law was passed requiring couples planning to marry to undergo free premarital counseling. These programs were accompanied by public education campaigns.
=== India and Nepal ===
Sickle cell disease is common in some ethnic groups of central India, where the prevalence has ranged from 9.4 to 22.2% in endemic areas of Madhya Pradesh, Rajasthan, and Chhattisgarh. It is also endemic among Tharu people of Nepal and India; however, they have a sevenfold lower rate of malaria despite living in a malaria infested zone.
=== Caribbean Islands ===
In Jamaica, 10% of the population carry the sickle cell gene, making it the most prevalent genetic disorder in the country.
== History ==
The first modern report of sickle cell disease may have been in 1846, where the autopsy of an executed runaway slave was discussed; the key finding was the absence of the spleen. Reportedly, African slaves in the United States exhibited resistance to malaria, but were prone to leg ulcers. The abnormal characteristics of the red blood cells, which later lent their name to the condition, was first described by Ernest E. Irons (1877–1959), intern to Chicago cardiologist and professor of medicine James B. Herrick (1861–1954), in 1910. Irons saw "peculiar elongated and sickle-shaped" cells in the blood of a man named Walter Clement Noel, a 20-year-old first-year dental student from Grenada. Noel had been admitted to the Chicago Presbyterian Hospital in December 1904 with anaemia. Noel was readmitted several times over the next three years for "muscular rheumatism" and "bilious attacks" but completed his studies and returned to the capital of Grenada (St. George's) to practice dentistry. He died of pneumonia in 1916 and is buried in the Catholic cemetery at Sauteurs in the north of Grenada. Shortly after the report by Herrick, another case appeared in the Virginia Medical Semi-Monthly with the same title, "Peculiar Elongated and Sickle-Shaped Red Blood Corpuscles in a Case of Severe Anemia." This article is based on a patient admitted to the University of Virginia Hospital on 15 November 1910. In the later description by Verne Mason in 1922, the name "sickle cell anemia" is first used. Childhood problems related to sickle cells disease were not reported until the 1930s, despite the fact that this cannot have been uncommon in African-American populations.
Memphis physician Lemuel Diggs, a prolific researcher into sickle cell disease, first introduced the distinction between sickle cell disease and trait in 1933, although until 1949, the genetic characteristics had not been elucidated by James V. Neel and E.A. Beet. 1949 was the year when Linus Pauling described the unusual chemical behaviour of haemoglobin S, and attributed this to an abnormality in the molecule itself. The molecular change in HbS was described in 1956 by Vernon Ingram. The late 1940s and early 1950s saw further understanding in the link between malaria and sickle cell disease. In 1954, the introduction of haemoglobin electrophoresis allowed the discovery of particular subtypes, such as HbSC disease.
Large-scale natural history studies and further intervention studies were introduced in the 1970s and 1980s, leading to widespread use of prophylaxis against pneumococcal infections amongst other interventions. Bill Cosby's Emmy-winning 1972 TV movie, To All My Friends on Shore, depicted the story of the parents of a child with sickle cell disease. The 1990s had the development of hydroxycarbamide, and reports of cure through bone marrow transplantation appeared in 2007.
Some old texts refer to it as drepanocytosis.
== Society and culture ==
=== United States ===
Sickle cell disease is frequently contested as a disability. Effective 15 September 2017, the U.S. Social Security Administration issued a Policy Interpretation Ruling providing background information on sickle cell disease and a description of how Social Security evaluates the disease during its adjudication process for disability claims.
In the US, there are stigmas surrounding SCD that discourage people with SCD from receiving necessary care. These stigmas mainly affect people of African American and Latin American ancestries, according to the National Heart, Lung, and Blood Institute. People with SCD experience the impact of stigmas of the disease on multiple aspects of life including social and psychological well-being. Studies have shown that those with SCD frequently feel as though they must keep their diagnosis a secret to avoid discrimination in the workplace and also among peers in relationships. In the 1960s, the US government supported initiatives for workplace screening for genetic diseases in an attempt to be protective towards people with SCD. By having this screening, it was intended that employees would not be placed in environments that could potentially be harmful and trigger SCD.
=== Uganda ===
Uganda has the 5th highest sickle cell disease (SCD) burden in the world. In Uganda, social stigma exists for those with sickle cell disease because of the lack of general knowledge of the disease. The general gap in knowledge surrounding sickle cell disease is noted among adolescents and young adults due to the culturally sanctioned secrecy about the disease. While most people have heard generally about the disease, a large portion of the population is relatively misinformed about how SCD is diagnosed or inherited. Those who are informed about the disease learned about it from family or friends and not from health professionals. Failure to provide the public with information about sickle cell disease results in a population with a poor understanding of the causes of the disease, symptoms, and prevention techniques. The differences, physically and socially, that arise in those with sickle cell disease, such as jaundice, stunted physical growth, and delayed sexual maturity, can also lead them to become targets of bullying, rejection, and stigma.
==== Rate of sickle cell disease in Uganda ====
The data compiled on sickle cell disease in Uganda has not been updated since the early 1970s. The deficiency of data is due to a lack of government research funds, even though Ugandans die daily from SCD. Data shows that the trait frequency of sickle cell disease is 20% of the population in Uganda. It is also estimated that about 25,000 Ugandans are born each year with SCD and 80% of those people do not live past five years old. SCD also contributes 25% to the child mortality rate in Uganda. The Bamba people of Uganda, located in the southwest of the country, carry 45% of the gene which is the highest trait frequency recorded in the world. The Sickle Cell Clinic in Mulago is only one sickle cell disease clinic in the country and on average sees 200 patients a day.
==== Misconceptions about sickle cell disease ====
The stigma around the disease is particularly bad in regions of the country that are not as affected. For example, Eastern Ugandans tend to be more knowledgeable of the disease than Western Ugandans, who are more likely to believe that sickle cell disease resulted as a punishment from God or witchcraft. Other misconceptions about SCD include the belief that it is caused by environmental factors but, in reality, SCD is a genetic disease. There have been efforts throughout Uganda to address the social misconceptions about the disease. In 2013, the Uganda Sickle Cell Rescue Foundation was established to spread awareness of sickle cell disease and combat the social stigma attached to the disease. In addition to this organization's efforts, there is a need for the inclusion of sickle cell disease education in preexisting community health education programs in order to reduce the stigmatization of sickle cell disease in Uganda.
==== Social isolation of people with sickle cell disease ====
The deeply rooted stigma of SCD from society causes families to often hide their family members' sick status for fear of being labeled, cursed, or left out of social events. Sometimes in Uganda, when it is confirmed that a family member has sickle cell disease, intimate relationships with all members of the family are avoided. The stigmatization and social isolation people with sickle cell disease tend to experience is often the consequence of popular misconceptions that people with SCD should not socialize with those free from the disease. This mentality robs people with SCD of the right to freely participate in community activities like everyone else SCD-related stigma and social isolation in schools, especially, can make a life for young people living with sickle cell disease extremely difficult. For school-aged children living with SCD, the stigma they face can lead to peer rejection. Peer rejection involves the exclusion from social groups or gatherings. It often leads the excluded individual to experience emotional distress and may result in their academic underperformance, avoidance of school, and occupational failure later in life. This social isolation is also likely to negatively impact people with SCD's self-esteem and overall quality of life.
Mothers of children with sickle cell disease tend to receive disproportionate amounts of stigma from their peers and family members. These women will often be blamed for their child's diagnosis of SCD, especially if SCD is not present in earlier generations, due to the suspicion that the child's poor health may have been caused by the mother's failure to implement preventative health measures or promote a healthy environment for her child to thrive. The reliance on theories related to environmental factors to place blame on the mother reflects many Ugandans’ poor knowledge of how the disease is acquired as it is determined by genetics, not environment. Mothers of children with sickle cell disease are also often left with very limited resources to safeguard their futures against the stigma of having SCD. This lack of access to resources results from their subordinating roles within familial structures as well as the class disparities that hinder many mothers' ability to satisfy additional childcare costs and responsibilities.
Women living with SCD who become pregnant often face extreme discrimination and discouragement in Uganda. These women are frequently branded by their peers as irresponsible for having a baby while living with sickle cell disease or even engaging in sex while living with SCD. The criticism and judgement these women receive, not only from healthcare professionals but also from their families, often leaves them feeling alone, depressed, anxious, ashamed, and with very little social support. Most pregnant women with SCD also go on to be single mothers as it is common for them to be left by their male partners who claim they were unaware of their partner's SCD status. Not only does the abandonment experienced by these women cause emotional distress for them, but this low level of parental support can be linked to depressive symptoms and overall lower quality of life for the child once they are born.
=== United Kingdom ===
In 2021 many patients were found to be afraid to visit hospitals, so purchased pain relief to treat themselves outside the NHS. They were often waiting a long time for pain relief, and sometimes suspected of "drugs-seeking" behaviour. Delays to treatment, failure to inform the hospital haematology team and poor pain management had caused deaths. Specialist haematology staff preferred to work in bigger, teaching hospitals, leading to shortages of expertise elsewhere. In 2021, the NHS initiated its first new treatment in 20 years for Sickle Cell. This involved the use of Crizanlizumab, a drug given via transfusion drips, which reduces the number of visits to A&E by sufferers. The treatment can be accessed, via consultants, at any of ten new hubs set up around the country. In the same year, however, an All-Party Parliamentary Group produced a report on Sickle Cell and Thalassaemia entitled 'No-one is listening'. Partly in response to this, on 19 June 2022, World Sickle Cell Day, the NHS launched a campaign called "Can you tell it's sickle cell?". The campaign had twin aims. One was to increase awareness of the key signs and symptoms of the blood disorder so that people would be as alert to signs of a sickle cell crisis as they are to an imminent heart attack or stroke. The second aim was to set up a new training programme to help paramedics, Accident and Emergency staff, carers and the general public to care effectively for sufferers in crisis.
== References ==
== Further reading ==
== External links == | Wikipedia/Sickle-cell_disease |
In chemistry, the term substrate is highly context-dependent. Broadly speaking, it can refer either to a chemical species being observed in a chemical reaction, or to a surface on which other chemical reactions or microscopy are performed.
In the former sense, a reagent is added to the substrate to generate a product through a chemical reaction. The term is used in a similar sense in synthetic and organic chemistry, where the substrate is the chemical of interest that is being modified. In biochemistry, an enzyme substrate is the material upon which an enzyme acts. When referring to Le Chatelier's principle, the substrate is the reagent whose concentration is changed.
In the latter sense, it may refer to a surface on which other chemical reactions are performed or play a supporting role in a variety of spectroscopic and microscopic techniques, as discussed in the first few subsections below.
== Microscopy ==
In three of the most common nano-scale microscopy techniques, atomic force microscopy (AFM), scanning tunneling microscopy (STM), and transmission electron microscopy (TEM), a substrate is required for sample mounting. Substrates are often thin and relatively free of chemical features or defects. Typically silver, gold, or silicon wafers are used due to their ease of manufacturing and lack of interference in the microscopy data. Samples are deposited onto the substrate in fine layers where it can act as a solid support of reliable thickness and malleability. Smoothness of the substrate is especially important for these types of microscopy because they are sensitive to very small changes in sample height.
Various other substrates are used in specific cases to accommodate a wide variety of samples. Thermally-insulating substrates are required for AFM of graphite flakes for instance, and conductive substrates are required for TEM. In some contexts, the word substrate can be used to refer to the sample itself, rather than the solid support on which it is placed.
== Spectroscopy ==
Various spectroscopic techniques also require samples to be mounted on substrates, such as powder diffraction. This type of diffraction, which involves directing high-powered X-rays at powder samples to deduce crystal structures, is often performed with an amorphous substrate such that it does not interfere with the resulting data collection. Silicon substrates are also commonly used because of their cost-effective nature and relatively little data interference in X-ray collection.
Single-crystal substrates are useful in powder diffraction because they are distinguishable from the sample of interest in diffraction patterns by differentiating by phase.
== Atomic layer deposition ==
In atomic layer deposition, the substrate acts as an initial surface on which reagents can combine to precisely build up chemical structures. A wide variety of substrates are used depending on the reaction of interest, but they frequently bind the reagents with some affinity to allow sticking to the substrate.
The substrate is exposed to different reagents sequentially and washed in between to remove excess. A substrate is critical in this technique because the first layer needs a place to bind to such that it is not lost when exposed to the second or third set of reagents.
== Biochemistry ==
In biochemistry, the substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate(s). In the case of a single substrate, the substrate bonds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or more products, which are then released from the active site. The active site is then free to accept another substrate molecule. In the case of more than one substrate, these may bind in a particular order to the active site, before reacting together to produce products. A substrate is called 'chromogenic' if it gives rise to a coloured product when acted on by an enzyme. In histological enzyme localization studies, the colored product of enzyme action can be viewed under a microscope, in thin sections of biological tissues. Similarly, a substrate is called 'fluorogenic' if it gives rise to a fluorescent product when acted on by an enzyme.
For example, curd formation (rennet coagulation) is a reaction that occurs upon adding the enzyme rennin to milk. In this reaction, the substrate is a milk protein (e.g., casein) and the enzyme is rennin. The products are two polypeptides that have been formed by the cleavage of the larger peptide substrate. Another example is the chemical decomposition of hydrogen peroxide carried out by the enzyme catalase. As enzymes are catalysts, they are not changed by the reactions they carry out. The substrate(s), however, is/are converted to product(s). Here, hydrogen peroxide is converted to water and oxygen gas.
E + S ⇌ ES → EP ⇌ E + P
Where E is enzyme, S is substrate, and P is product
While the first (binding) and third (unbinding) steps are, in general, reversible, the middle step may be irreversible (as in the rennin and catalase reactions just mentioned) or reversible (e.g. many reactions in the glycolysis metabolic pathway).
By increasing the substrate concentration, the rate of reaction will increase due to the likelihood that the number of enzyme-substrate complexes will increase; this occurs until the enzyme concentration becomes the limiting factor.
=== Substrate promiscuity ===
Although enzymes are typically highly specific, some are able to perform catalysis on more than one substrate, a property termed enzyme promiscuity. An enzyme may have many native substrates and broad specificity (e.g. oxidation by cytochrome p450s) or it may have a single native substrate with a set of similar non-native substrates that it can catalyse at some lower rate. The substrates that a given enzyme may react with in vitro, in a laboratory setting, may not necessarily reflect the physiological, endogenous substrates of the enzyme's reactions in vivo. That is to say that enzymes do not necessarily perform all the reactions in the body that may be possible in the laboratory. For example, while fatty acid amide hydrolase (FAAH) can hydrolyze the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide at comparable rates in vitro, genetic or pharmacological disruption of FAAH elevates anandamide but not 2-AG, suggesting that 2-AG is not an endogenous, in vivo substrate for FAAH. In another example, the N-acyl taurines (NATs) are observed to increase dramatically in FAAH-disrupted animals, but are actually poor in vitro FAAH substrates.
=== Sensitivity ===
Sensitive substrates, also known as sensitive index substrates, are drugs that demonstrate an increase in AUC of ≥5-fold with strong index inhibitors of a given metabolic pathway in clinical drug-drug interaction (DDI) studies.
Moderate sensitive substrates are drugs that demonstrate an increase in AUC of ≥2 to <5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies.
==== Interaction between substrates ====
Metabolism by the same cytochrome P450 isozyme can result in several clinically significant drug-drug interactions.
== See also ==
Limiting reagent
Reaction progress kinetic analysis
Solvent
== References == | Wikipedia/Substrate_(biochemistry) |
This enzyme is not to be confused with Bisphosphoglycerate mutase which catalyzes the conversion of 1,3-bisphosphoglycerate to 2,3-bisphosphoglycerate.
Phosphoglycerate mutase (PGM) is any enzyme that catalyzes step 8 of glycolysis - the internal transfer of a phosphate group from C-3 to C-2 which results in the conversion of 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG) through a 2,3-bisphosphoglycerate intermediate. These enzymes are categorized into the two distinct classes of either cofactor-dependent (dPGM) or cofactor-independent (iPGM). The dPGM enzyme (EC 5.4.2.11) is composed of approximately 250 amino acids and is found in all vertebrates as well as in some invertebrates, fungi, and bacteria. The iPGM (EC 5.4.2.12) class is found in all plants and algae as well as in some invertebrate, fungi, and Gram-positive bacteria. This class of PGM enzyme shares the same superfamily as alkaline phosphatase.
== Mechanism ==
PGM is an isomerase enzyme, effectively transferring a phosphate group (PO43−) from the C-3 carbon of 3-phosphoglycerate to the C-2 carbon forming 2-phosphoglycerate. There are a total of three reactions dPGM can catalyze: a mutase reaction resulting in the conversion of 3PG to 2PG and vice versa, a phosphatase reaction creating phosphoglycerate from 2,3-bisphosphoglycerate, and a synthase reaction producing 2,3-bisphosphoglycerate from 1,3-bisphosphoglycerate similar to the enzyme bisphosphoglycerate mutase. Kinetic and structural studies have provided evidence that indicate dPGM and bisphosphoglycerate mutase are paralogous structures. Both enzymes are contained in the superfamily that also contains the phosphatase portion of phosphofructokinase 2 and prostatic acid phosphatase.
The catalyzed mutase reaction involves two separate phosphoryl groups and the ending phosphate on the 2-carbon is not the same phosphate removed from the 3-carbon.
In the cofactor-dependent enzyme's initial state, the active site contains a phosphohistidine complex formed by phosphorylation of a specific histidine residue. When 3-phosphoglycerate enters the active site, the phosphohistidine complex is positioned as to facilitate transfer of phosphate from enzyme to substrate C-2 creating a 2,3-bisphosphoglycerate intermediate.
Dephosphorylation of the enzyme histidine actuates a local allosteric change in enzyme configuration which now aligns the substrates 3-C phosphate group with enzyme active site histidine and facilitates phosphate transfer returning the enzyme to its initial phosphorylated state and releasing product 2-phosphoglycerate. 2,3-bisphosphoglycerate is required a cofactor for dPGM. In contrast, the iPGM class is independent of 2,3-bisphosphoglycerate and catalyzes the intramolecular transfer of the phosphate group on monophosphoglycerates using a phosphoserineintermediate.
=== Reaction summary ===
3PG + P-Enzyme → 2,3BPG + Enzyme → 2PG + P-Enzyme
3-phosphoglycerate intermediate 2-phosphoglycerate
ΔG°′=+1.1kcal/mol
== Isozymes ==
Phosphoglycerate mutase exists primarily as a dimer of two either identical or closely related subunits of about 32kDa. The enzyme is found in organisms as simple as yeast through Homo sapiens and its structure is highly conserved throughout. (Yeast PGM≈74% conserved vs mammal form).
In mammals, the enzyme subunits appear to be either a muscle-derived form (m-type) or other tissue (b-type for brain where the b-isozyme was originally isolated). Existing as a dimer, the enzyme then has 3 isozymes depending on which subunit forms makeup the whole molecule (mm, bb or mb). The mm-type is found mainly in smooth muscle almost exclusively. The mb-isozyme is found in cardiac and skeletal muscle and the bb-type is found in the rest of tissues. While all three isozymes may be found in any tissue, the above distributions are based on prevalence in each.
== Interactive pathway map ==
Click on genes, proteins and metabolites below to link to respective articles.
== Regulation ==
Phosphoglycerate mutase has a small positive Gibbs free energy and this reaction proceeds easily in both directions. Since it is a reversible reaction, it is not the site of major regulation mechanisms or regulation schemes for the glycolytic pathway.
Anionic molecules such as vanadate, acetate, chloride ion, phosphate, 2-phosphoglycolate, and N-[tris(hydroxymethyl)methyl-2-amino]ethanesulfonate are known inhibitors of the mutase activity of dPGM. Studies have shown dPGM to be sensitive to changes in ionic concentration, where increasing concentrations of salts result in the activation of the enzyme's phosphatase activity while inhibiting its mutase activity. Certain salts, such as KCl, are known to be competitive inhibitors in respect to 2-phosphoglycerate and mutase activity. Both phosphate and 2-phosphoglycolate are competitive inhibitors of mutase activity in respect to the substrates 2-phosphoglycerate and 2,3-bisphosphoglycerate.
== Clinical significance ==
In humans the PGAM2 gene which encodes this enzyme is located on the short arm of chromosome 7.
Deficiency of phosphoglycerate mutase causes glycogen storage disease type X, a rare autosomal recessive genetic disorder with symptoms ranging from mild to moderate; is not thought life-threatening and can be managed with changes in lifestyle. This presents as a metabolic myopathy and is one of the many forms of syndromes formerly referred to as muscular dystrophy. PGAM1 deficiency affects the liver, while PGAM2 deficiency affects the muscle.
Onset is generally noted as childhood to early adult though some who may be mildly affected by the disorder may not know they have it. Patients with PGAM deficiency are usually asymptomatic, except when they engage in brief, strenuous efforts which may trigger myalgias, cramps, muscle necrosis and myoglobinuria. An unusual pathologic feature of PGAM deficiency is the association with tubular aggregates. The symptoms are an intolerance to physical exertion or activity, cramps and muscle pain. Permanent weakness is rare. The disease is not progressive and has an excellent prognosis.
== Human proteins containing this domain ==
BPGM; PFKFB1; PFKFB2; PFKFB3; PFKFB4; PGAM1; PGAM2;
PGAM4; PGAM5; STS1; UBASH3A;
== References ==
== External links ==
Phosphoglycerate+Mutase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
PDBe-KB provides an overview of all the structure information available in the PDB for Human Phosphoglycerate mutase 1 | Wikipedia/Phosphoglycerate_mutase |
Water (H2O) is a polar inorganic compound that is at room temperature a tasteless and odorless liquid, which is nearly colorless apart from an inherent hint of blue. It is by far the most studied chemical compound and is described as the "universal solvent" and the "solvent of life". It is the most abundant substance on the surface of Earth and the only common substance to exist as a solid, liquid, and gas on Earth's surface. It is also the third most abundant molecule in the universe (behind molecular hydrogen and carbon monoxide).
Water molecules form hydrogen bonds with each other and are strongly polar. This polarity allows it to dissociate ions in salts and bond to other polar substances such as alcohols and acids, thus dissolving them. Its hydrogen bonding causes its many unique properties, such as having a solid form less dense than its liquid form, a relatively high boiling point of 100 °C for its molar mass, and a high heat capacity.
Water is amphoteric, meaning that it can exhibit properties of an acid or a base, depending on the pH of the solution that it is in; it readily produces both H+ and OH− ions. Related to its amphoteric character, it undergoes self-ionization. The product of the activities, or approximately, the concentrations of H+ and OH− is a constant, so their respective concentrations are inversely proportional to each other.
== Physical properties ==
Water is the chemical substance with chemical formula H2O; one molecule of water has two hydrogen atoms covalently bonded to a single oxygen atom. Water is a tasteless, odorless liquid at ambient temperature and pressure. Liquid water has weak absorption bands at wavelengths of around 750 nm which cause it to appear to have a blue color. This can easily be observed in a water-filled bath or wash-basin whose lining is white. Large ice crystals, as in glaciers, also appear blue.
Under standard conditions, water is primarily a liquid, unlike other analogous hydrides of the oxygen family, which are generally gaseous. This unique property of water is due to hydrogen bonding. The molecules of water are constantly moving concerning each other, and the hydrogen bonds are continually breaking and reforming at timescales faster than 200 femtoseconds (2 × 10−13 seconds). However, these bonds are strong enough to create many of the peculiar properties of water, some of which make it integral to life.
=== Water, ice, and vapor ===
Within the Earth's atmosphere and surface, the liquid phase is the most common and is the form that is generally denoted by the word "water". The solid phase of water is known as ice and commonly takes the structure of hard, amalgamated crystals, such as ice cubes, or loosely accumulated granular crystals, like snow. Aside from common hexagonal crystalline ice, other crystalline and amorphous phases of ice are known. The gaseous phase of water is known as water vapor (or steam). Visible steam and clouds are formed from minute droplets of water suspended in the air.
Water also forms a supercritical fluid. The critical temperature is 647 K and the critical pressure is 22.064 MPa. In nature, this only rarely occurs in extremely hostile conditions. A likely example of naturally occurring supercritical water is in the hottest parts of deep water hydrothermal vents, in which water is heated to the critical temperature by volcanic plumes and the critical pressure is caused by the weight of the ocean at the extreme depths where the vents are located. This pressure is reached at a depth of about 2200 meters: much less than the mean depth of the ocean (3800 meters).
==== Heat capacity and heats of vaporization and fusion ====
Water has a very high specific heat capacity of 4184 J/(kg·K) at 20 °C (4182 J/(kg·K) at 25 °C)—the second-highest among all the heteroatomic species (after ammonia), as well as a high heat of vaporization (40.65 kJ/mol or 2257 kJ/kg at the normal boiling point), both of which are a result of the extensive hydrogen bonding between its molecules. These unusual properties allow water to moderate Earth's climate by buffering large fluctuations in temperature. Most of the additional energy stored in the climate system since 1970 has accumulated in the oceans.
The specific enthalpy of fusion (more commonly known as latent heat) of water is 333.55 kJ/kg at 0 °C: the same amount of energy is required to melt ice as to warm ice from −160 °C up to its melting point or to heat the same amount of water by about 80 °C. Of common substances, only that of ammonia is higher. This property confers resistance to melting on the ice of glaciers and drift ice. Before and since the advent of mechanical refrigeration, ice was and still is in common use for retarding food spoilage.
The specific heat capacity of ice at −10 °C is 2030 J/(kg·K) and the heat capacity of steam at 100 °C is 2080 J/(kg·K).
==== Density of water and ice ====
The density of water is about 1 gram per cubic centimetre (62 lb/cu ft): this relationship was originally used to define the gram. The density varies with temperature, but not linearly: as the temperature increases, the density rises to a peak at 3.98 °C (39.16 °F) and then decreases; the initial increase is unusual because most liquids undergo thermal expansion so that the density only decreases as a function of temperature. The increase observed for water from 0 °C (32 °F) to 3.98 °C (39.16 °F) and for a few other liquids is described as negative thermal expansion. Regular, hexagonal ice is also less dense than liquid water—upon freezing, the density of water decreases by about 9%.
These peculiar effects are due to the highly directional bonding of water molecules via the hydrogen bonds: ice and liquid water at low temperature have comparatively low-density, low-energy open lattice structures. The breaking of hydrogen bonds on melting with increasing temperature in the range 0–4 °C allows for a denser molecular packing in which some of the lattice cavities are filled by water molecules. Above 4 °C, however, thermal expansion becomes the dominant effect, and water near the boiling point (100 °C) is about 4% less dense than water at 4 °C (39 °F).
Under increasing pressure, ice undergoes a number of transitions to other polymorphs with higher density than liquid water, such as ice II, ice III, high-density amorphous ice (HDA), and very-high-density amorphous ice (VHDA).
The unusual density curve and lower density of ice than of water is essential for much of the life on earth—if water were most dense at the freezing point, then in winter the cooling at the surface would lead to convective mixing. Once 0 °C are reached, the water body would freeze from the bottom up, and all life in it would be killed. Furthermore, given that water is a good thermal insulator (due to its heat capacity), some frozen lakes might not completely thaw in summer. As it is, the inversion of the density curve leads to a stable layering for surface temperatures below 4 °C, and with the layer of ice that floats on top insulating the water below, even e.g., Lake Baikal in central Siberia freezes only to about 1 m thickness in winter. In general, for deep enough lakes, the temperature at the bottom stays constant at about 4 °C (39 °F) throughout the year (see diagram).
==== Density of saltwater and ice ====
The density of saltwater depends on the dissolved salt content as well as the temperature. Ice still floats in the oceans, otherwise, they would freeze from the bottom up. However, the salt content of oceans lowers the freezing point by about 1.9 °C (due to freezing-point depression of a solvent containing a solute) and lowers the temperature of the density maximum of water to the former freezing point at 0 °C. This is why, in ocean water, the downward convection of colder water is not blocked by an expansion of water as it becomes colder near the freezing point. The oceans' cold water near the freezing point continues to sink. So creatures that live at the bottom of cold oceans like the Arctic Ocean generally live in water 4 °C colder than at the bottom of frozen-over fresh water lakes and rivers.
As the surface of saltwater begins to freeze (at −1.9 °C for normal salinity seawater, 3.5%) the ice that forms is essentially salt-free, with about the same density as freshwater ice. This ice floats on the surface, and the salt that is "frozen out" adds to the salinity and density of the seawater just below it, in a process known as brine rejection. This denser saltwater sinks by convection and the replacing seawater is subject to the same process. This produces essentially freshwater ice at −1.9 °C on the surface. The increased density of the seawater beneath the forming ice causes it to sink towards the bottom. On a large scale, the process of brine rejection and sinking cold salty water results in ocean currents forming to transport such water away from the Poles, leading to a global system of currents called the thermohaline circulation.
==== Miscibility and condensation ====
Water is miscible with many liquids, including ethanol in all proportions. Water and most oils are immiscible, usually forming layers according to increasing density from the top. This can be predicted by comparing the polarity. Water being a relatively polar compound will tend to be miscible with liquids of high polarity such as ethanol and acetone, whereas compounds with low polarity will tend to be immiscible and poorly soluble such as with hydrocarbons.
As a gas, water vapor is completely miscible with air. On the other hand, the maximum water vapor pressure that is thermodynamically stable with the liquid (or solid) at a given temperature is relatively low compared with total atmospheric pressure. For example, if the vapor's partial pressure is 2% of atmospheric pressure and the air is cooled from 25 °C, starting at about 22 °C, water will start to condense, defining the dew point, and creating fog or dew. The reverse process accounts for the fog burning off in the morning. If the humidity is increased at room temperature, for example, by running a hot shower or a bath, and the temperature stays about the same, the vapor soon reaches the pressure for phase change and then condenses out as minute water droplets, commonly referred to as steam.
A saturated gas or one with 100% relative humidity is when the vapor pressure of water in the air is at equilibrium with vapor pressure due to (liquid) water; water (or ice, if cool enough) will fail to lose mass through evaporation when exposed to saturated air. Because the amount of water vapor in the air is small, relative humidity, the ratio of the partial pressure due to the water vapor to the saturated partial vapor pressure, is much more useful. Vapor pressure above 100% relative humidity is called supersaturated and can occur if the air is rapidly cooled, for example, by rising suddenly in an updraft.
==== Vapour pressure ====
==== Compressibility ====
The compressibility of water is a function of pressure and temperature. At 0 °C, at the limit of zero pressure, the compressibility is 5.1×10−10 Pa−1. At the zero-pressure limit, the compressibility reaches a minimum of 4.4×10−10 Pa−1 around 45 °C before increasing again with increasing temperature. As the pressure is increased, the compressibility decreases, being 3.9×10−10 Pa−1 at 0 °C and 100 megapascals (1,000 bar).
The bulk modulus of water is about 2.2 GPa. The low compressibility of non-gasses, and of water in particular, leads to their often being assumed as incompressible. The low compressibility of water means that even in the deep oceans at 4 kilometres (2.5 mi) depth, where pressures are 40 MPa, there is only a 1.8% decrease in volume.
The bulk modulus of water ice ranges from 11.3 GPa at 0 K up to 8.6 GPa at 273 K. The large change in the compressibility of ice as a function of temperature is the result of its relatively large thermal expansion coefficient compared to other common solids.
==== Triple point ====
The temperature and pressure at which ordinary solid, liquid, and gaseous water coexist in equilibrium is a triple point of water. Since 1954, this point had been used to define the base unit of temperature, the kelvin, but, starting in 2019, the kelvin is now defined using the Boltzmann constant, rather than the triple point of water.
Due to the existence of many polymorphs (forms) of ice, water has other triple points, which have either three polymorphs of ice or two polymorphs of ice and liquid in equilibrium. Gustav Heinrich Johann Apollon Tammann in Göttingen produced data on several other triple points in the early 20th century. Kamb and others documented further triple points in the 1960s.
==== Melting point ====
The melting point of ice is 0 °C (32 °F; 273 K) at standard pressure; however, pure liquid water can be supercooled well below that temperature without freezing if the liquid is not mechanically disturbed. It can remain in a fluid state down to its homogeneous nucleation point of about 231 K (−42 °C; −44 °F). The melting point of ordinary hexagonal ice falls slightly under moderately high pressures, by 0.0073 °C (0.0131 °F)/atm or about 0.5 °C (0.90 °F)/70 atm as the stabilization energy of hydrogen bonding is exceeded by intermolecular repulsion, but as ice transforms into its polymorphs (see crystalline states of ice) above 209.9 MPa (2,072 atm), the melting point increases markedly with pressure, i.e., reaching 355 K (82 °C) at 2.216 GPa (21,870 atm) (triple point of Ice VII).
=== Electrical properties ===
==== Electrical conductivity ====
Pure water containing no exogenous ions is an excellent electronic insulator, but not even "deionized" water is completely free of ions. Water undergoes autoionization in the liquid state when two water molecules form one hydroxide anion (OH−) and one hydronium cation (H3O+). Because of autoionization, at ambient temperatures pure liquid water has a similar intrinsic charge carrier concentration to the semiconductor germanium and an intrinsic charge carrier concentration three orders of magnitude greater than the semiconductor silicon, hence, based on charge carrier concentration, water can not be considered to be a completely dielectric material or electrical insulator but to be a limited conductor of ionic charge.
Because water is such a good solvent, it almost always has some solute dissolved in it, often a salt. If water has even a tiny amount of such an impurity, then the ions can carry charges back and forth, allowing the water to conduct electricity far more readily.
It is known that the theoretical maximum electrical resistivity for water is approximately 18.2 MΩ·cm (182 kΩ·m) at 25 °C. This figure agrees well with what is typically seen on reverse osmosis, ultra-filtered and deionized ultra-pure water systems used, for instance, in semiconductor manufacturing plants. A salt or acid contaminant level exceeding even 100 parts per trillion (ppt) in otherwise ultra-pure water begins to noticeably lower its resistivity by up to several kΩ·m.
In pure water, sensitive equipment can detect a very slight electrical conductivity of 0.05501 ± 0.0001 μS/cm at 25.00 °C. Water can also be electrolyzed into oxygen and hydrogen gases but in the absence of dissolved ions this is a very slow process, as very little current is conducted. In ice, the primary charge carriers are protons (see proton conductor). Ice was previously thought to have a small but measurable conductivity of 1×10−10 S/cm, but this conductivity is now thought to be almost entirely from surface defects, and without those, ice is an insulator with an immeasurably small conductivity.
=== Polarity and hydrogen bonding ===
An important feature of water is its polar nature. The structure has a bent molecular geometry for the two hydrogens from the oxygen vertex. The oxygen atom also has two lone pairs of electrons. One effect usually ascribed to the lone pairs is that the H–O–H gas-phase bend angle is 104.48°, which is smaller than the typical tetrahedral angle of 109.47°. The lone pairs are closer to the oxygen atom than the electrons sigma bonded to the hydrogens, so they require more space. The increased repulsion of the lone pairs forces the O–H bonds closer to each other.
Another consequence of its structure is that water is a polar molecule. Due to the difference in electronegativity, a bond dipole moment points from each H to the O, making the oxygen partially negative and each hydrogen partially positive. A large molecular dipole, points from a region between the two hydrogen atoms to the oxygen atom. The charge differences cause water molecules to aggregate (the relatively positive areas being attracted to the relatively negative areas). This attraction, hydrogen bonding, explains many of the properties of water, such as its solvent properties.
Although hydrogen bonding is a relatively weak attraction compared to the covalent bonds within the water molecule itself, it is responsible for several of the water's physical properties. These properties include its relatively high melting and boiling point temperatures: more energy is required to break the hydrogen bonds between water molecules. In contrast, hydrogen sulfide (H2S), has much weaker hydrogen bonding due to sulfur's lower electronegativity. H2S is a gas at room temperature, despite hydrogen sulfide having nearly twice the molar mass of water. The extra bonding between water molecules also gives liquid water a large specific heat capacity. This high heat capacity makes water a good heat storage medium (coolant) and heat shield.
==== Cohesion and adhesion ====
Water molecules stay close to each other (cohesion), due to the collective action of hydrogen bonds between water molecules. These hydrogen bonds are constantly breaking, with new bonds being formed with different water molecules; but at any given time in a sample of liquid water, a large portion of the molecules are held together by such bonds.
Water also has high adhesion properties because of its polar nature. On clean, smooth glass the water may form a thin film because the molecular forces between glass and water molecules (adhesive forces) are stronger than the cohesive forces. In biological cells and organelles, water is in contact with membrane and protein surfaces that are hydrophilic; that is, surfaces that have a strong attraction to water. Irving Langmuir observed a strong repulsive force between hydrophilic surfaces. To dehydrate hydrophilic surfaces—to remove the strongly held layers of water of hydration—requires doing substantial work against these forces, called hydration forces. These forces are very large but decrease rapidly over a nanometer or less. They are important in biology, particularly when cells are dehydrated by exposure to dry atmospheres or to extracellular freezing.
==== Surface tension ====
Water has an unusually high surface tension of 71.99 mN/m at 25 °C which is caused by the strength of the hydrogen bonding between water molecules. This allows insects to walk on water.
==== Capillary action ====
Because water has strong cohesive and adhesive forces, it exhibits capillary action. Strong cohesion from hydrogen bonding and adhesion allows trees to transport water more than 100 m upward.
==== Water as a solvent ====
Water is an excellent solvent due to its high dielectric constant. Substances that mix well and dissolve in water are known as hydrophilic ("water-loving") substances, while those that do not mix well with water are known as hydrophobic ("water-fearing") substances. The ability of a substance to dissolve in water is determined by whether or not the substance can match or better the strong attractive forces that water molecules generate between other water molecules. If a substance has properties that do not allow it to overcome these strong intermolecular forces, the molecules are precipitated out from the water. Contrary to the common misconception, water and hydrophobic substances do not "repel", and the hydration of a hydrophobic surface is energetically, but not entropically, favorable.
When an ionic or polar compound enters water, it is surrounded by water molecules (hydration). The relatively small size of water molecules (~3 angstroms) allows many water molecules to surround one molecule of solute. The partially negative dipole ends of the water are attracted to positively charged components of the solute, and vice versa for the positive dipole ends.
In general, ionic and polar substances such as acids, alcohols, and salts are relatively soluble in water, and nonpolar substances such as fats and oils are not. Nonpolar molecules stay together in water because it is energetically more favorable for the water molecules to hydrogen bond to each other than to engage in van der Waals interactions with non-polar molecules.
An example of an ionic solute is table salt; the sodium chloride, NaCl, separates into Na+ cations and Cl− anions, each being surrounded by water molecules. The ions are then easily transported away from their crystalline lattice into solution. An example of a nonionic solute is table sugar. The water dipoles make hydrogen bonds with the polar regions of the sugar molecule (OH groups) and allow it to be carried away into solution.
==== Quantum tunneling ====
The quantum tunneling dynamics in water was reported as early as 1992. At that time it was known that there are motions which destroy and regenerate the weak hydrogen bond by internal rotations of the substituent water monomers. On 18 March 2016, it was reported that the hydrogen bond can be broken by quantum tunneling in the water hexamer. Unlike previously reported tunneling motions in water, this involved the concerted breaking of two hydrogen bonds. Later in the same year, the discovery of the quantum tunneling of water molecules was reported.
=== Electromagnetic absorption ===
Water is relatively transparent to visible light, near ultraviolet light, and far-red light, but it absorbs most ultraviolet light, infrared light, and microwaves. Most photoreceptors and photosynthetic pigments utilize the portion of the light spectrum that is transmitted well through water. Microwave ovens take advantage of water's opacity to microwave radiation to heat the water inside of foods. Water's light blue color is caused by weak absorption in the red part of the visible spectrum.
== Structure ==
A single water molecule can participate in a maximum of four hydrogen bonds because it can accept two bonds using the lone pairs on oxygen and donate two hydrogen atoms. Other molecules like hydrogen fluoride, ammonia, and methanol can also form hydrogen bonds. However, they do not show anomalous thermodynamic, kinetic, or structural properties like those observed in water because none of them can form four hydrogen bonds: either they cannot donate or accept hydrogen atoms, or there are steric effects in bulky residues. In water, intermolecular tetrahedral structures form due to the four hydrogen bonds, thereby forming an open structure and a three-dimensional bonding network, resulting in the anomalous decrease in density when cooled below 4 °C. This repeated, constantly reorganising unit defines a three-dimensional network extending throughout the liquid. This view is based upon neutron scattering studies and computer simulations, and it makes sense in the light of the unambiguously tetrahedral arrangement of water molecules in ice structures.
However, there is an alternative theory for the structure of water. In 2004, a controversial paper from Stockholm University suggested that water molecules in the liquid state typically bind not to four but only two others; thus forming chains and rings. The term "string theory of water" (which is not to be confused with the string theory of physics) was coined. These observations were based upon X-ray absorption spectroscopy that probed the local environment of individual oxygen atoms.
=== Molecular structure ===
The repulsive effects of the two lone pairs on the oxygen atom cause water to have a bent, not linear, molecular structure, allowing it to be polar. The hydrogen–oxygen–hydrogen angle is 104.45°, which is less than the 109.47° for ideal sp3 hybridization. The valence bond theory explanation is that the oxygen atom's lone pairs are physically larger and therefore take up more space than the oxygen atom's bonds to the hydrogen atoms. The molecular orbital theory explanation (Bent's rule) is that lowering the energy of the oxygen atom's nonbonding hybrid orbitals (by assigning them more s character and less p character) and correspondingly raising the energy of the oxygen atom's hybrid orbitals bonded to the hydrogen atoms (by assigning them more p character and less s character) has the net effect of lowering the energy of the occupied molecular orbitals because the energy of the oxygen atom's nonbonding hybrid orbitals contributes completely to the energy of the oxygen atom's lone pairs while the energy of the oxygen atom's other two hybrid orbitals contributes only partially to the energy of the bonding orbitals (the remainder of the contribution coming from the hydrogen atoms' 1s orbitals).
== Chemical properties ==
=== Self-ionization ===
In liquid water there is some self-ionization giving hydronium ions and hydroxide ions.
2 H2O ⇌ H3O+ + OH−
The equilibrium constant for this reaction, known as the ionic product of water,
K
w
=
[
H
3
O
+
]
[
O
H
−
]
{\displaystyle K_{\rm {w}}=[{\rm {H_{3}O^{+}}}][{\rm {OH^{-}}}]}
, has a value of about 10−14 at 25 °C. At neutral pH, the concentration of the hydroxide ion (OH−) equals that of the (solvated) hydrogen ion (H+), with a value close to 10−7 mol L−1 at 25 °C. See data page for values at other temperatures.
The thermodynamic equilibrium constant is a quotient of thermodynamic activities of all products and reactants including water:
K
e
q
=
a
H
3
O
+
⋅
a
O
H
−
a
H
2
O
2
{\displaystyle K_{\rm {eq}}={\frac {a_{\rm {H_{3}O^{+}}}\cdot a_{\rm {OH^{-}}}}{a_{\rm {H_{2}O}}^{2}}}}
However, for dilute solutions, the activity of a solute such as H3O+ or OH− is approximated by its concentration, and the activity of the solvent H2O is approximated by 1, so that we obtain the simple ionic product
K
e
q
≈
K
w
=
[
H
3
O
+
]
[
O
H
−
]
{\displaystyle K_{\rm {eq}}\approx K_{\rm {w}}=[{\rm {H_{3}O^{+}}}][{\rm {OH^{-}}}]}
=== Geochemistry ===
The action of water on rock over long periods of time typically leads to weathering and water erosion, physical processes that convert solid rocks and minerals into soil and sediment, but under some conditions chemical reactions with water occur as well, resulting in metasomatism or mineral hydration, a type of chemical alteration of a rock which produces clay minerals. It also occurs when Portland cement hardens.
Water ice can form clathrate compounds, known as clathrate hydrates, with a variety of small molecules that can be embedded in its spacious crystal lattice. The most notable of these is methane clathrate, 4 CH4·23H2O, naturally found in large quantities on the ocean floor.
=== Acidity in nature ===
Rain is generally mildly acidic, with a pH between 5.2 and 5.8 if not having any acid stronger than carbon dioxide. If high amounts of nitrogen and sulfur oxides are present in the air, they too will dissolve into the cloud and raindrops, producing acid rain.
== Isotopologues ==
Several isotopes of both hydrogen and oxygen exist, giving rise to several known isotopologues of water. Vienna Standard Mean Ocean Water is the current international standard for water isotopes. Naturally occurring water is almost completely composed of the neutron-less hydrogen isotope protium. Only 155 ppm include deuterium (2H or D), a hydrogen isotope with one neutron, and fewer than 20 parts per quintillion include tritium (3H or T), which has two neutrons. Oxygen also has three stable isotopes, with 16O present in 99.76%, 17O in 0.04%, and 18O in 0.2% of water molecules.
Deuterium oxide, D2O, is also known as heavy water because of its higher density. It is used in nuclear reactors as a neutron moderator. Tritium is radioactive, decaying with a half-life of 4500 days; THO exists in nature only in minute quantities, being produced primarily via cosmic ray-induced nuclear reactions in the atmosphere. Water with one protium and one deuterium atom HDO occur naturally in ordinary water in low concentrations (~0.03%) and D2O in far lower amounts (0.000003%) and any such molecules are temporary as the atoms recombine.
The most notable physical differences between H2O and D2O, other than the simple difference in specific mass, involve properties that are affected by hydrogen bonding, such as freezing and boiling, and other kinetic effects. This is because the nucleus of deuterium is twice as heavy as protium, and this causes noticeable differences in bonding energies. The difference in boiling points allows the isotopologues to be separated. The self-diffusion coefficient of H2O at 25 °C is 23% higher than the value of D2O. Because water molecules exchange hydrogen atoms with one another, hydrogen deuterium oxide (DOH) is much more common in low-purity heavy water than pure dideuterium monoxide D2O.
Consumption of pure isolated D2O may affect biochemical processes—ingestion of large amounts impairs kidney and central nervous system function. Small quantities can be consumed without any ill-effects; humans are generally unaware of taste differences, but sometimes report a burning sensation or sweet flavor. Very large amounts of heavy water must be consumed for any toxicity to become apparent. Rats, however, are able to avoid heavy water by smell, and it is toxic to many animals.
Light water refers to deuterium-depleted water (DDW), water in which the deuterium content has been reduced below the standard 155 ppm level.
== Occurrence ==
Water is the most abundant substance on Earth's surface and also the third most abundant molecule in the universe, after H2 and CO. 0.23 ppm of the earth's mass is water and 97.39% of the global water volume of 1.38×109 km3 is found in the oceans.
Water is far more prevalent in the outer Solar System, beyond a point called the frost line, where the Sun's radiation is too weak to vaporize solid and liquid water (as well as other elements and chemical compounds with relatively low melting points, such as methane and ammonia). In the inner Solar System, planets, asteroids, and moons formed almost entirely of metals and silicates. Water has since been delivered to the inner Solar System via an as-yet unknown mechanism, theorized to be the impacts of asteroids or comets carrying water from the outer Solar System, where bodies contain much more water ice. The difference between planetary bodies located inside and outside the frost line can be stark. Earth's mass is 0.000023% water, while Tethys, a moon of Saturn, is almost entirely made of water.
== Reactions ==
=== Acid–base reactions ===
Water is amphoteric: it has the ability to act as either an acid or a base in chemical reactions. According to the Brønsted-Lowry definition, an acid is a proton (H+) donor and a base is a proton acceptor. When reacting with a stronger acid, water acts as a base; when reacting with a stronger base, it acts as an acid. For instance, water receives an H+ ion from HCl when hydrochloric acid is formed:
HCl(acid) + H2O(base) ⇌ H3O+ + Cl−
In the reaction with ammonia, NH3, water donates a H+ ion, and is thus acting as an acid:
NH3(base) + H2O(acid) ⇌ NH+4 + OH−
Because the oxygen atom in water has two lone pairs, water often acts as a Lewis base, or electron-pair donor, in reactions with Lewis acids, although it can also react with Lewis bases, forming hydrogen bonds between the electron pair donors and the hydrogen atoms of water. HSAB theory describes water as both a weak hard acid and a weak hard base, meaning that it reacts preferentially with other hard species:
H+(Lewis acid) + H2O(Lewis base) → H3O+
Fe3+(Lewis acid) + H2O(Lewis base) → Fe(H2O)3+6
Cl−(Lewis base) + H2O(Lewis acid) → Cl(H2O)−6
When a salt of a weak acid or of a weak base is dissolved in water, water can partially hydrolyze the salt, producing the corresponding base or acid, which gives aqueous solutions of soap and baking soda their basic pH:
Na2CO3 + H2O ⇌ NaOH + NaHCO3
=== Ligand chemistry ===
Water's Lewis base character makes it a common ligand in transition metal complexes, examples of which include metal aquo complexes such as Fe(H2O)2+6 to perrhenic acid, which contains two water molecules coordinated to a rhenium center. In solid hydrates, water can be either a ligand or simply lodged in the framework, or both. Thus, FeSO4·7H2O consists of [Fe(H2O)6]2+ centers and one "lattice water". Water is typically a monodentate ligand, i.e., it forms only one bond with the central atom.
=== Organic chemistry ===
As a hard base, water reacts readily with organic carbocations; for example in a hydration reaction, a hydroxyl group (OH−) and an acidic proton are added to the two carbon atoms bonded together in the carbon-carbon double bond, resulting in an alcohol. When the addition of water to an organic molecule cleaves the molecule in two, hydrolysis is said to occur. Notable examples of hydrolysis are the saponification of fats and the digestion of proteins and polysaccharides. Water can also be a leaving group in SN2 substitution and E2 elimination reactions; the latter is then known as a dehydration reaction.
=== Water in redox reactions ===
Water contains hydrogen in the oxidation state +1 and oxygen in the oxidation state −2. It oxidizes chemicals such as hydrides, alkali metals, and some alkaline earth metals. One example of an alkali metal reacting with water is:
2 Na + 2 H2O → H2 + 2 Na+ + 2 OH−
Some other reactive metals, such as aluminium and beryllium, are oxidized by water as well, but their oxides adhere to the metal and form a passive protective layer. Note that the rusting of iron is a reaction between iron and oxygen that is dissolved in water, not between iron and water.
Water can be oxidized to emit oxygen gas, but very few oxidants react with water even if their reduction potential is greater than the potential of O2/H2O. Almost all such reactions require a catalyst. An example of the oxidation of water is:
4 AgF2 + 2 H2O → 4 AgF + 4 HF + O2
=== Electrolysis ===
Water can be split into its constituent elements, hydrogen and oxygen, by passing an electric current through it. This process is called electrolysis. The cathode half reaction is:
2 H+ + 2 e− → H2
The anode half reaction is:
2 H2O → O2 + 4 H+ + 4 e−
The gases produced bubble to the surface, where they can be collected or ignited with a flame above the water if this was the intention. The required potential for the electrolysis of pure water is 1.23 V at 25 °C. The operating potential is actually 1.48 V or higher in practical electrolysis.
== History ==
Henry Cavendish showed that water was composed of oxygen and hydrogen in 1781. The first decomposition of water into hydrogen and oxygen, by electrolysis, was done in 1800 by English chemist William Nicholson and Anthony Carlisle. In 1805, Joseph Louis Gay-Lussac and Alexander von Humboldt showed that water is composed of two parts hydrogen and one part oxygen.
Gilbert Newton Lewis isolated the first sample of pure heavy water in 1933.
The properties of water have historically been used to define various temperature scales. Notably, the Kelvin, Celsius, Rankine, and Fahrenheit scales were, or currently are, defined by the freezing and boiling points of water. The less common scales of Delisle, Newton, Réaumur, and Rømer were defined similarly. The triple point of water is a more commonly used standard point today.
== Nomenclature ==
The accepted IUPAC name of water is oxidane or simply water, or its equivalent in different languages, although there are other systematic names which can be used to describe the molecule. Oxidane is only intended to be used as the name of the mononuclear parent hydride used for naming derivatives of water by substituent nomenclature. These derivatives commonly have other recommended names. For example, the name hydroxyl is recommended over oxidanyl for the –OH group. The name oxane is explicitly mentioned by the IUPAC as being unsuitable for this purpose, since it is already the name of a cyclic ether also known as tetrahydropyran.
The simplest systematic name of water is hydrogen oxide. This is analogous to related compounds such as hydrogen peroxide, hydrogen sulfide, and deuterium oxide (heavy water). Using chemical nomenclature for type I ionic binary compounds, water would take the name hydrogen monoxide, but this is not among the names published by the International Union of Pure and Applied Chemistry (IUPAC). Another name is dihydrogen monoxide, which is a rarely used name of water, and mostly used in the dihydrogen monoxide parody.
Other systematic names for water include hydroxic acid, hydroxylic acid, and hydrogen hydroxide, using acid and base names. None of these exotic names are used widely. The polarized form of the water molecule, H+OH−, is also called hydron hydroxide by IUPAC nomenclature.
Water substance is a rare term used for H2O when one does not wish to specify the phase of matter (liquid water, water vapor, some form of ice, or a component in a mixture) though the term water is also used with this general meaning.
Oxygen dihydride is another way of referring to water, but modern usage often restricts the term "hydride" to ionic compounds (which water is not).
== See also ==
== Footnotes ==
== References ==
=== Notes ===
=== Bibliography ===
== Further reading ==
Ben-Naim, A. (2011), Molecular Theory of Water and Aqueous Solutions, World Scientific
== External links ==
"Water Properties and Measurements". United States Geological Survey. May 2, 2016. Retrieved August 31, 2016.
Release on the IAPWS Formulation 1995 for the Thermodynamic Properties of Ordinary Water Substance for General and Scientific Use (simpler formulation)
Online calculator using the IAPWS Supplementary Release on Properties of Liquid Water at 0.1 MPa, September 2008
Chaplin, Martin (2019). "Structure and Properties of Water in its Various States". Encyclopedia of Water. Wiley Online Library 2019. pp. 1–19. doi:10.1002/9781119300762.wsts0002. ISBN 9781119300755. S2CID 213738895.
Calculation of vapor pressure, liquid density, dynamic liquid viscosity, and surface tension of water
Water Density Calculator
Why does ice float in my drink?, NASA | Wikipedia/Water_molecule |
Phosphoglycerate kinase (EC 2.7.2.3) (PGK 1) is an enzyme that catalyzes the reversible transfer of a phosphate group from 1,3-bisphosphoglycerate (1,3-BPG) to ADP producing 3-phosphoglycerate (3-PG) and ATP :
1,3-bisphosphoglycerate + ADP ⇌ glycerate 3-phosphate + ATP
Like all kinases it is a transferase. PGK is a major enzyme used in glycolysis, in the first ATP-generating step of the glycolytic pathway. In gluconeogenesis, the reaction catalyzed by PGK proceeds in the opposite direction, generating ADP and 1,3-BPG.
In humans, two isozymes of PGK have been so far identified, PGK1 and PGK2. The isozymes have 87-88% identical amino acid sequence identity and though they are structurally and functionally similar, they have different localizations: PGK2, encoded by an autosomal gene, is unique to meiotic and postmeiotic spermatogenic cells, while PGK1, encoded on the X-chromosome, is ubiquitously expressed in all cells.
== Biological function ==
PGK is present in all living organisms as one of the two ATP-generating enzymes in glycolysis. In the gluconeogenic pathway, PGK catalyzes the reverse reaction. Under biochemical standard conditions, the glycolytic direction is favored.
In the Calvin cycle in photosynthetic organisms, PGK catalyzes the phosphorylation of 3-PG, producing 1,3-BPG and ADP, as part of the reactions that regenerate ribulose-1,5-bisphosphate.
PGK has been reported to exhibit thiol reductase activity on plasmin, leading to angiostatin formation, which inhibits angiogenesis and tumor growth. The enzyme was also shown to participate in DNA replication and repair in mammal cell nuclei.
The human isozyme PGK2, which is only expressed during spermatogenesis, was shown to be essential for sperm function in mice.
=== Interactive pathway map ===
Click on genes, proteins and metabolites below to link to respective articles.
== Structure ==
=== Overview ===
PGK is found in all living organisms and its sequence has been highly conserved throughout evolution. The enzyme exists as a 415-residue monomer containing two nearly equal-sized domains that correspond to the N- and C-termini of the protein. 3-phosphoglycerate (3-PG) binds to the N-terminal, while the nucleotide substrates, MgATP or MgADP, bind to the C-terminal domain of the enzyme. This extended two-domain structure is associated with large-scale 'hinge-bending' conformational changes, similar to those found in hexokinase. The two domains of the protein are separated by a cleft and linked by two alpha-helices. At the core of each domain is a 6-stranded parallel beta-sheet surrounded by alpha helices. The two lobes are capable of folding independently, consistent with the presence of intermediates on the folding pathway with a single domain folded. Though the binding of either substrate triggers a conformational change, only through the binding of both substrates does domain closure occur, leading to the transfer of the phosphate group.
The enzyme has a tendency to exist in the open conformation with short periods of closure and catalysis, which allow for rapid diffusion of substrate and products through the binding sites; the open conformation of PGK is more conformationally stable due to the exposure of a hydrophobic region of the protein upon domain closure.
=== Role of magnesium ===
Magnesium ions are normally complexed to the phosphate groups the nucleotide substrates of PGK. It is known that in the absence of magnesium, no enzyme activity occurs. The bivalent metal assists the enzyme ligands in shielding the bound phosphate group's negative charges, allowing the nucleophilic attack to occur; this charge-stabilization is a typical characteristic of phosphotransfer reaction. It is theorized that the ion may also encourage domain closure when PGK has bound both substrates.
== Mechanism ==
Without either substrate bound, PGK exists in an "open" conformation. After both the triose and nucleotide substrates are bound to the N- and C-terminal domains, respectively, an extensive hinge-bending motion occurs, bringing the domains and their bound substrates into close proximity and leading to a "closed" conformation. Then, in the case of the forward glycolytic reaction, the beta-phosphate of ADP initiates a nucleophilic attack on the 1-phosphate of 1,3-BPG. The Lys219 on the enzyme guides the phosphate group to the substrate.
PGK proceeds through a charge-stabilized transition state that is favored over the arrangement of the bound substrate in the closed enzyme because in the transition state, all three phosphate oxygens are stabilized by ligands, as opposed to only two stabilized oxygens in the initial bound state.
In the glycolytic pathway, 1,3-BPG is the phosphate donor and has a high phosphoryl-transfer potential. The PGK-catalyzed transfer of the phosphate group from 1,3-BPG to ADP to yield ATP can power the carbon-oxidation reaction of the previous glycolytic step (converting glyceraldehyde 3-phosphate to 3-phosphoglycerate).
== Regulation ==
The enzyme is activated by low concentrations of various multivalent anions, such as pyrophosphate, sulfate, phosphate, and citrate. High concentrations of MgATP and 3-PG activates PGK, while Mg2+ at high concentrations non-competitively inhibits the enzyme.
PGK exhibits a wide specificity toward nucleotide substrates. Its activity is inhibited by salicylates, which appear to mimic the enzyme's nucleotide substrate.
Macromolecular crowding has been shown to increase PGK activity in both computer simulations and in vitro environments simulating a cell interior; as a result of crowding, the enzyme becomes more enzymatically active and more compact.
== Disease relevance ==
Phosphoglycerate kinase (PGK) deficiency is an X-linked recessive trait associated with hemolytic anemia, mental disorders and myopathy in humans, depending on form – there exists a hemolytic form and a myopathic form. Since the trait is X-linked, it is usually fully expressed in males, who have one X chromosome; affected females are typically asymptomatic. The condition results from mutations in Pgk1, the gene encoding PGK1, and twenty mutations have been identified. On a molecular level, the mutation in Pgk1 impairs the thermal stability and inhibits the catalytic activity of the enzyme. PGK is the only enzyme in the immediate glycolytic pathway encoded by an X-linked gene. In the case of hemolytic anemia, PGK deficiency occurs in the erythrocytes. Currently, no definitive treatment exists for PGK deficiency.
PGK1 overexpression has been associated with gastric cancer and has been found to increase the invasiveness of gastric cancer cells in vitro. The enzyme is secreted by tumor cells and participates in the angiogenic process, leading to the release of angiostatin and the inhibition of tumor blood vessel growth.
Due to its wide specificity towards nucleotide substrates, PGK is known to participate in the phosphorylation and activation of HIV antiretroviral drugs, which are nucleotide-based.
== Human isozymes ==
== References ==
== External links ==
Phosphoglycerate+kinase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Illustration at arizona.edu | Wikipedia/Phosphoglycerate_kinase |
Proteinogenic amino acids are amino acids that are incorporated biosynthetically into proteins during translation from RNA. The word "proteinogenic" means "protein creating". Throughout known life, there are 22 genetically encoded (proteinogenic) amino acids, 20 in the standard genetic code and an additional 2 (selenocysteine and pyrrolysine) that can be incorporated by special translation mechanisms.
In contrast, non-proteinogenic amino acids are amino acids that are either not incorporated into proteins (like GABA, L-DOPA, or triiodothyronine), misincorporated in place of a genetically encoded amino acid, or not produced directly and in isolation by standard cellular machinery (like hydroxyproline). The latter often results from post-translational modification of proteins. Some non-proteinogenic amino acids are incorporated into nonribosomal peptides which are synthesized by non-ribosomal peptide synthetases.
Both eukaryotes and prokaryotes can incorporate selenocysteine into their proteins via a nucleotide sequence known as a SECIS element, which directs the cell to translate a nearby UGA codon as selenocysteine (UGA is normally a stop codon). In some methanogenic prokaryotes, the UAG codon (normally a stop codon) can also be translated to pyrrolysine.
In eukaryotes, there are only 21 proteinogenic amino acids, the 20 of the standard genetic code, plus selenocysteine. Humans can synthesize 12 of these from each other or from other molecules of intermediary metabolism. The other nine must be consumed (usually as their protein derivatives), and so they are called essential amino acids. The essential amino acids are histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine (i.e. H, I, L, K, M, F, T, W, V).
The proteinogenic amino acids have been found to be related to the set of amino acids that can be recognized by ribozyme autoaminoacylation systems. Thus, non-proteinogenic amino acids would have been excluded by the contingent evolutionary success of nucleotide-based life forms. Other reasons have been offered to explain why certain specific non-proteinogenic amino acids are not generally incorporated into proteins; for example, ornithine and homoserine cyclize against the peptide backbone and fragment the protein with relatively short half-lives, while others are toxic because they can be mistakenly incorporated into proteins, such as the arginine analog canavanine.
The evolutionary selection of certain proteinogenic amino acids from the primordial soup has been suggested to be because of their better incorporation into a polypeptide chain as opposed to non-proteinogenic amino acids.
== Structures ==
The following illustrates the structures and abbreviations of the 21 amino acids that are directly encoded for protein synthesis by the genetic code of eukaryotes. The structures given below are standard chemical structures, not the typical zwitterion forms that exist in aqueous solutions.
IUPAC/IUBMB now also recommends standard abbreviations for the following two amino acids:
== Chemical properties ==
Following is a table listing the one-letter symbols, the three-letter symbols, and the chemical properties of the side chains of the standard amino acids. The masses listed are based on weighted averages of the elemental isotopes at their natural abundances. Forming a peptide bond results in elimination of a molecule of water. Therefore, the protein's mass is equal to the mass of amino acids the protein is composed of minus 18.01524 Da per peptide bond.
=== General chemical properties ===
=== Side-chain properties ===
§: Values for Asp, Cys, Glu, His, Lys & Tyr were determined using the amino acid residue placed centrally in an alanine pentapeptide. The value for Arg is from Pace et al. (2009). The value for Sec is from Byun & Kang (2011).
N.D.: The pKa value of Pyrrolysine has not been reported.
Note: The pKa value of an amino-acid residue in a small peptide is typically slightly different when it is inside a protein. Protein pKa calculations are sometimes used to calculate the change in the pKa value of an amino-acid residue in this situation.
=== Gene expression and biochemistry ===
* UAG is normally the amber stop codon, but in organisms containing the biological machinery encoded by the pylTSBCD cluster of genes the amino acid pyrrolysine will be incorporated.
** UGA is normally the opal (or umber) stop codon, but encodes selenocysteine if a SECIS element is present.
† The stop codon is not an amino acid, but is included for completeness.
†† UAG and UGA do not always act as stop codons (see above).
‡ An essential amino acid cannot be synthesized in humans and must, therefore, be supplied in the diet. Conditionally essential amino acids are not normally required in the diet, but must be supplied exogenously to specific populations that do not synthesize it in adequate amounts.
& Occurrence of amino acids is based on 135 Archaea, 3775 Bacteria, 614 Eukaryota proteomes and human proteome (21 006 proteins) respectively.
=== Mass spectrometry ===
In mass spectrometry of peptides and proteins, knowledge of the masses of the residues is useful. The mass of the peptide or protein is the sum of the residue masses plus the mass of water (Monoisotopic mass = 18.01056 Da; average mass = 18.0153 Da). The residue masses are calculated from the tabulated chemical formulas and atomic weights. In mass spectrometry, ions may also include one or more protons (Monoisotopic mass = 1.00728 Da; average mass* = 1.0074 Da). *Protons cannot have an average mass, this confusingly infers to Deuterons as a valid isotope, but they should be a different species (see Hydron (chemistry))
§ Monoisotopic mass
=== Stoichiometry and metabolic cost in cell ===
The table below lists the abundance of amino acids in E.coli cells and the metabolic cost (ATP) for synthesis of the amino acids. Negative numbers indicate the metabolic processes are energy favorable and do not cost net ATP of the cell. The abundance of amino acids includes amino acids in free form and in polymerization form (proteins).
=== Remarks ===
=== Catabolism ===
Amino acids can be classified according to the properties of their main products:
Glucogenic, with the products having the ability to form glucose by gluconeogenesis
Ketogenic, with the products not having the ability to form glucose: These products may still be used for ketogenesis or lipid synthesis.
Amino acids catabolized into both glucogenic and ketogenic products
== See also ==
Glucogenic amino acid
Ketogenic amino acid
== References ==
== General references ==
== External links ==
The origin of the single-letter code for the amino acids | Wikipedia/Proteinogenic_amino_acid |
The plug flow reactor model (PFR, sometimes called continuous tubular reactor, CTR, or piston flow reactors) is a model used to describe chemical reactions in continuous, flowing systems of cylindrical geometry. The PFR model is used to predict the behavior of chemical reactors of such design, so that key reactor variables, such as the dimensions of the reactor, can be estimated.
Fluid going through a PFR may be modeled as flowing through the reactor as a series of infinitely thin coherent "plugs", each with a uniform composition, traveling in the axial direction of the reactor, with each plug having a different composition from the ones before and after it. The key assumption is that as a plug flows through a PFR, the fluid is perfectly mixed in the radial direction but not in the axial direction (forwards or backwards). Each plug of differential volume is considered as a separate entity, effectively an infinitesimally small continuous stirred tank reactor, limiting to zero volume. As it flows down the tubular PFR, the residence time (
τ
{\displaystyle \tau }
) of the plug is a function of its position in the reactor. In the ideal PFR, the residence time distribution is therefore a Dirac delta function with a value equal to
τ
{\displaystyle \tau }
.
== PFR modeling ==
The stationary PFR is governed by ordinary differential equations, the solution for which can be calculated providing that appropriate boundary conditions are known.
The PFR model works well for many fluids: liquids, gases, and slurries. Although turbulent flow and axial diffusion cause a degree of mixing in the axial direction in real reactors, the PFR model is appropriate when these effects are sufficiently small that they can be ignored.
In the simplest case of a PFR model, several key assumptions must be made in order to simplify the problem, some of which are outlined below. Note that not all of these assumptions are necessary, however the removal of these assumptions does increase the complexity of the problem. The PFR model can be used to model multiple reactions as well as reactions involving changing temperatures, pressures and densities of the flow. Although these complications are ignored in what follows, they are often relevant to industrial processes.
Assumptions:
Plug flow
Steady state
Constant density (reasonable for some liquids but a 20% error for polymerizations; valid for gases only if there is no pressure drop, no net change in the number of moles, nor any large temperature change)
Single reaction occurring in the bulk of the fluid (homogeneously).
A material balance on the differential volume of a fluid element, or plug, on species i of axial length dx between x and x + dx gives:
[accumulation] = [in] - [out] + [generation] - [consumption]
Accumulation is 0 under steady state; therefore, the above mass balance can be re-written as follows:
1.
F
i
(
x
)
−
F
i
(
x
+
d
x
)
+
A
t
d
x
ν
i
r
=
0
{\displaystyle F_{i}(x)-F_{i}(x+dx)+A_{t}dx\nu _{i}r=0}
.
where:
x is the reactor tube axial position, m
dx the differential thickness of fluid plug
the index i refers to the species i
Fi(x) is the molar flow rate of species i at the position x, mol/s
D is the tube diameter, m
At is the tube transverse cross sectional area, m2
ν is the stoichiometric coefficient, dimensionless
r is the volumetric source/sink term (the reaction rate), mol/m3s.
The flow linear velocity, u (m/s) and the concentration of species i, Ci (mol/m3) can be introduced as:
u
=
v
˙
A
t
=
4
v
˙
π
D
2
{\displaystyle u={\frac {\dot {v}}{A_{t}}}={\frac {4{\dot {v}}}{\pi D^{2}}}}
and
F
i
=
A
t
u
C
i
{\displaystyle F_{i}=A_{t}uC_{i}\,}
where
v
˙
{\displaystyle {\dot {v}}}
is the volumetric flow rate.
On application of the above to Equation 1, the mass balance on i becomes:
2.
A
t
u
[
C
i
(
x
)
−
C
i
(
x
+
d
x
)
]
+
A
t
d
x
ν
i
r
=
0
{\displaystyle A_{t}u[C_{i}(x)-C_{i}(x+dx)]+A_{t}dx\nu _{i}r=0\,}
.
When like terms are cancelled and the limit dx → 0 is applied to Equation 2 the mass balance on species i becomes
3.
u
d
C
i
d
x
=
ν
i
r
{\displaystyle u{\frac {dC_{i}}{dx}}=\nu _{i}r}
,
The temperature dependence of the reaction rate, r, can be estimated using the Arrhenius equation. Generally, as the temperature increases so does the rate at which the reaction occurs. Residence time,
τ
{\displaystyle \tau }
, is the average amount of time a discrete quantity of reagent spends inside the tank.
Assume:
isothermal conditions, or constant temperature (k is constant)
single, irreversible reaction (νA = -1)
first-order reaction (r = k CA)
After integration of Equation 3 using the above assumptions, solving for CA(x) we get an explicit equation for the concentration of species A as a function of position:
4.
C
A
(
x
)
=
C
A
0
e
−
k
τ
{\displaystyle C_{A}(x)=C_{A0}e^{-k\tau }\,}
,
where CA0 is the concentration of species A at the inlet to the reactor, appearing from the integration boundary condition.
== Operation and uses ==
PFRs are used to model the chemical transformation of compounds as they are transported in systems resembling "pipes". The "pipe" can represent a variety of engineered or natural conduits through which liquids or gases flow. (e.g. rivers, pipelines, regions between two mountains, etc.)
An ideal plug flow reactor has a fixed residence time: Any fluid (plug) that enters the reactor at time
t
{\displaystyle t}
will exit the reactor at time
t
+
τ
{\displaystyle t+\tau }
, where
τ
{\displaystyle \tau }
is the residence time of the reactor. The residence time distribution function is therefore a Dirac delta function at
τ
{\displaystyle \tau }
. A real plug flow reactor has a residence time distribution that is a narrow pulse around the mean residence time distribution.
A typical plug flow reactor could be a tube packed with some solid material (frequently a catalyst). Typically these types of reactors are called packed bed reactors or PBR's. Sometimes the tube will be a tube in a shell and tube heat exchanger.
When a plug flow model can not be applied, the dispersion model is usually employed.
== Residence-time distribution ==
The residence-time distribution (RTD) of a reactor is a characteristic of the mixing that occurs in the chemical reactor. There is no axial mixing in a plug-flow reactor, and this omission is reflected in the RTD which is exhibited by this class of reactors.
Real plug flow reactors do not satisfy the idealized flow patterns, back mix flow or plug flow deviation from ideal behavior can be due to channeling of fluid through the vessel, recycling of fluid within the vessel or due to the presence of stagnant region or dead zone of fluid in the vessel. Real plug flow reactors with non-ideal behavior have also been modelled. To predict the exact behavior of a vessel as a chemical reactor, RTD or stimulus response technique is used. The tracer technique, the most widely used method for the study of axial dispersion, is usually used in the form of:
Pulse input
Step input
Cyclic input
Random input
The RTD is determined experimentally by injecting an inert chemical, molecule, or atom, called a tracer, into the reactor at some time t = 0 and then measuring the tracer concentration, C, in the effluent stream as a function of time.
The RTD curve of fluid leaving a vessel is called the E-Curve. This curve is normalized in such a way that the area under it is unity:
(1)
∫
E
∂
t
=
1
{\displaystyle \int E\partial t=1}
The mean age of the exit stream or mean residence time is:
(2)
τ
=
∫
t
E
∂
t
=
∑
t
E
∇
t
{\displaystyle \tau =\int tE\partial t=\sum tE\nabla t}
When a tracer is injected into a reactor at a location more than two or three particle diameters downstream from the entrance and measured some distance upstream from the exit, the system can be described by the dispersion model with combinations of open or close boundary conditions. For such a system where there is no discontinuity in type of flow at the point of tracer injection or at the point of tracer measurement, the variance for open-open system is:
(3)
(
σ
θ
)
2
=
(
σ
t
)
2
/
τ
2
=
2
/
P
e
+
8
/
(
P
e
)
2
{\displaystyle (\sigma _{\theta })^{2}=(\sigma _{t})^{2}/\tau ^{2}=2/P_{e}+8/(P_{e})^{2}}
Where,
(4)
P
e
=
L
U
/
D
L
{\displaystyle P_{e}=LU/D_{L}}
which represents the ratio of rate of transport by convection to rate of transport by diffusion or dispersion.
L
{\displaystyle L}
= characteristic length (m)
D
L
{\displaystyle D_{L}}
= effective dispersion coefficient ( m2/s)
U
{\displaystyle U}
= superficial velocity (m/s) based on empty cross-section
Vessel dispersion number is defined as:
1
/
P
e
=
D
L
/
L
U
{\displaystyle 1/P_{e}=D_{L}/LU}
The variance of a continuous distribution measured at a finite number of equidistant locations is given by:
(5)
(
σ
t
)
2
=
∑
t
i
2
C
i
/
∑
C
i
−
∑
[
t
i
C
i
/
∑
C
i
]
2
{\displaystyle (\sigma _{t})^{2}=\sum t_{i}^{2}C_{i}/\sum C_{i}-\sum [t_{i}C_{i}/\sum C_{i}]^{2}}
Where mean residence time τ is given by:
(6)
τ
=
∑
t
i
C
i
/
∑
C
i
{\displaystyle \tau =\sum t_{i}C_{i}/\sum C_{i}}
(7)
(
σ
θ
)
2
=
(
σ
t
)
2
/
τ
2
{\displaystyle (\sigma _{\theta })^{2}=(\sigma _{t})^{2}/\tau ^{2}}
Thus (σθ)2 can be evaluated from the experimental data on C vs. t and for known values of
(
σ
θ
)
2
{\displaystyle (\sigma _{\theta })^{2}}
, the dispersion number
(
1
/
P
e
)
{\displaystyle (1/P_{e})}
can be obtained from eq. (3) as:
(8)
D
L
/
L
U
=
−
1
+
1
+
8
(
σ
θ
)
2
8
{\displaystyle D_{L}/LU={-1+{\sqrt {1+8(\sigma _{\theta })^{2}}} \over 8}}
Thus axial dispersion coefficient DL can be estimated (L = packed height)
As mentioned before, there are also other boundary conditions that can be applied to the dispersion model giving different relationships for the dispersion number.
Advantages
From the safety technical point of view the PFR has the advantages that
It operates in a steady state
It is well controllable
Large heat transfer areas can be installed
Concerns
The main problems lies in difficult and sometimes critical start-up and shut down operations.
== Applications ==
Plug flow reactors are used for some of the following applications:
Large-scale production
Fast reactions
Homogeneous or heterogeneous reactions
Continuous production
High-temperature reactions
== See also ==
== Reference and sources == | Wikipedia/Plug_flow_reactor_model |
A protein family is a group of evolutionarily related proteins. In many cases, a protein family has a corresponding gene family, in which each gene encodes a corresponding protein with a 1:1 relationship. The term "protein family" should not be confused with family as it is used in taxonomy.
Proteins in a family descend from a common ancestor and typically have similar three-dimensional structures, functions, and significant sequence similarity. Sequence similarity (usually amino-acid sequence) is one of the most common indicators of homology, or common evolutionary ancestry. Some frameworks for evaluating the significance of similarity between sequences use sequence alignment methods. Proteins that do not share a common ancestor are unlikely to show statistically significant sequence similarity, making sequence alignment a powerful tool for identifying the members of protein families. Families are sometimes grouped together into larger clades called superfamilies based on structural similarity, even if there is no identifiable sequence homology.
Currently, over 60,000 protein families have been defined, although ambiguity in the definition of "protein family" leads different researchers to highly varying numbers.
== Terminology and usage ==
The term protein family has broad usage and can be applied to large groups of proteins with barely detectable sequence similarity as well as narrow groups of proteins with near identical sequence, function, and structure. To distinguish between these cases, a hierarchical terminology is in use. At the highest level of classification are protein superfamilies, which group distantly related proteins, often based on their structural similarity. Next are protein families, which refer to proteins with a shared evolutionary origin exhibited by significant sequence similarity. Subfamilies can be defined within families to denote closely related proteins that have similar or identical functions. For example, a superfamily like the PA clan of proteases has less sequence conservation than the C04 family within it.
== Protein domains and motifs ==
Protein families were first recognised when most proteins that were structurally understood were small, single-domain proteins such as myoglobin, hemoglobin, and cytochrome c. Since then, many proteins have been found with multiple independent structural and functional units called domains. Due to evolutionary shuffling, different domains in a protein have evolved independently. This has led to a focus on families of protein domains. Several online resources are devoted to identifying and cataloging these domains.
Different regions of a protein have differing functional constraints. For example, the active site of an enzyme requires certain amino-acid residues to be precisely oriented. A protein–protein binding interface may consist of a large surface with constraints on the hydrophobicity or polarity of the amino-acid residues. Functionally constrained regions of proteins evolve more slowly than unconstrained regions such as surface loops, giving rise to blocks of conserved sequence when the sequences of a protein family are compared (see multiple sequence alignment). These blocks are most commonly referred to as motifs, although many other terms are used (blocks, signatures, fingerprints, etc.). Several online resources are devoted to identifying and cataloging protein motifs.
== Evolution of protein families ==
According to current consensus, protein families arise in two ways. First, the separation of a parent species into two genetically isolated descendant species allows a gene/protein to independently accumulate variations (mutations) in these two lineages. This results in a family of orthologous proteins, usually with conserved sequence motifs. Second, a gene duplication may create a second copy of a gene (termed a paralog). Because the original gene is still able to perform its function, the duplicated gene is free to diverge and may acquire new functions (by random mutation).
Certain gene/protein families, especially in eukaryotes, undergo extreme expansions and contractions in the course of evolution, sometimes in concert with whole genome duplications. Expansions are less likely, and losses more likely, for intrinsically disordered proteins and for protein domains whose hydrophobic amino acids are further from the optimal degree of dispersion along the primary sequence. This expansion and contraction of protein families is one of the salient features of genome evolution, but its importance and ramifications are currently unclear.
== Use and importance of protein families ==
As the total number of sequenced proteins increases and interest expands in proteome analysis, an effort is ongoing to organize proteins into families and to describe their component domains and motifs. Reliable identification of protein families is critical to phylogenetic analysis, functional annotation, and the exploration of the diversity of protein function in a given phylogenetic branch. The Enzyme Function Initiative uses protein families and superfamilies as the basis for development of a sequence/structure-based strategy for large scale functional assignment of enzymes of unknown function. The algorithmic means for establishing protein families on a large scale are based on a notion of similarity.
== Protein family resources ==
Many biological databases catalog protein families and allow users to match query sequences to known families. These include:
Pfam - Protein families database of alignments and HMMs
PROSITE - Database of protein domains, families and functional sites
PIRSF - SuperFamily Classification System
PASS2 - Protein Alignment as Structural Superfamilies v2 - PASS2@NCBS
SUPERFAMILY - Library of HMMs representing superfamilies and database of (superfamily and family) annotations for all completely sequenced organisms
SCOP and CATH - Classifications of protein structures into superfamilies, families and domains
Similarly, many database-searching algorithms exist, for example:
BLAST - DNA sequence similarity search
BLASTp - Protein sequence similarity search
OrthoFinder - Method for clustering proteins into families (orthogroups)
== See also ==
=== Protein families ===
== References ==
== External links ==
Media related to Protein families at Wikimedia Commons | Wikipedia/Protein_family |
3-Phosphoglyceric acid (3PG, 3-PGA, or PGA) is the conjugate acid of 3-phosphoglycerate or glycerate 3-phosphate (GP or G3P). This glycerate is a biochemically significant metabolic intermediate in both glycolysis and the Calvin-Benson cycle. The anion is often termed as PGA when referring to the Calvin-Benson cycle. In the Calvin-Benson cycle, 3-phosphoglycerate is typically the product of the spontaneous scission of an unstable 6-carbon intermediate formed upon CO2 fixation. Thus, two equivalents of 3-phosphoglycerate are produced for each molecule of CO2 that is fixed. In glycolysis, 3-phosphoglycerate is an intermediate following the dephosphorylation (reduction) of 1,3-bisphosphoglycerate.: 14
== Glycolysis ==
In the glycolytic pathway, 1,3-bisphosphoglycerate is dephosphorylated to form 3-phosphoglyceric acid in a coupled reaction producing two ATP via substrate-level phosphorylation. The single phosphate group left on the 3-PGA molecule then moves from an end carbon to a central carbon, producing 2-phosphoglycerate. This phosphate group relocation is catalyzed by phosphoglycerate mutase, an enzyme that also catalyzes the reverse reaction.
Compound C00236 at KEGG Pathway Database. Enzyme 2.7.2.3 at KEGG Pathway Database. Compound C00197 at KEGG Pathway Database. Enzyme 5.4.2.1 at KEGG Pathway Database. Compound C00631 at KEGG Pathway Database.
Click on genes, proteins and metabolites below to link to respective articles.
== Calvin-Benson cycle ==
In the light-independent reactions (also known as the Calvin-Benson cycle), two 3-phosphoglycerate molecules are synthesized. RuBP, a 5-carbon sugar, undergoes carbon fixation, catalyzed by the rubisco enzyme, to become an unstable 6-carbon intermediate. This intermediate is then cleaved into two, separate 3-carbon molecules of 3-PGA. One of the resultant 3-PGA molecules continues through the Calvin-Benson cycle to be regenerated into RuBP while the other is reduced to form one molecule of glyceraldehyde 3-phosphate (G3P) in two steps: the phosphorylation of 3-PGA into 1,3-bisphosphoglyceric acid via the enzyme phosphoglycerate kinase (the reverse of the reaction seen in glycolysis) and the subsequent catalysis by glyceraldehyde 3-phosphate dehydrogenase into G3P. G3P eventually reacts to form the sugars such as glucose or fructose or more complex starches.: 156
== Amino acid synthesis ==
Glycerate 3-phosphate (formed from 3-phosphoglycerate) is also a precursor for serine, which, in turn, can create cysteine and glycine through the homocysteine cycle.
== Measurement ==
3-phosphoglycerate can be separated and measured using paper chromatography as well as with column chromatography and other chromatographic separation methods. It can be identified using both gas-chromatography and liquid-chromatography mass spectrometry and has been optimized for evaluation using tandem MS techniques.
== See also ==
2-Phosphoglyceric acid
Calvin-Benson cycle
Photosynthesis
Ribulose 1,5-bisphosphate
== References == | Wikipedia/3-phosphoglycerate |
Cellular respiration is the process of oxidizing biological fuels using an inorganic electron acceptor, such as oxygen, to drive production of adenosine triphosphate (ATP), which stores chemical energy in a biologically accessible form. Cellular respiration may be described as a set of metabolic reactions and processes that take place in the cells of organisms to transfer chemical energy from nutrients to ATP, with the flow of electrons to an electron acceptor, and then release waste products.
If the electron acceptor is oxygen, the process is more specifically known as aerobic cellular respiration. If the electron acceptor is a molecule other than oxygen, this is anaerobic cellular respiration. Fermentation, which is also an anaerobic process, is not respiration, as no external electron acceptor is involved.
The reactions involved in respiration are catabolic reactions, which break large molecules into smaller ones, producing large amounts of energy (ATP). Respiration is one of the key ways a cell releases chemical energy to fuel cellular activity. The overall reaction occurs in a series of biochemical steps, some of which are redox reactions. Although cellular respiration is technically a combustion reaction, it is an unusual one because of the slow, controlled release of energy from the series of reactions.
Nutrients that are commonly used by animal and plant cells in respiration include sugar, amino acids and fatty acids, and the most common oxidizing agent is molecular oxygen (O2). The chemical energy stored in ATP (the bond of its third phosphate group to the rest of the molecule can be broken allowing more stable products to form, thereby releasing energy for use by the cell) can then be used to drive processes requiring energy, including biosynthesis, locomotion or transportation of molecules across cell membranes.
== Aerobic respiration ==
Aerobic respiration requires oxygen (O2) in order to create ATP. Although carbohydrates, fats and proteins are consumed as reactants, aerobic respiration is the preferred method of pyruvate production in glycolysis, and requires pyruvate be transported by the mitochondria in order to be oxidized by the citric acid cycle. The products of this process are carbon dioxide and water, and the energy transferred is used to make bonds between ADP and a third phosphate group to form ATP (adenosine triphosphate), by substrate-level phosphorylation, NADH and FADH2.
The negative ΔG indicates that the reaction is exothermic (exergonic) and can occur spontaneously.
The potential of NADH and FADH2 is converted to more ATP through an electron transport chain with oxygen and protons (hydrogen ions) as the "terminal electron acceptors". Most of the ATP produced by aerobic cellular respiration is made by oxidative phosphorylation. The energy released is used to create a chemiosmotic potential by pumping protons across a membrane. This potential is then used to drive ATP synthase and produce ATP from ADP and a phosphate group. Biology textbooks often state that 38 ATP molecules can be made per oxidized glucose molecule during cellular respiration (2 from glycolysis, 2 from the Krebs cycle, and about 34 from the electron transport system). However, this maximum yield is never quite reached because of losses due to leaky membranes as well as the cost of moving pyruvate and ADP into the mitochondrial matrix, and current estimates range around 29 to 30 ATP per glucose.
Aerobic metabolism is up to 15 times more efficient than anaerobic metabolism (which yields 2 molecules of ATP per 1 molecule of glucose). However, some anaerobic organisms, such as methanogens are able to continue with anaerobic respiration, yielding more ATP by using inorganic molecules other than oxygen as final electron acceptors in the electron transport chain. They share the initial pathway of glycolysis but aerobic metabolism continues with the Krebs cycle and oxidative phosphorylation. The post-glycolytic reactions take place in the mitochondria in eukaryotic cells, and in the cytoplasm in prokaryotic cells.
Although plants are net consumers of carbon dioxide and producers of oxygen via photosynthesis, plant respiration accounts for about half of the CO2 generated annually by terrestrial ecosystems.: 87
=== Glycolysis ===
Glycolysis is a metabolic pathway that takes place in the cytosol of cells in all living organisms. Glycolysis can be literally translated as "sugar splitting", and occurs regardless of oxygen's presence or absence. The process converts one molecule of glucose into two molecules of pyruvate (pyruvic acid), generating energy in the form of two net molecules of ATP. Four molecules of ATP per glucose are actually produced, but two are consumed as part of the preparatory phase. The initial phosphorylation of glucose is required to increase the reactivity (decrease its stability) in order for the molecule to be cleaved into two pyruvate molecules by the enzyme aldolase. During the pay-off phase of glycolysis, four phosphate groups are transferred to four ADP by substrate-level phosphorylation to make four ATP, and two NADH are also produced during the pay-off phase. The overall reaction can be expressed this way:
Glucose + 2 NAD+ + 2 Pi + 2 ADP → 2 pyruvate + 2 NADH + 2 ATP + 2 H+ + 2 H2O + energy
Starting with glucose, 1 ATP is used to donate a phosphate to glucose to produce glucose 6-phosphate. Glycogen can be converted into glucose 6-phosphate as well with the help of glycogen phosphorylase. During energy metabolism, glucose 6-phosphate becomes fructose 6-phosphate. An additional ATP is used to phosphorylate fructose 6-phosphate into fructose 1,6-bisphosphate by the help of phosphofructokinase. Fructose 1,6-biphosphate then splits into two phosphorylated molecules with three carbon chains which later degrades into pyruvate.: 88–90
=== Oxidative decarboxylation of pyruvate ===
Pyruvate is oxidized to acetyl-CoA and CO2 by the pyruvate dehydrogenase complex (PDC). The PDC contains multiple copies of three enzymes and is located in the mitochondria of eukaryotic cells and in the cytosol of prokaryotes. In the conversion of pyruvate to acetyl-CoA, one molecule of NADH and one molecule of CO2 is formed.
=== Citric acid cycle ===
The citric acid cycle is also called the Krebs cycle or the tricarboxylic acid cycle. When oxygen is present, acetyl-CoA is produced from the pyruvate molecules created from glycolysis. Once acetyl-CoA is formed, aerobic or anaerobic respiration can occur. When oxygen is present, the mitochondria will undergo aerobic respiration which leads to the Krebs cycle. However, if oxygen is not present, fermentation of the pyruvate molecule will occur. In the presence of oxygen, when acetyl-CoA is produced, the molecule then enters the citric acid cycle (Krebs cycle) inside the mitochondrial matrix, and is oxidized to CO2 while at the same time reducing NAD to NADH. NADH can be used by the electron transport chain to create further ATP as part of oxidative phosphorylation. To fully oxidize the equivalent of one glucose molecule, two acetyl-CoA must be metabolized by the Krebs cycle. Two low-energy waste products, H2O and CO2, are created during this cycle.
The citric acid cycle is an 8-step process involving 18 different enzymes and co-enzymes. During the cycle, acetyl-CoA (2 carbons) + oxaloacetate (4 carbons) yields citrate (6 carbons), which is rearranged to a more reactive form called isocitrate (6 carbons). Isocitrate is modified to become α-ketoglutarate (5 carbons), succinyl-CoA, succinate, fumarate, malate and, finally, oxaloacetate.
The net gain from one cycle is 3 NADH and 1 FADH2 as hydrogen (proton plus electron) carrying compounds and 1 high-energy GTP, which may subsequently be used to produce ATP. Thus, the total yield from 1 glucose molecule (2 pyruvate molecules) is 6 NADH, 2 FADH2, and 2 ATP.: 90–91
=== Oxidative phosphorylation ===
In eukaryotes, oxidative phosphorylation occurs in the mitochondrial cristae. It comprises the electron transport chain that establishes a proton gradient (chemiosmotic potential) across the boundary of the inner membrane by oxidizing the NADH produced from the Krebs cycle. ATP is synthesized by the ATP synthase enzyme when the chemiosmotic gradient is used to drive the phosphorylation of ADP. The electrons are finally transferred to exogenous oxygen and, with the addition of two protons, water is formed.
== Efficiency of ATP production ==
The table below describes the reactions involved when one glucose molecule is fully oxidized into carbon dioxide. It is assumed that all the reduced coenzymes are oxidized by the electron transport chain and used for oxidative phosphorylation.
Although there is a theoretical yield of 38 ATP molecules per glucose during cellular respiration, such conditions are generally not realized because of losses such as the cost of moving pyruvate (from glycolysis), phosphate, and ADP (substrates for ATP synthesis) into the mitochondria. All are actively transported using carriers that utilize the stored energy in the proton electrochemical gradient.
Pyruvate is taken up by a specific, low Km transporter to bring it into the mitochondrial matrix for oxidation by the pyruvate dehydrogenase complex.
The phosphate carrier (PiC) mediates the electroneutral exchange (antiport) of phosphate (H2PO−4; Pi) for OH− or symport of phosphate and protons (H+) across the inner membrane, and the driving force for moving phosphate ions into the mitochondria is the proton motive force.
The ATP-ADP translocase (also called adenine nucleotide translocase, ANT) is an antiporter and exchanges ADP and ATP across the inner membrane. The driving force is due to the ATP (−4) having a more negative charge than the ADP (−3), and thus it dissipates some of the electrical component of the proton electrochemical gradient.
The outcome of these transport processes using the proton electrochemical gradient is that more than 3 H+ are needed to make 1 ATP. Obviously, this reduces the theoretical efficiency of the whole process and the likely maximum is closer to 28–30 ATP molecules. In practice the efficiency may be even lower because the inner membrane of the mitochondria is slightly leaky to protons. Other factors may also dissipate the proton gradient creating an apparently leaky mitochondria. An uncoupling protein known as thermogenin is expressed in some cell types and is a channel that can transport protons. When this protein is active in the inner membrane it short circuits the coupling between the electron transport chain and ATP synthesis. The potential energy from the proton gradient is not used to make ATP but generates heat. This is particularly important in brown fat thermogenesis of newborn and hibernating mammals.
According to some newer sources, the ATP yield during aerobic respiration is not 36–38, but only about 30–32 ATP molecules / 1 molecule of glucose , because:
ATP : NADH+H+ and ATP : FADH2 ratios during the oxidative phosphorylation appear to be not 3 and 2, but 2.5 and 1.5 respectively. Unlike in the substrate-level phosphorylation, the stoichiometry here is difficult to establish.
ATP synthase produces 1 ATP / 3 H+. However the exchange of matrix ATP for cytosolic ADP and Pi (antiport with OH− or symport with H+) mediated by ATP–ADP translocase and phosphate carrier consumes 1 H+ / 1 ATP as a result of regeneration of the transmembrane potential changed during this transfer, so the net ratio is 1 ATP : 4 H+.
The mitochondrial electron transport chain proton pump transfers across the inner membrane 10 H+ / 1 NADH+H+ (4 + 2 + 4) or 6 H+ / 1 FADH2 (2 + 4).
So the final stoichiometry is
1 NADH+H+ : 10 H+ : 10/4 ATP = 1 NADH+H+ : 2.5 ATP
1 FADH2 : 6 H+ : 6/4 ATP = 1 FADH2 : 1.5 ATP
ATP : NADH+H+ coming from glycolysis ratio during the oxidative phosphorylation is
1.5, as for FADH2, if hydrogen atoms (2H++2e−) are transferred from cytosolic NADH+H+ to mitochondrial FAD by the glycerol phosphate shuttle located in the inner mitochondrial membrane.
2.5 in case of malate-aspartate shuttle transferring hydrogen atoms from cytosolic NADH+H+ to mitochondrial NAD+
So finally we have, per molecule of glucose
Substrate-level phosphorylation: 2 ATP from glycolysis + 2 ATP (directly GTP) from Krebs cycle
Oxidative phosphorylation
2 NADH+H+ from glycolysis: 2 × 1.5 ATP (if glycerol phosphate shuttle transfers hydrogen atoms) or 2 × 2.5 ATP (malate-aspartate shuttle)
2 NADH+H+ from the oxidative decarboxylation of pyruvate and 6 from Krebs cycle: 8 × 2.5 ATP
2 FADH2 from the Krebs cycle: 2 × 1.5 ATP
Altogether this gives 4 + 3 (or 5) + 20 + 3 = 30 (or 32) ATP per molecule of glucose
These figures may still require further tweaking as new structural details become available. The above value of 3 H+ / ATP for the synthase assumes that the synthase translocates 9 protons, and produces 3 ATP, per rotation. The number of protons depends on the number of c subunits in the Fo c-ring, and it is now known that this is 10 in yeast Fo and 8 for vertebrates. Including one H+ for the transport reactions, this means that synthesis of one ATP requires 1 + 10/3 = 4.33 protons in yeast and 1 + 8/3 = 3.67 in vertebrates. This would imply that in human mitochondria the 10 protons from oxidizing NADH would produce 2.72 ATP (instead of 2.5) and the 6 protons from oxidizing succinate or ubiquinol would produce 1.64 ATP (instead of 1.5). This is consistent with experimental results within the margin of error described in a recent review.
The total ATP yield in ethanol or lactic acid fermentation is only 2 molecules coming from glycolysis, because pyruvate is not transferred to the mitochondrion and finally oxidized to the carbon dioxide (CO2), but reduced to ethanol or lactic acid in the cytoplasm.
== Fermentation ==
Without oxygen, pyruvate (pyruvic acid) is not metabolized by cellular respiration but undergoes a process of fermentation. The pyruvate is not transported into the mitochondrion but remains in the cytoplasm, where it is converted to waste products that may be removed from the cell. This serves the purpose of oxidizing the electron carriers so that they can perform glycolysis again and removing the excess pyruvate. Fermentation oxidizes NADH to NAD+ so it can be re-used in glycolysis. In the absence of oxygen, fermentation prevents the buildup of NADH in the cytoplasm and provides NAD+ for glycolysis. This waste product varies depending on the organism. In skeletal muscles, the waste product is lactic acid. This type of fermentation is called lactic acid fermentation. In strenuous exercise, when energy demands exceed energy supply, the respiratory chain cannot process all of the hydrogen atoms joined by NADH. During anaerobic glycolysis, NAD+ regenerates when pairs of hydrogen combine with pyruvate to form lactate. Lactate formation is catalyzed by lactate dehydrogenase in a reversible reaction. Lactate can also be used as an indirect precursor for liver glycogen. During recovery, when oxygen becomes available, NAD+ attaches to hydrogen from lactate to form ATP. In yeast, the waste products are ethanol and carbon dioxide. This type of fermentation is known as alcoholic or ethanol fermentation. The ATP generated in this process is made by substrate-level phosphorylation, which does not require oxygen.
Fermentation is less efficient at using the energy from glucose: only 2 ATP are produced per glucose, compared to the 38 ATP per glucose nominally produced by aerobic respiration. Glycolytic ATP, however, is produced more quickly. For prokaryotes to continue a rapid growth rate when they are shifted from an aerobic environment to an anaerobic environment, they must increase the rate of the glycolytic reactions. For multicellular organisms, during short bursts of strenuous activity, muscle cells use fermentation to supplement the ATP production from the slower aerobic respiration, so fermentation may be used by a cell even before the oxygen levels are depleted, as is the case in sports that do not require athletes to pace themselves, such as sprinting.
== Anaerobic respiration ==
Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor, such as oxygen, to produce large amounts of energy and drive the bulk production of ATP.
Anaerobic respiration is used by microorganisms, either bacteria or archaea, in which neither oxygen (aerobic respiration) nor pyruvate derivatives (fermentation) is the final electron acceptor. Rather, an inorganic acceptor such as sulfate (SO2−4), nitrate (NO−3), or sulfur (S) is used. Such organisms could be found in unusual places such as underwater caves or near hydrothermal vents at the bottom of the ocean.,: 66–68 as well as in anoxic soils or sediment in wetland ecosystems.
In July 2019, a scientific study of Kidd Mine in Canada discovered sulfur-breathing organisms which live 7900 feet (2400 meters) below the surface. These organisms are also remarkable because they consume minerals such as pyrite as their food source.
== See also ==
Maintenance respiration: maintenance as a functional component of cellular respiration
Microphysiometry
Pasteur point
Respirometry: research tool to explore cellular respiration
Tetrazolium chloride: cellular respiration indicator
Complex 1: NADH:ubiquinone oxidoreductes
== References ==
== External links ==
A detailed description of respiration vs. fermentation
Kimball's online resource for cellular respiration
Cellular Respiration and Fermentation at Clermont College | Wikipedia/Cell_energy |
Pest control is the regulation or management of a species defined as a pest; such as any animal, plant or fungus that impacts adversely on human activities or environment. The human response depends on the importance of the damage done and will range from tolerance, through deterrence and management, to attempts to completely eradicate the pest. Pest control measures may be performed as part of an integrated pest management strategy.
In agriculture, pests are kept at bay by mechanical, cultural, chemical and biological means. Ploughing and cultivation of the soil before sowing mitigate the pest burden, and crop rotation helps to reduce the build-up of a certain pest species. Concern about environment means limiting the use of pesticides in favour of other methods. This can be achieved by monitoring the crop, only applying pesticides when necessary, and by growing varieties and crops which are resistant to pests. Where possible, biological means are used, encouraging the natural enemies of the pests and introducing suitable predators or parasites.
In homes and urban environments, the pests are the rodents, birds, insects and other organisms that share the habitat with humans, and that feed on or spoil possessions. Control of these pests is attempted through exclusion or quarantine, repulsion, physical removal or chemical means. Alternatively, various methods of biological control can be used including sterilisation programmes.
== History ==
Pest control is at least as old as agriculture, as there has always been a need to keep crops free from pests. As long ago as 3000 BC in Egypt, cats were used to control pests of grain stores such as rodents. Ferrets were domesticated by 1500 BC in Europe for use as mousers. Mongooses were introduced into homes to control rodents and snakes, probably by the ancient Egyptians.
The conventional approach was probably the first to be employed, since it is comparatively easy to destroy weeds by burning them or ploughing them under, and to kill larger competing herbivores. Techniques such as crop rotation, companion planting (also known as intercropping or mixed cropping), and the selective breeding of pest-resistant cultivars have a long history.
Chemical pesticides were first used around 2500 BC, when the Sumerians used sulphur compounds as insecticides. Modern pest control was stimulated by the spread across the United States of the Colorado potato beetle. After much discussion, arsenical compounds were used to control the beetle and the predicted poisoning of the human population did not occur. This led the way to a widespread acceptance of insecticides across the continent. With the industrialisation and mechanization of agriculture in the 18th and 19th centuries, and the introduction of the insecticides pyrethrum and derris, chemical pest control became widespread. In the 20th century, the discovery of several synthetic insecticides, such as DDT, and herbicides boosted this development.
The harmful side effect of pesticides on humans has now resulted in the development of newer approaches, such as the use of biological control to eliminate the ability of pests to reproduce or to modify their behavior to make them less troublesome. Biological control is first recorded around 300 AD in China, when colonies of weaver ants, Oecophylla smaragdina, were intentionally placed in citrus plantations to control beetles and caterpillars. Also around 4000 BC in China, ducks were used in paddy fields to consume pests, as illustrated in ancient cave art. In 1762, an Indian mynah was brought to Mauritius to control locusts, and about the same time, citrus trees in Burma were connected by bamboos to allow ants to pass between them and help control caterpillars. In the 1880s, ladybirds were used in citrus plantations in California to control scale insects, and other biological control experiments followed. The introduction of DDT, a cheap and effective compound, put an effective stop to biological control experiments. By the 1960s, problems of resistance to chemicals and damage to the environment began to emerge, and biological control had a renaissance. Chemical pest control is still the predominant type of pest control today, although a renewed interest in traditional and biological pest control developed towards the end of the 20th century and continues to this day.
== In agriculture ==
=== Control methods ===
==== Biological pest control ====
Biological pest control is a method of controlling pests such as insects and mites by using other organisms. It relies on predation, parasitism, herbivory, parasitody or other natural mechanisms, but typically also involves an active human management role. Classical biological control involves the introduction of natural enemies of the pest that are bred in the laboratory and released into the environment. An alternative approach is to augment the natural enemies that occur in a particular area by releasing more, either in small, repeated batches, or in a single large-scale release. Ideally, the released organism will breed and survive, and provide long-term control. Biological control can be an important component of an integrated pest management programme.
For example: mosquitoes are often controlled by putting Bt Bacillus thuringiensis ssp. israelensis, a bacterium that infects and kills mosquito larvae, in local water sources.
==== Cultural control ====
Mechanical pest control is the use of hands-on techniques as well as simple equipment and devices, that provides a protective barrier between plants and insects. This is referred to as tillage and is one of the oldest methods of weed control as well as being useful for pest control; wireworms, the larvae of the common click beetle, are very destructive pests of newly ploughed grassland, and repeated cultivation exposes them to the birds and other predators that feed on them.
Crop rotation can help to control pests by depriving them of their host plants. It is a major tactic in the control of corn rootworm, and has reduced early season incidence of Colorado potato beetle by as much as 95%.
==== Trap cropping ====
A trap crop is a crop of a plant that attracts pests, diverting them from nearby crops. Pests aggregated on the trap crop can be more easily controlled using pesticides or other methods. However, trap-cropping, on its own, has often failed to cost effectively reduce pest densities on large commercial scales, without the use of pesticides, possibly due to the pests' ability to disperse back into the main field.
==== Pesticides ====
Pesticides are substances applied to crops to control pests, they include herbicides to kill weeds, fungicides to kill fungi and insecticides to kill insects. They can be applied as sprays by hand, tractors, or aircraft or as seed dressings. To be effective, the correct substance must be applied at the correct time and the method of application is important to ensure adequate coverage and retention on the crop. The killing of natural enemies of the target pest should be minimized. This is particularly important in countries where there are natural reservoirs of pests and their enemies in the countryside surrounding plantation crops, and these co-exist in a delicate balance. Often in less-developed countries, the crops are well adapted to the local situation and no pesticides are needed. Where progressive farmers are using fertilizers to grow improved crop varieties, these are often more susceptible to pest damage, but the indiscriminate application of pesticides may be detrimental in the longer term.
The efficacy of chemical pesticides tends to diminish over time. This is because any organism that manages to survive the initial application will pass on its genes to its offspring and a resistant strain will be developed. In this way, some of the most serious pests have developed resistance and are no longer killed by pesticides that used to kill their ancestors. This necessitates higher concentrations of chemical, more frequent applications and a movement to more expensive formulations.
Pesticides are intended to kill pests, but many have detrimental effects on non-target species; of particular concern is the damage done to honey-bees, solitary bees and other pollinating insects and in this regard, the time of day when the spray is applied can be important. The widely used neonicotinoids have been banned on flowering crops in some countries because of their effects on bees. Some pesticides may cause cancer and other health problems in humans, as well as being harmful to wildlife. There can be acute effects immediately after exposure or chronic effects after continuous low-level, or occasional exposure. Maximum residue limits for pesticides in foodstuffs and animal feed are set by many nations.
==== Genetics ====
Using crops with inheritable resistance to pests is referred to as host-plant resistance and reduces the need for pesticide use. These crops can harm or even kill pests, repel feeding, prevent colonization, or tolerate the presence of a pest without significantly impacting yield. Resistance can also occur through genetic engineering to have traits with resistance to insects, such as with Bt corn, or papaya resistance to ringspot virus. When farmers are purchasing seed, variety information often includes resistance to selected pests in addition to other traits.
==== Hunting ====
Pest control can also be achieved via culling the pest animals — generally small- to medium-sized wild or feral mammals or birds that inhabit the ecological niches near farms, pastures or other human settlements — by employing human hunters or trappers to physically track down, kill and remove them from the area. The culled animals, known as vermin, may be targeted because they are deemed harmful to agricultural crops, livestock or facilities; serve as hosts or vectors that transmit pathogens across species or to humans; or for population control as a mean of protecting other vulnerable species and ecosystems.
Pest control via hunting, like all forms of harvest, has imposed an artificial selective pressure on the organisms being targeted. While varmint hunting is potentially selecting for desired behavioural and demographic changes (e.g. animals avoiding human populated areas, crops and livestock), it can also result in unpredicted outcomes such as the targeted animal adapting for faster reproductive cycles.
=== Forestry ===
Forest pests present a significant problem because it is not easy to access the canopy and monitor pest populations. In addition, forestry pests such as bark beetles, kept under control by natural enemies in their native range, may be transported large distances in cut timber to places where they have no natural predators, enabling them to cause extensive economic damage. Pheromone traps have been used to monitor pest populations in the canopy. These release volatile chemicals that attract males. Pheromone traps can detect the arrival of pests or alert foresters to outbreaks. For example, the spruce budworm, a destructive pest of spruce and balsam fir, has been monitored using pheromone traps in Canadian forests for several decades. In some regions, such as New Brunswick, areas of forest are sprayed with pesticide to control the budworm population and prevent the damage caused during outbreaks.
== In homes and cities ==
Many unwelcome animals visit or make their home in residential buildings, industrial sites and urban areas. Some contaminate foodstuffs, damage structural timbers, chew through fabrics or infest stored dry goods. Some inflict great economic loss, others carry diseases or cause fire hazards, and some are just a nuisance. Control of these pests has been attempted by improving sanitation and garbage control, modifying the habitat, and using repellents, growth regulators, traps, baits and pesticides.
=== General methods ===
==== Physical pest control ====
Physical pest control involves trapping or killing pests such as insects and rodents. Historically, local people or paid rat-catchers caught and killed rodents using dogs and traps. On a domestic scale, sticky flypapers are used to trap flies. In larger buildings, insects may be trapped using such means as pheromones, synthetic volatile chemicals or ultraviolet light to attract the insects; some have a sticky base or an electrically charged grid to kill them. Glueboards are sometimes used for monitoring cockroaches and to catch rodents. Rodents can be killed by suitably baited spring traps and can be caught in cage traps for relocation. Talcum powder or "tracking powder" can be used to establish routes used by rodents inside buildings and acoustic devices can be used for detecting beetles in structural timbers.
Historically, firearms have been one of the primary methods used for pest control. "Garden Guns" are smooth bore shotguns specifically made to fire .22 caliber snake shot or 9mm Flobert, and are commonly used by gardeners and farmers for snakes, rodents, birds, and other pest. Garden Guns are short-range weapons that can do little harm past 15 to 20 yards, and they're relatively quiet when fired with snake shot, compared to standard ammunition. These guns are especially effective inside of barns and sheds, as the snake shot will not shoot holes in the roof or walls, or more importantly, injure livestock with a ricochet. They are also used for pest control at airports, warehouses, stockyards, etc.
The most common shot cartridge is .22 Long Rifle loaded with #12 shot. At a distance of about 10 ft (3.0 m), which is about the maximum effective range, the pattern is about 8 in (20 cm) in diameter from a standard rifle. Special smoothbore shotguns, such as the Marlin Model 25MG can produce effective patterns out to 15 or 20 yards using .22 WMR shotshells, which hold 1/8 oz. of #12 shot contained in a plastic capsule.
==== Poisoned bait ====
Poisoned bait is a common method for controlling rats, mice, birds, slugs, snails, ants, cockroaches, and other pests. The basic granules, or other formulation, contains a food attractant for the target species and a suitable poison. For ants, a slow-acting toxin is needed so that the workers have time to carry the substance back to the colony, and for flies, a quick-acting substance to prevent further egg-laying and nuisance. Baits for slugs and snails often contain the molluscide metaldehyde, dangerous to children and household pets.
An article in Scientific American in 1885 described effective elimination of a cockroach infestation using fresh cucumber peels.
Warfarin has traditionally been used to kill rodents, but many populations have developed resistance to this anticoagulant, and difenacoum may be substituted. These are cumulative poisons, requiring bait stations to be topped up regularly. Poisoned meat has been used for centuries to kill animals such as wolves and birds of prey. Poisoned carcasses however kill a wide range of carrion feeders, not only the targeted species. Raptors in Israel were nearly wiped out following a period of intense poisoning of rats and other crop pests.
==== Fumigation ====
Fumigation is the treatment of a structure to kill pests such as wood-boring beetles by sealing it or surrounding it with an airtight cover such as a tent, and fogging with liquid insecticide for an extended period, typically of 24–72 hours. This is costly and inconvenient as the structure cannot be used during the treatment, but it targets all life stages of pests.
An alternative, space treatment, is fogging or misting to disperse a liquid insecticide in the atmosphere within a building without evacuation or airtight sealing, allowing most work within the building to continue, at the cost of reduced penetration. Contact insecticides are generally used to minimize long-lasting residual effects.
==== Sterilization ====
Populations of pest insects can sometimes be dramatically reduced by the release of sterile individuals. This involves the mass rearing of a pest, sterilising it by means of X-rays or some other means, and releasing it into a wild population. It is particularly useful where a female only mates once and where the insect does not disperse widely. This technique has been successfully used against the New World screw-worm fly, some species of tsetse fly, tropical fruit flies, the pink bollworm and the codling moth, among others.
To chemically sterilize pests using chemosterilants, laboratory studies conducted using U-5897 (3-chloro-1,2-propanediol) attempted in the early 1970s for rat control, although these proved unsuccessful. In 2013, New York City tested sterilization traps, demonstrating a 43% reduction in rat populations. The product ContraPest was approved for the sterilization of rodents by the U.S. Environmental Protection Agency in August 2016 as a chemosterilant.
==== Insulation ====
Boron, a known pesticide can be impregnated into the paper fibers of cellulose insulation at certain levels to achieve a mechanical kill factor for self-grooming insects such as ants, cockroaches, termites, and more. The addition of insulation into the attic and walls of a structure can provide control of common pests in addition to known insulation benefits such a robust thermal envelope and acoustic noise-canceling properties. The EPA regulates this type of general-use pesticide within the United States allowing it to only be sold and installed by licensed pest management professionals as part of an integrated pest management program. Simply adding Boron or an EPA-registered pesticide to an insulation does not qualify it as a pesticide. The dosage and method must be carefully controlled and monitored.
=== Methods for specific pests ===
==== Rodent control ====
===== Urban rodent control =====
Rodent control is vital in cities.: 133 New York City and cities across the state dramatically reduced their rodent populations in the early 1970s.: 133 Rio de Janeiro claims a reduction of 80% over only 2 years shortly thereafter.: 133 To better target efforts, London began scientifically surveying populations in 1972 and this was so useful that all Local Authorities in England and Wales soon followed.: 133
===== Natural rodent control =====
Several wildlife rehabilitation organizations encourage natural form of rodent control through exclusion and predator support and preventing secondary poisoning altogether. The United States Environmental Protection Agency notes in its Proposed Risk Mitigation Decision for Nine Rodenticides that "without habitat modification to make areas less attractive to commensal rodents, even eradication will not prevent new populations from recolonizing the habitat." The United States Environmental Protection Agency has prescribed guidelines for natural rodent control and for safe trapping in residential areas with subsequent release to the wild. People sometimes attempt to limit rodent damage using repellents. Balsam fir oil from the tree Abies balsamea is an EPA approved non-toxic rodent repellent. Acacia polyacantha subsp. campylacantha root emits chemical compounds that repel animals including rats.
==== Pantry pests ====
Insect pests including the Mediterranean flour moth, the Indian mealmoth, the cigarette beetle, the drugstore beetle, the confused flour beetle, the red flour beetle, the merchant grain beetle, the sawtoothed grain beetle, the wheat weevil, the maize weevil and the rice weevil infest stored dry foods such as flour, cereals and pasta.
In the home, foodstuffs found to be infested are usually discarded, and storing such products in sealed containers should prevent the problem from reoccurring. The eggs of these insects are likely to go unnoticed, with the larvae being the destructive life stage, and the adult the most noticeable stage. Since pesticides are not safe to use near food, alternative treatments such as freezing for four days at 0 °F (−18 °C) or baking for half an hour at 130 °F (54 °C) should kill any insects present.
==== Clothes moths ====
The larvae of clothes moths (mainly Tineola bisselliella and Tinea pellionella) feed on fabrics and carpets, particularly those that are stored or soiled. The adult females lay batches of eggs on natural fibres, including wool, silk, and fur, as well as cotton and linen in blends. The developing larvae spin protective webbing and chew into the fabric, creating holes and specks of excrement. Damage is often concentrated in concealed locations, under collars and near seams of clothing, in folds and crevices in upholstery and round the edges of carpets as well as under furniture. Methods of control include using airtight containers for storage, periodic laundering of garments, trapping, freezing, heating and the use of chemicals; mothballs contain volatile insect repellents such as 1,4-Dichlorobenzene which deter adults, but to kill the larvae, permethrin, pyrethroids or other insecticides may need to be used.
==== Carpet beetles ====
Carpet beetles are members of the family Dermestidae, and while the adult beetles feed on nectar and pollen, the larvae are destructive pests in homes, warehouses, and museums. They feed on animal products including wool, silk, leather, fur, the bristles of hair brushes, pet hair, feathers, and museum specimens. They tend to infest hidden locations and may feed on larger areas of fabrics than do clothes moths, leaving behind specks of excrement and brown, hollow, bristly-looking cast skins. Management of infestations is difficult and is based on exclusion and sanitation where possible, resorting to pesticides when necessary. The beetles can fly in from outdoors and the larvae can survive on lint fragments, dust, and inside the bags of vacuum cleaners. In warehouses and museums, sticky traps baited with suitable pheromones can be used to identify problems, and heating, freezing, spraying the surface with insecticide, and fumigation will kill the insects when suitably applied. Susceptible items can be protected from attack by keeping them in clean airtight containers.
==== Bookworms ====
Books are sometimes attacked by cockroaches, silverfish, book mites, booklice, and various beetles which feed on the covers, paper, bindings and glue. They leave behind physical damage in the form of tiny holes as well as staining from their faeces. Book pests include the larder beetle, and the larvae of the black carpet beetle and the drugstore beetle which attack leather-bound books, while the common clothes moth and the brown house moth attack cloth bindings. These attacks are largely a problem with historic books, because modern bookbinding materials are less susceptible to this type of damage.
Evidence of attack may be found in the form of tiny piles of book-dust and specks of frass. Damage may be concentrated in the spine, the projecting edges of pages and the cover. Prevention of attack relies on keeping books in cool, clean, dry positions with low humidity, and occasional inspections should be made. Treatment can be by freezing for lengthy periods, but some insect eggs are very resistant and can survive for long periods at low temperatures.
==== Beetles ====
Various beetles in the Bostrichoidea superfamily attack the dry, seasoned wood used as structural timber in houses and to make furniture. In most cases, it is the larvae that do the damage; these are invisible from the outside of the timber but are chewing away at the wood in the interior of the item. Examples of these are the powderpost beetles, which attack the sapwood of hardwoods, and the furniture beetles, which attacks softwoods, including plywood. The damage has already been done by the time the adult beetles bore their way out, leaving neat round holes behind them. The first that a householder knows about the beetle damage is often when a chair leg breaks off or a piece of structural timber caves in. Prevention is possible through chemical treatment of the timber prior to its use in construction or in furniture manufacturing.
==== Termites ====
Termites with colonies in close proximity to houses can extend their galleries underground and make mud tubes to enter homes. The insects keep out of sight and chew their way through structural and decorative timbers, leaving the surface layers intact, as well as through cardboard, plastic and insulation materials. Their presence may become apparent when winged insects appear and swarm in the home in spring. Regular inspection of structures by a trained professional may help detect termite activity before the damage becomes substantial.; Inspection and monitoring of termites is important because termite alates (winged reproductives) may not always swarm inside a structure. Control and extermination is a professional job involving trying to exclude the insects from the building and trying to kill those already present. Soil-applied liquid termiticides provide a chemical barrier that prevents termites from entering buildings, and lethal baits can be used; these are eaten by foraging insects, and carried back to the nest and shared with other members of the colony, which goes into slow decline.
==== Mosquitoes ====
Mosquitoes are midge-like flies in the family Culicidae. Females of most species feed on blood and some act as vectors for malaria and other diseases. Historically they have been controlled by use of DDT and other chemical means, but since the adverse environmental effects of these insecticides have been realized, other means of control have been attempted. The insects rely on water in which to breed and the first line of control is to reduce possible breeding locations by draining marshes and reducing accumulations of standing water. Other approaches include biological control of larvae by the use of fish or other predators, genetic control, the introduction of pathogens, growth-regulating hormones, the release of pheromones and mosquito trapping.
== On airfields ==
Birds are a significant hazard to aircraft, but it is difficult to keep them away from airfields. Several methods have been explored. Stunning birds by feeding them a bait containing stupefying substances has been tried, and it may be possible to reduce their numbers on airfields by reducing the number of earthworms and other invertebrates by soil treatment. Leaving the grass long on airfields rather than mowing it is also a deterrent to birds. Sonic nets are being trialled; these produce sounds that birds find distracting and seem effective at keeping birds away from affected areas.
== See also ==
Bee removal
Electronic pest control
Garden guns
Nuisance wildlife management
Rabbits in Australia
Wildlife contraceptive
== References ==
== External links ==
Pest Control and Pesticide Safety for Consumers | Wikipedia/Pest_control |
Biotechnology is a multidisciplinary field that involves the integration of natural sciences and engineering sciences in order to achieve the application of organisms and parts thereof for products and services. Specialists in the field are known as biotechnologists.
The term biotechnology was first used by Károly Ereky in 1919 to refer to the production of products from raw materials with the aid of living organisms. The core principle of biotechnology involves harnessing biological systems and organisms, such as bacteria, yeast, and plants, to perform specific tasks or produce valuable substances.
Biotechnology had a significant impact on many areas of society, from medicine to agriculture to environmental science. One of the key techniques used in biotechnology is genetic engineering, which allows scientists to modify the genetic makeup of organisms to achieve desired outcomes. This can involve inserting genes from one organism into another, and consequently, create new traits or modifying existing ones.
Other important techniques used in biotechnology include tissue culture, which allows researchers to grow cells and tissues in the lab for research and medical purposes, and fermentation, which is used to produce a wide range of products such as beer, wine, and cheese.
The applications of biotechnology are diverse and have led to the development of products like life-saving drugs, biofuels, genetically modified crops, and innovative materials. It has also been used to address environmental challenges, such as developing biodegradable plastics and using microorganisms to clean up contaminated sites.
Biotechnology is a rapidly evolving field with significant potential to address pressing global challenges and improve the quality of life for people around the world; however, despite its numerous benefits, it also poses ethical and societal challenges, such as questions around genetic modification and intellectual property rights. As a result, there is ongoing debate and regulation surrounding the use and application of biotechnology in various industries and fields.
== Definition ==
The concept of biotechnology encompasses a wide range of procedures for modifying living organisms for human purposes, going back to domestication of animals, cultivation of plants, and "improvements" to these through breeding programs that employ artificial selection and hybridization. Modern usage also includes genetic engineering, as well as cell and tissue culture technologies. The American Chemical Society defines biotechnology as the application of biological organisms, systems, or processes by various industries to learning about the science of life and the improvement of the value of materials and organisms, such as pharmaceuticals, crops, and livestock. As per the European Federation of Biotechnology, biotechnology is the integration of natural science and organisms, cells, parts thereof, and molecular analogues for products and services. Biotechnology is based on the basic biological sciences (e.g., molecular biology, biochemistry, cell biology, embryology, genetics, microbiology) and conversely provides methods to support and perform basic research in biology.
Biotechnology is the research and development in the laboratory using bioinformatics for exploration, extraction, exploitation, and production from any living organisms and any source of biomass by means of biochemical engineering where high value-added products could be planned (reproduced by biosynthesis, for example), forecasted, formulated, developed, manufactured, and marketed for the purpose of sustainable operations (for the return from bottomless initial investment on R & D) and gaining durable patents rights (for exclusives rights for sales, and prior to this to receive national and international approval from the results on animal experiment and human experiment, especially on the pharmaceutical branch of biotechnology to prevent any undetected side-effects or safety concerns by using the products). The utilization of biological processes, organisms or systems to produce products that are anticipated to improve human lives is termed biotechnology.
By contrast, bioengineering is generally thought of as a related field that more heavily emphasizes higher systems approaches (not necessarily the altering or using of biological materials directly) for interfacing with and utilizing living things. Bioengineering is the application of the principles of engineering and natural sciences to tissues, cells, and molecules. This can be considered as the use of knowledge from working with and manipulating biology to achieve a result that can improve functions in plants and animals. Relatedly, biomedical engineering is an overlapping field that often draws upon and applies biotechnology (by various definitions), especially in certain sub-fields of biomedical or chemical engineering such as tissue engineering, biopharmaceutical engineering, and genetic engineering.
== History ==
Although not normally what first comes to mind, many forms of human-derived agriculture clearly fit the broad definition of "utilizing a biotechnological system to make products". Indeed, the cultivation of plants may be viewed as the earliest biotechnological enterprise.
Agriculture has been theorized to have become the dominant way of producing food since the Neolithic Revolution. Through early biotechnology, the earliest farmers selected and bred the best-suited crops (e.g., those with the highest yields) to produce enough food to support a growing population. As crops and fields became increasingly large and difficult to maintain, it was discovered that specific organisms and their by-products could effectively fertilize, restore nitrogen, and control pests. Throughout the history of agriculture, farmers have inadvertently altered the genetics of their crops through introducing them to new environments and breeding them with other plants — one of the first forms of biotechnology.
These processes also were included in early fermentation of beer. These processes were introduced in early Mesopotamia, Egypt, China and India, and still use the same basic biological methods. In brewing, malted grains (containing enzymes) convert starch from grains into sugar and then adding specific yeasts to produce beer. In this process, carbohydrates in the grains broke down into alcohols, such as ethanol. Later, other cultures produced the process of lactic acid fermentation, which produced other preserved foods, such as soy sauce. Fermentation was also used in this time period to produce leavened bread. Although the process of fermentation was not fully understood until Louis Pasteur's work in 1857, it is still the first use of biotechnology to convert a food source into another form.
Before the time of Charles Darwin's work and life, animal and plant scientists had already used selective breeding. Darwin added to that body of work with his scientific observations about the ability of science to change species. These accounts contributed to Darwin's theory of natural selection.
For thousands of years, humans have used selective breeding to improve the production of crops and livestock to use them for food. In selective breeding, organisms with desirable characteristics are mated to produce offspring with the same characteristics. For example, this technique was used with corn to produce the largest and sweetest crops.
In the early twentieth century scientists gained a greater understanding of microbiology and explored ways of manufacturing specific products. In 1917, Chaim Weizmann first used a pure microbiological culture in an industrial process, that of manufacturing corn starch using Clostridium acetobutylicum, to produce acetone, which the United Kingdom desperately needed to manufacture explosives during World War I.
Biotechnology has also led to the development of antibiotics. In 1928, Alexander Fleming discovered the mold Penicillium. His work led to the purification of the antibiotic formed by the mold by Howard Florey, Ernst Boris Chain and Norman Heatley – to form what we today know as penicillin. In 1940, penicillin became available for medicinal use to treat bacterial infections in humans.
The field of modern biotechnology is generally thought of as having been born in 1971 when Paul Berg's (Stanford) experiments in gene splicing had early success. Herbert W. Boyer (Univ. Calif. at San Francisco) and Stanley N. Cohen (Stanford) significantly advanced the new technology in 1972 by transferring genetic material into a bacterium, such that the imported material would be reproduced. The commercial viability of a biotechnology industry was significantly expanded on June 16, 1980, when the United States Supreme Court ruled that a genetically modified microorganism could be patented in the case of Diamond v. Chakrabarty. Indian-born Ananda Chakrabarty, working for General Electric, had modified a bacterium (of the genus Pseudomonas) capable of breaking down crude oil, which he proposed to use in treating oil spills. (Chakrabarty's work did not involve gene manipulation but rather the transfer of entire organelles between strains of the Pseudomonas bacterium).
The MOSFET invented at Bell Labs between 1955 and 1960, Two years later, Leland C. Clark and Champ Lyons invented the first biosensor in 1962. Biosensor MOSFETs were later developed, and they have since been widely used to measure physical, chemical, biological and environmental parameters. The first BioFET was the ion-sensitive field-effect transistor (ISFET), invented by Piet Bergveld in 1970. It is a special type of MOSFET, where the metal gate is replaced by an ion-sensitive membrane, electrolyte solution and reference electrode. The ISFET is widely used in biomedical applications, such as the detection of DNA hybridization, biomarker detection from blood, antibody detection, glucose measurement, pH sensing, and genetic technology.
By the mid-1980s, other BioFETs had been developed, including the gas sensor FET (GASFET), pressure sensor FET (PRESSFET), chemical field-effect transistor (ChemFET), reference ISFET (REFET), enzyme-modified FET (ENFET) and immunologically modified FET (IMFET). By the early 2000s, BioFETs such as the DNA field-effect transistor (DNAFET), gene-modified FET (GenFET) and cell-potential BioFET (CPFET) had been developed.
A factor influencing the biotechnology sector's success is improved intellectual property rights legislation—and enforcement—worldwide, as well as strengthened demand for medical and pharmaceutical products.
Rising demand for biofuels is expected to be good news for the biotechnology sector, with the Department of Energy estimating ethanol usage could reduce U.S. petroleum-derived fuel consumption by up to 30% by 2030. The biotechnology sector has allowed the U.S. farming industry to rapidly increase its supply of corn and soybeans—the main inputs into biofuels—by developing genetically modified seeds that resist pests and drought. By increasing farm productivity, biotechnology boosts biofuel production.
== Examples ==
Biotechnology has applications in four major industrial areas, including health care (medical), crop production and agriculture, non-food (industrial) uses of crops and other products (e.g., biodegradable plastics, vegetable oil, biofuels), and environmental uses.
For example, one application of biotechnology is the directed use of microorganisms for the manufacture of organic products (examples include beer and milk products). Another example is using naturally present bacteria by the mining industry in bioleaching. Biotechnology is also used to recycle, treat waste, clean up sites contaminated by industrial activities (bioremediation), and also to produce biological weapons.
A series of derived terms have been coined to identify several branches of biotechnology, for example:
Bioinformatics (or "gold biotechnology") is an interdisciplinary field that addresses biological problems using computational techniques, and makes the rapid organization as well as analysis of biological data possible. The field may also be referred to as computational biology, and can be defined as, "conceptualizing biology in terms of molecules and then applying informatics techniques to understand and organize the information associated with these molecules, on a large scale". Bioinformatics plays a key role in various areas, such as functional genomics, structural genomics, and proteomics, and forms a key component in the biotechnology and pharmaceutical sector.
Blue biotechnology is based on the exploitation of sea resources to create products and industrial applications. This branch of biotechnology is the most used for the industries of refining and combustion principally on the production of bio-oils with photosynthetic micro-algae.
Green biotechnology is biotechnology applied to agricultural processes. An example would be the selection and domestication of plants via micropropagation. Another example is the designing of transgenic plants to grow under specific environments in the presence (or absence) of chemicals. One hope is that green biotechnology might produce more environmentally friendly solutions than traditional industrial agriculture. An example of this is the engineering of a plant to express a pesticide, thereby ending the need of external application of pesticides. An example of this would be Bt corn. Whether or not green biotechnology products such as this are ultimately more environmentally friendly is a topic of considerable debate. It is commonly considered as the next phase of green revolution, which can be seen as a platform to eradicate world hunger by using technologies which enable the production of more fertile and resistant, towards biotic and abiotic stress, plants and ensures application of environmentally friendly fertilizers and the use of biopesticides, it is mainly focused on the development of agriculture. On the other hand, some of the uses of green biotechnology involve microorganisms to clean and reduce waste.
Red biotechnology is the use of biotechnology in the medical and pharmaceutical industries, and health preservation. This branch involves the production of vaccines and antibiotics, regenerative therapies, creation of artificial organs and new diagnostics of diseases. As well as the development of hormones, stem cells, antibodies, siRNA and diagnostic tests.
White biotechnology, also known as industrial biotechnology, is biotechnology applied to industrial processes. An example is the designing of an organism to produce a useful chemical. Another example is the using of enzymes as industrial catalysts to either produce valuable chemicals or destroy hazardous/polluting chemicals. White biotechnology tends to consume less in resources than traditional processes used to produce industrial goods.
Yellow biotechnology refers to the use of biotechnology in food production (food industry), for example in making wine (winemaking), cheese (cheesemaking), and beer (brewing) by fermentation. It has also been used to refer to biotechnology applied to insects. This includes biotechnology-based approaches for the control of harmful insects, the characterisation and utilisation of active ingredients or genes of insects for research, or application in agriculture and medicine and various other approaches.
Gray biotechnology is dedicated to environmental applications, and focused on the maintenance of biodiversity and the remotion of pollutants.
Brown biotechnology is related to the management of arid lands and deserts. One application is the creation of enhanced seeds that resist extreme environmental conditions of arid regions, which is related to the innovation, creation of agriculture techniques and management of resources.
Violet biotechnology is related to law, ethical and philosophical issues around biotechnology.
Microbial biotechnology has been proposed for the rapidly emerging area of biotechnology applications in space and microgravity (space bioeconomy)
Dark biotechnology is the color associated with bioterrorism or biological weapons and biowarfare which uses microorganisms, and toxins to cause diseases and death in humans, livestock and crops.
=== Medicine ===
In medicine, modern biotechnology has many applications in areas such as pharmaceutical drug discoveries and production, pharmacogenomics, and genetic testing (or genetic screening). In 2021, nearly 40% of the total company value of pharmaceutical biotech companies worldwide were active in Oncology with Neurology and Rare Diseases being the other two big applications.
Pharmacogenomics (a combination of pharmacology and genomics) is the technology that analyses how genetic makeup affects an individual's response to drugs. Researchers in the field investigate the influence of genetic variation on drug responses in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity. The purpose of pharmacogenomics is to develop rational means to optimize drug therapy, with respect to the patients' genotype, to ensure maximum efficacy with minimal adverse effects. Such approaches promise the advent of "personalized medicine"; in which drugs and drug combinations are optimized for each individual's unique genetic makeup.
Biotechnology has contributed to the discovery and manufacturing of traditional small molecule pharmaceutical drugs as well as drugs that are the product of biotechnology – biopharmaceutics. Modern biotechnology can be used to manufacture existing medicines relatively easily and cheaply. The first genetically engineered products were medicines designed to treat human diseases. To cite one example, in 1978 Genentech developed synthetic humanized insulin by joining its gene with a plasmid vector inserted into the bacterium Escherichia coli. Insulin, widely used for the treatment of diabetes, was previously extracted from the pancreas of abattoir animals (cattle or pigs). The genetically engineered bacteria are able to produce large quantities of synthetic human insulin at relatively low cost. Biotechnology has also enabled emerging therapeutics like gene therapy. The application of biotechnology to basic science (for example through the Human Genome Project) has also dramatically improved our understanding of biology and as our scientific knowledge of normal and disease biology has increased, our ability to develop new medicines to treat previously untreatable diseases has increased as well.
Genetic testing allows the genetic diagnosis of vulnerabilities to inherited diseases, and can also be used to determine a child's parentage (genetic mother and father) or in general a person's ancestry. In addition to studying chromosomes to the level of individual genes, genetic testing in a broader sense includes biochemical tests for the possible presence of genetic diseases, or mutant forms of genes associated with increased risk of developing genetic disorders. Genetic testing identifies changes in chromosomes, genes, or proteins. Most of the time, testing is used to find changes that are associated with inherited disorders. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person's chance of developing or passing on a genetic disorder. As of 2011 several hundred genetic tests were in use. Since genetic testing may open up ethical or psychological problems, genetic testing is often accompanied by genetic counseling.
=== Agriculture ===
Genetically modified crops ("GM crops", or "biotech crops") are plants used in agriculture, the DNA of which has been modified with genetic engineering techniques. In most cases, the main aim is to introduce a new trait that does not occur naturally in the species. Biotechnology firms can contribute to future food security by improving the nutrition and viability of urban agriculture. Furthermore, the protection of intellectual property rights encourages private sector investment in agrobiotechnology.
Examples in food crops include resistance to certain pests, diseases, stressful environmental conditions, resistance to chemical treatments (e.g. resistance to a herbicide), reduction of spoilage, or improving the nutrient profile of the crop. Examples in non-food crops include production of pharmaceutical agents, biofuels, and other industrially useful goods, as well as for bioremediation.
Farmers have widely adopted GM technology. Between 1996 and 2011, the total surface area of land cultivated with GM crops had increased by a factor of 94, from 17,000 to 1,600,000 square kilometers (4,200,000 to 395,400,000 acres). 10% of the world's crop lands were planted with GM crops in 2010. As of 2011, 11 different transgenic crops were grown commercially on 395 million acres (160 million hectares) in 29 countries such as the US, Brazil, Argentina, India, Canada, China, Paraguay, Pakistan, South Africa, Uruguay, Bolivia, Australia, Philippines, Myanmar, Burkina Faso, Mexico and Spain.
Genetically modified foods are foods produced from organisms that have had specific changes introduced into their DNA with the methods of genetic engineering. These techniques have allowed for the introduction of new crop traits as well as a far greater control over a food's genetic structure than previously afforded by methods such as selective breeding and mutation breeding. Commercial sale of genetically modified foods began in 1994, when Calgene first marketed its Flavr Savr delayed ripening tomato. To date most genetic modification of foods have primarily focused on cash crops in high demand by farmers such as soybean, corn, canola, and cotton seed oil. These have been engineered for resistance to pathogens and herbicides and better nutrient profiles. GM livestock have also been experimentally developed; in November 2013 none were available on the market, but in 2015 the FDA approved the first GM salmon for commercial production and consumption.
There is a scientific consensus that currently available food derived from GM crops poses no greater risk to human health than conventional food, but that each GM food needs to be tested on a case-by-case basis before introduction. Nonetheless, members of the public are much less likely than scientists to perceive GM foods as safe. The legal and regulatory status of GM foods varies by country, with some nations banning or restricting them, and others permitting them with widely differing degrees of regulation.
GM crops also provide a number of ecological benefits, if not used in excess. Insect-resistant crops have proven to lower pesticide usage, therefore reducing the environmental impact of pesticides as a whole. However, opponents have objected to GM crops per se on several grounds, including environmental concerns, whether food produced from GM crops is safe, whether GM crops are needed to address the world's food needs, and economic concerns raised by the fact these organisms are subject to intellectual property law.
Biotechnology has several applications in the realm of food security. Crops like Golden rice are engineered to have higher nutritional content, and there is potential for food products with longer shelf lives. Though not a form of agricultural biotechnology, vaccines can help prevent diseases found in animal agriculture. Additionally, agricultural biotechnology can expedite breeding processes in order to yield faster results and provide greater quantities of food. Transgenic biofortification in cereals has been considered as a promising method to combat malnutrition in India and other countries.
=== Industrial ===
Industrial biotechnology (known mainly in Europe as white biotechnology) is the application of biotechnology for industrial purposes, including industrial fermentation. It includes the practice of using cells such as microorganisms, or components of cells like enzymes, to generate industrially useful products in sectors such as chemicals, food and feed, detergents, paper and pulp, textiles and biofuels. In the current decades, significant progress has been done in creating genetically modified organisms (GMOs) that enhance the diversity of applications and economical viability of industrial biotechnology. By using renewable raw materials to produce a variety of chemicals and fuels, industrial biotechnology is actively advancing towards lowering greenhouse gas emissions and moving away from a petrochemical-based economy.
Synthetic biology is considered one of the essential cornerstones in industrial biotechnology due to its financial and sustainable contribution to the manufacturing sector. Jointly biotechnology and synthetic biology play a crucial role in generating cost-effective products with nature-friendly features by using bio-based production instead of fossil-based. Synthetic biology can be used to engineer model microorganisms, such as Escherichia coli, by genome editing tools to enhance their ability to produce bio-based products, such as bioproduction of medicines and biofuels. For instance, E. coli and Saccharomyces cerevisiae in a consortium could be used as industrial microbes to produce precursors of the chemotherapeutic agent paclitaxel by applying the metabolic engineering in a co-culture approach to exploit the benefits from the two microbes.
Another example of synthetic biology applications in industrial biotechnology is the re-engineering of the metabolic pathways of E. coli by CRISPR and CRISPRi systems toward the production of a chemical known as 1,4-butanediol, which is used in fiber manufacturing. In order to produce 1,4-butanediol, the authors alter the metabolic regulation of the Escherichia coli by CRISPR to induce point mutation in the gltA gene, knockout of the sad gene, and knock-in six genes (cat1, sucD, 4hbd, cat2, bld, and bdh). Whereas CRISPRi system used to knockdown the three competing genes (gabD, ybgC, and tesB) that affect the biosynthesis pathway of 1,4-butanediol. Consequently, the yield of 1,4-butanediol significantly increased from 0.9 to 1.8 g/L.
=== Environmental ===
Environmental biotechnology includes various disciplines that play an essential role in reducing environmental waste and providing environmentally safe processes, such as biofiltration and biodegradation. The environment can be affected by biotechnologies, both positively and adversely. Vallero and others have argued that the difference between beneficial biotechnology (e.g., bioremediation is to clean up an oil spill or hazard chemical leak) versus the adverse effects stemming from biotechnological enterprises (e.g., flow of genetic material from transgenic organisms into wild strains) can be seen as applications and implications, respectively. Cleaning up environmental wastes is an example of an application of environmental biotechnology; whereas loss of biodiversity or loss of containment of a harmful microbe are examples of environmental implications of biotechnology.
Many cities have installed CityTrees, which use biotechnology to filter pollutants from urban atmospheres.
=== Regulation ===
The regulation of genetic engineering concerns approaches taken by governments to assess and manage the risks associated with the use of genetic engineering technology, and the development and release of genetically modified organisms (GMO), including genetically modified crops and genetically modified fish. There are differences in the regulation of GMOs between countries, with some of the most marked differences occurring between the US and Europe. Regulation varies in a given country depending on the intended use of the products of the genetic engineering. For example, a crop not intended for food use is generally not reviewed by authorities responsible for food safety. The European Union differentiates between approval for cultivation within the EU and approval for import and processing. While only a few GMOs have been approved for cultivation in the EU a number of GMOs have been approved for import and processing. The cultivation of GMOs has triggered a debate about the coexistence of GM and non-GM crops. Depending on the coexistence regulations, incentives for the cultivation of GM crops differ.
=== Database for the GMOs used in the EU ===
The EUginius (European GMO Initiative for a Unified Database System) database is intended to help companies, interested private users and competent authorities to find precise information on the presence, detection and identification of GMOs used in the European Union. The information is provided in English.
== Learning ==
In 1988, after prompting from the United States Congress, the National Institute of General Medical Sciences (National Institutes of Health) (NIGMS) instituted a funding mechanism for biotechnology training. Universities nationwide compete for these funds to establish Biotechnology Training Programs (BTPs). Each successful application is generally funded for five years then must be competitively renewed. Graduate students in turn compete for acceptance into a BTP; if accepted, then stipend, tuition and health insurance support are provided for two or three years during the course of their PhD thesis work. Nineteen institutions offer NIGMS supported BTPs. Biotechnology training is also offered at the undergraduate level and in community colleges.
== References and notes ==
== External links ==
What is Biotechnology? – A curated collection of resources about the people, places and technologies that have enabled biotechnology | Wikipedia/Industrial_biotechnology |
Gene therapy is medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells.
The first attempt at modifying human DNA was performed in 1980, by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989. The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990. Between 1989 and December 2018, over 2,900 clinical trials were conducted, with more than half of them in phase I. In 2003, Gendicine became the first gene therapy to receive regulatory approval. Since that time, further gene therapy drugs were approved, such as alipogene tiparvovec (2012), Strimvelis (2016), tisagenlecleucel (2017), voretigene neparvovec (2017), patisiran (2018), onasemnogene abeparvovec (2019), idecabtagene vicleucel (2021), nadofaragene firadenovec, valoctocogene roxaparvovec and etranacogene dezaparvovec (all 2022). Most of these approaches utilize adeno-associated viruses (AAVs) and lentiviruses for performing gene insertions, in vivo and ex vivo, respectively. AAVs are characterized by stabilizing the viral capsid, lower immunogenicity, ability to transduce both dividing and nondividing cells, the potential to integrate site specifically and to achieve long-term expression in the in-vivo treatment. ASO / siRNA approaches such as those conducted by Alnylam and Ionis Pharmaceuticals require non-viral delivery systems, and utilize alternative mechanisms for trafficking to liver cells by way of GalNAc transporters.
Not all medical procedures that introduce alterations to a patient's genetic makeup can be considered gene therapy. Bone marrow transplantation and organ transplants in general have been found to introduce foreign DNA into patients.
== Background ==
Gene therapy was first conceptualized in the 1960s, when the feasibility of adding new genetic functions to mammalian cells began to be researched. Several methods to do so were tested, including injecting genes with a micropipette directly into a living mammalian cell, and exposing cells to a precipitate of DNA that contained the desired genes. Scientists theorized that a virus could also be used as a vehicle, or vector, to deliver new genes into cells.
One of the first scientists to report the successful direct incorporation of functional DNA into a mammalian cell was biochemist Dr. Lorraine Marquardt Kraus (6 September 1922 – 1 July 2016) at the University of Tennessee Health Science Center in Memphis, Tennessee. In 1961, she managed to genetically alter the hemoglobin of cells from bone marrow taken from a patient with sickle cell anaemia. She did this by incubating the patient's cells in tissue culture with DNA extracted from a donor with normal hemoglobin. In 1968, researchers Theodore Friedmann, Jay Seegmiller, and John Subak-Sharpe at the National Institutes of Health (NIH), Bethesda, in the United States successfully corrected genetic defects associated with Lesch-Nyhan syndrome, a debilitating neurological disease, by adding foreign DNA to cultured cells collected from patients suffering from the disease.
The first attempt, an unsuccessful one, at gene therapy (as well as the first case of medical transfer of foreign genes into humans not counting organ transplantation) was performed by geneticist Martin Cline of the University of California, Los Angeles in California, United States on 10 July 1980. Cline claimed that one of the genes in his patients was active six months later, though he never published this data or had it verified.
After extensive research on animals throughout the 1980s and a 1989 bacterial gene tagging trial on humans, the first gene therapy widely accepted as a success was demonstrated in a trial that started on 14 September 1990, when Ashanthi DeSilva was treated for ADA-SCID.
The first somatic treatment that produced a permanent genetic change was initiated in 1993. The goal was to cure malignant brain tumors by using recombinant DNA to transfer a gene making the tumor cells sensitive to a drug that in turn would cause the tumor cells to die.
The polymers are either translated into proteins, interfere with target gene expression, or possibly correct genetic mutations. The most common form uses DNA that encodes a functional, therapeutic gene to replace a mutated gene. The polymer molecule is packaged within a "vector", which carries the molecule inside cells.
Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers' attention, although as of 2014, it was still largely an experimental technique. These include treatment of retinal diseases Leber's congenital amaurosis and choroideremia, X-linked SCID, ADA-SCID, adrenoleukodystrophy, chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), multiple myeloma, haemophilia, and Parkinson's disease. Between 2013 and April 2014, US companies invested over $600 million in the field.
The first commercial gene therapy, Gendicine, was approved in China in 2003, for the treatment of certain cancers. In 2011, Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia.
In 2012, alipogene tiparvovec, a treatment for a rare inherited disorder, lipoprotein lipase deficiency, became the first treatment to be approved for clinical use in either the European Union or the United States after its endorsement by the European Commission.
Following early advances in genetic engineering of bacteria, cells, and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered – replacing or disrupting defective genes. Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia, and sickle cell anemia. alipogene tiparvovec treats one such disease, caused by a defect in lipoprotein lipase.
DNA must be administered, reach the damaged cells, enter the cell and either express or disrupt a protein. Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered virus to deliver the DNA into a chromosome. Naked DNA approaches have also been explored, especially in the context of vaccine development.
Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of nuclease function has led to more direct DNA editing, using techniques such as zinc finger nucleases and CRISPR. The vector incorporates genes into chromosomes. The expressed nucleases then knock out and replace genes in the chromosome. As of 2014 these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.
Gene editing is a potential approach to alter the human genome to treat genetic diseases, viral diseases, and cancer. As of 2020 these approaches are being studied in clinical trials.
== Classification ==
=== Breadth of definition ===
In 1986, a meeting at the Institute Of Medicine defined gene therapy as the addition or replacement of a gene in a targeted cell type. In the same year, the FDA announced that it had jurisdiction over approving "gene therapy" without defining the term. The FDA added a very broad definition in 1993 of any treatment that would 'modify or manipulate the expression of genetic material or to alter the biological properties of living cells'. In 2018 this was narrowed to 'products that mediate their effects by transcription or translation of transferred genetic material or by specifically altering host (human) genetic sequences'.
Writing in 2018, in the Journal of Law and the Biosciences, Sherkow et al. argued for a narrower definition of gene therapy than the FDA's in light of new technology that would consist of any treatment that intentionally and permanently modified a cell's genome, with the definition of genome including episomes outside the nucleus but excluding changes due to episomes that are lost over time. This definition would also exclude introducing cells that did not derive from a patient themselves, but include ex vivo approaches, and would not depend on the vector used.
During the COVID-19 pandemic, some academics insisted that the mRNA vaccines for COVID were not gene therapy to prevent the spread of incorrect information that the vaccine could alter DNA, other academics maintained that the vaccines were a gene therapy because they introduced genetic material into a cell. Fact-checkers, such as Full Fact, Reuters, PolitiFact, and FactCheck.org said that calling the vaccines a gene therapy was incorrect. Podcast host Joe Rogan was criticized for calling mRNA vaccines gene therapy as was British politician Andrew Bridgen, with fact checker Full Fact calling for Bridgen to be removed from the conservative party for this and other statements.
=== Genes present or added ===
Gene therapy encapsulates many forms of adding different nucleic acids to a cell. Gene augmentation adds a new protein coding gene to a cell. One form of gene augmentiation is gene replacement therapy, a treatment for monogenic recessive disorders where a single gene is not functional; an additional functional gene is added. For diseases caused by multiple genes or a dominant gene, gene silencing or gene editing approaches are more appropriate but gene addition, a form of gene augmentation where new gene is added, may improve a cells function without modifying the genes that cause a disorder.: 117
=== Cell types ===
Gene therapy may be classified into two types by the type of cell it affects: somatic cell and germline gene therapy.
In somatic cell gene therapy (SCGT), the therapeutic genes are transferred into any cell other than a gamete, germ cell, gametocyte, or undifferentiated stem cell. Any such modifications affect the individual patient only, and are not inherited by offspring. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the genome or as an external episome or plasmid) is used to treat disease. Over 600 clinical trials utilizing SCGT are underway in the US. Most focus on severe genetic disorders, including immunodeficiencies, haemophilia, thalassaemia, and cystic fibrosis. Such single gene disorders are good candidates for somatic cell therapy. The complete correction of a genetic disorder or the replacement of multiple genes is not yet possible. Only a few of the trials are in the advanced stages.
In germline gene therapy (GGT), germ cells (sperm or egg cells) are modified by the introduction of functional genes into their genomes. Modifying a germ cell causes all the organism's cells to contain the modified gene. The change is therefore heritable and passed on to later generations. Australia, Canada, Germany, Israel, Switzerland, and the Netherlands prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations and higher risks versus SCGT. The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general).
=== In vivo versus ex vivo therapies ===
In in vivo gene therapy, a vector (typically, a virus) is introduced to the patient, which then achieves the desired biological effect by passing the genetic material (e.g. for a missing protein) into the patient's cells. In ex vivo gene therapies, such as CAR-T therapeutics, the patient's own cells (autologous) or healthy donor cells (allogeneic) are modified outside the body (hence, ex vivo) using a vector to express a particular protein, such as a chimeric antigen receptor.
In vivo gene therapy is seen as simpler, since it does not require the harvesting of mitotic cells. However, ex vivo gene therapies are better tolerated and less associated with severe immune responses. The death of Jesse Gelsinger in a trial of an adenovirus-vectored treatment for ornithine transcarbamylase deficiency due to a systemic inflammatory reaction led to a temporary halt on gene therapy trials across the United States. As of 2021, in vivo and ex vivo therapeutics are both seen as safe.
=== Gene editing ===
The concept of gene therapy is to fix a genetic problem at its source. If, for instance, a mutation in a certain gene causes the production of a dysfunctional protein resulting (usually recessively) in an inherited disease, gene therapy could be used to deliver a copy of this gene that does not contain the deleterious mutation and thereby produces a functional protein. This strategy is referred to as gene replacement therapy and could be employed to treat inherited retinal diseases.
While the concept of gene replacement therapy is mostly suitable for recessive diseases, novel strategies have been suggested that are capable of also treating conditions with a dominant pattern of inheritance.
The introduction of CRISPR gene editing has opened new doors for its application and utilization in gene therapy, as instead of pure replacement of a gene, it enables correction of the particular genetic defect. Solutions to medical hurdles, such as the eradication of latent human immunodeficiency virus (HIV) reservoirs and correction of the mutation that causes sickle cell disease, may be available as a therapeutic option in the future.
Prosthetic gene therapy aims to enable cells of the body to take over functions they physiologically do not carry out. One example is the so-called vision restoration gene therapy, that aims to restore vision in patients with end-stage retinal diseases. In end-stage retinal diseases, the photoreceptors, as the primary light sensitive cells of the retina are irreversibly lost. By the means of prosthetic gene therapy light sensitive proteins are delivered into the remaining cells of the retina, to render them light sensitive and thereby enable them to signal visual information towards the brain.
In vivo, gene editing systems using CRISPR have been used in studies with mice to treat cancer and have been effective at reducing tumors.: 18 In vitro, the CRISPR system has been used to treat HPV cancer tumors. Adeno-associated virus, Lentivirus based vectors have been to introduce the genome for the CRISPR system.: 6
== Vectors ==
The delivery of DNA into cells can be accomplished by multiple methods. The two major classes are recombinant viruses (sometimes called biological nanoparticles or viral vectors) and naked DNA or DNA complexes (non-viral methods).
=== Viruses ===
In order to replicate, viruses introduce their genetic material into the host cell, tricking the host's cellular machinery into using it as blueprints for viral proteins.: 39 Retroviruses go a stage further by having their genetic material copied into the nuclear genome of the host cell. Scientists exploit this by substituting part of a virus's genetic material with therapeutic DNA or RNA.: 40 Like the genetic material (DNA or RNA) in viruses, therapeutic genetic material can be designed to simply serve as a temporary blueprint that degrades naturally, as in a non-integrative vectors, or to enter the host's nucleus becoming a permanent part of the host's nuclear DNA in infected cells.: 50
A number of viruses have been used for human gene therapy, including viruses such as lentivirus, adenoviruses, herpes simplex, vaccinia, and adeno-associated virus.
Adenovirus viral vectors (Ad) temporarily modify a cell's genetic expression with genetic material that is not integrated into the host cell's DNA.: 5 As of 2017, such vectors were used in 20% of trials for gene therapy.: 10 Adenovirus vectors are mostly used in cancer treatments and novel genetic vaccines such as the Ebola vaccine, vaccines used in clinical trials for HIV and SARS-CoV-2, or cancer vaccines.: 5
Lentiviral vectors based on lentivirus, a retrovirus, can modify a cell's nuclear genome to permanently express a gene, although vectors can be modified to prevent integration.: 40,50 Retroviruses were used in 18% of trials before 2018.: 10 Libmeldy is an ex vivo stem cell treatment for metachromatic leukodystrophy which uses a lentiviral vector and was approved by the European medical agency in 2020.
Adeno-associated virus (AAV) is a virus that is incapable of transmission between cells unless the cell is infected by another virus, a helper virus. Adenovirus and the herpes viruses act as helper viruses for AAV. AAV persists within the cell outside of the cell's nuclear genome for an extended period of time through the formation of concatemers mostly organized as episomes.: 4 Genetic material from AAV vectors is integrated into the host cell's nuclear genome at a low frequency and likely mediated by the DNA-modifying enzymes of the host cell.: 2647 Animal models suggest that integration of AAV genetic material into the host cell's nuclear genome may cause hepatocellular carcinoma, a form of liver cancer. Several AAV investigational agents have been explored in treatment of wet age related macular degeneration by both intravitreal and subretinal approaches as a potential application of AAV gene therapy for human disease.
=== Non-viral ===
Non-viral vectors for gene therapy present certain advantages over viral methods, such as large scale production and low host immunogenicity. However, non-viral methods initially produced lower levels of transfection and gene expression, and thus lower therapeutic efficacy. Newer technologies offer promise of solving these problems, with the advent of increased cell-specific targeting and subcellular trafficking control.
Methods for non-viral gene therapy include the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles. These therapeutics can be administered directly or through scaffold enrichment.
More recent approaches, such as those performed by companies such as Ligandal, offer the possibility of creating cell-specific targeting technologies for a variety of gene therapy modalities, including RNA, DNA and gene editing tools such as CRISPR. Other companies, such as Arbutus Biopharma and Arcturus Therapeutics, offer non-viral, non-cell-targeted approaches that mainly exhibit liver trophism. In more recent years, startups such as Sixfold Bio, GenEdit, and Spotlight Therapeutics have begun to solve the non-viral gene delivery problem. Non-viral techniques offer the possibility of repeat dosing and greater tailorability of genetic payloads, which in the future will be more likely to take over viral-based delivery systems.
Companies such as Editas Medicine, Intellia Therapeutics, CRISPR Therapeutics, Casebia, Cellectis, Precision Biosciences, bluebird bio, Excision BioTherapeutics, and Sangamo have developed non-viral gene editing techniques, however frequently still use viruses for delivering gene insertion material following genomic cleavage by guided nucleases. These companies focus on gene editing, and still face major delivery hurdles.
BioNTech, Moderna Therapeutics and CureVac focus on delivery of mRNA payloads, which are necessarily non-viral delivery problems.
Alnylam, Dicerna Pharmaceuticals, and Ionis Pharmaceuticals focus on delivery of siRNA (antisense oligonucleotides) for gene suppression, which also necessitate non-viral delivery systems.
In academic contexts, a number of laboratories are working on delivery of PEGylated particles, which form serum protein coronas and chiefly exhibit LDL receptor mediated uptake in cells in vivo.
== Treatment ==
=== Cancer ===
There have been attempts to treat cancer using gene therapy. As of 2017, 65% of gene therapy trials were for cancer treatment.: 7 The promising results observed in cancer treatment were recorded.
Adenovirus vectors are useful for some cancer gene therapies because adenovirus can transiently insert genetic material into a cell without permanently altering the cell's nuclear genome. These vectors can be used to cause antigens to be added to cancers causing an immune response, or hinder angiogenesis by expressing certain proteins.: 5 An Adenovirus vector is used in the commercial products Gendicine and Oncorine.: 10 Another commercial product, Rexin G, uses a retrovirus-based vector and selectively binds to receptors that are more expressed in tumors.: 10
One approach, suicide gene therapy, works by introducing genes encoding enzymes that will cause a cancer cell to die. Another approach is the use oncolytic viruses, such as Oncorine,: 165 which are viruses that selectively reproduce in cancerous cells leaving other cells unaffected.: 6 : 280
mRNA has been suggested as a non-viral vector for cancer gene therapy that would temporarily change a cancerous cell's function to create antigens or kill the cancerous cells and there have been several trials.
Afamitresgene autoleucel, sold under the brand name Tecelra, is an autologous T cell immunotherapy used for the treatment of synovial sarcoma. It is a T cell receptor (TCR) gene therapy. It is the first FDA-approved engineered cell therapy for a solid tumor. It uses a self-inactivating lentiviral vector to express a T-cell receptor specific for MAGE-A4, a melanoma-associated antigen.
=== Genetic diseases ===
Gene therapy approaches to replace a faulty gene with a healthy gene have been proposed and are being studied for treating some genetic diseases. As of 2017, 11.1% of gene therapy clinical trials targeted monogenic diseases.: 9
Diseases such as sickle cell disease that are caused by autosomal recessive disorders for which a person's normal phenotype or cell function may be restored in cells that have the disease by a normal copy of the gene that is mutated, may be a good candidate for gene therapy treatment. The risks and benefits related to gene therapy for sickle cell disease are not known.
Gene therapy has been used in the eye. The eye is especially suitable for adeno-associated virus vectors. Voretigene neparvovec is an approved gene therapy to treat Leber's hereditary optic neuropathy.: 1354 alipogene tiparvovec, a treatment for pancreatitis caused by a genetic condition, and Zolgensma for the treatment of spinal muscular atrophy both use an adeno-associated virus vector.: 2647
=== Infectious diseases ===
As of 2017, 7% of genetic therapy trials targeted infectious diseases. 69.2% of trials targeted HIV, 11% hepatitis B or C, and 7.1% malaria.
=== List of gene therapies for treatment of disease ===
Some genetic therapies have been approved by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and for use in Russia and China.
== Adverse effects, contraindications and hurdles for use ==
Some of the unsolved problems include:
Off-target effects – The possibility of unwanted, likely harmful, changes to the genome present a large barrier to the widespread implementation of this technology. Improvements to the specificity of gRNAs and Cas enzymes present viable solutions to this issue as well as the refinement of the delivery method of CRISPR. It is likely that different diseases will benefit from different delivery methods.
Short-lived nature – Before gene therapy can become a permanent cure for a condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be stable. Problems with integrating therapeutic DNA into the nuclear genome and the rapidly dividing nature of many cells prevent it from achieving long-term benefits. Patients require multiple treatments.
Immune response – Any time a foreign object is introduced into human tissues, the immune system is stimulated to attack the invader. Stimulating the immune system in a way that reduces gene therapy effectiveness is possible. The immune system's enhanced response to viruses that it has seen before reduces the effectiveness to repeated treatments.
Problems with viral vectors – Viral vectors carry the risks of toxicity, inflammatory responses, and gene control and targeting issues.
Multigene disorders – Some commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis, and diabetes, are affected by variations in multiple genes, which complicate gene therapy.
Some therapies may breach the Weismann barrier (between soma and germ-line) protecting the testes, potentially modifying the germline, falling afoul of regulations in countries that prohibit the latter practice.
Insertional mutagenesis – If the DNA is integrated in a sensitive spot in the genome, for example in a tumor suppressor gene, the therapy could induce a tumor. This has occurred in clinical trials for X-linked severe combined immunodeficiency (X-SCID) patients, in which hematopoietic stem cells were transduced with a corrective transgene using a retrovirus, and this led to the development of T cell leukemia in 3 of 20 patients. One possible solution is to add a functional tumor suppressor gene to the DNA to be integrated. This may be problematic since the longer the DNA is, the harder it is to integrate into cell genomes. CRISPR technology allows researchers to make much more precise genome changes at exact locations.
Cost – alipogene tiparvovec (Glybera), for example, at a cost of $1.6 million per patient, was reported in 2013, to be the world's most expensive drug.
=== Deaths ===
Three patients' deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger, who died in 1999, because of immune rejection response. One X-SCID patient died of leukemia in 2003. In 2007, a rheumatoid arthritis patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy.
== Regulations ==
Regulations covering genetic modification are part of general guidelines about human-involved biomedical research. There are no international treaties which are legally binding in this area, but there are recommendations for national laws from various bodies.
The Helsinki Declaration (Ethical Principles for Medical Research Involving Human Subjects) was amended by the World Medical Association's General Assembly in 2008. This document provides principles physicians and researchers must consider when involving humans as research subjects. The Statement on Gene Therapy Research initiated by the Human Genome Organization (HUGO) in 2001, provides a legal baseline for all countries. HUGO's document emphasizes human freedom and adherence to human rights, and offers recommendations for somatic gene therapy, including the importance of recognizing public concerns about such research.
=== United States ===
No federal legislation lays out protocols or restrictions about human genetic engineering. This subject is governed by overlapping regulations from local and federal agencies, including the Department of Health and Human Services, the FDA and NIH's Recombinant DNA Advisory Committee. Researchers seeking federal funds for an investigational new drug application, (commonly the case for somatic human genetic engineering,) must obey international and federal guidelines for the protection of human subjects.
NIH serves as the main gene therapy regulator for federally funded research. Privately funded research is advised to follow these regulations. NIH provides funding for research that develops or enhances genetic engineering techniques and to evaluate the ethics and quality in current research. The NIH maintains a mandatory registry of human genetic engineering research protocols that includes all federally funded projects.
An NIH advisory committee published a set of guidelines on gene manipulation. The guidelines discuss lab safety as well as human test subjects and various experimental types that involve genetic changes. Several sections specifically pertain to human genetic engineering, including Section III-C-1. This section describes required review processes and other aspects when seeking approval to begin clinical research involving genetic transfer into a human patient. The protocol for a gene therapy clinical trial must be approved by the NIH's Recombinant DNA Advisory Committee prior to any clinical trial beginning; this is different from any other kind of clinical trial.
As with other kinds of drugs, the FDA regulates the quality and safety of gene therapy products and supervises how these products are used clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as clinical trials, must be reviewed and approved by the FDA and an Institutional Review Board.
== Gene doping ==
Athletes may adopt gene therapy technologies to improve their performance. Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.
== Genetic enhancement ==
Genetic engineering could be used to cure diseases, but also to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. Ethical claims about germline engineering include beliefs that every fetus has a right to remain genetically unmodified, that parents hold the right to genetically modify their offspring, and that every child has the right to be born free of preventable diseases. For parents, genetic engineering could be seen as another child enhancement technique to add to diet, exercise, education, training, cosmetics, and plastic surgery. Another theorist claims that moral concerns limit but do not prohibit germline engineering.
A 2020 issue of the journal Bioethics was devoted to moral issues surrounding germline genetic engineering in people.
Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. The American Medical Association's Council on Ethical and Judicial Affairs stated that "genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics."
As early in the history of biotechnology as 1990, there have been scientists opposed to attempts to modify the human germline using these new tools, and such concerns have continued as technology progressed. With the advent of new techniques like CRISPR, in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit the human genome in a way that can be inherited. In April 2015, researchers sparked controversy when they reported results of basic research to edit the DNA of non-viable human embryos using CRISPR. A committee of the American National Academy of Sciences and National Academy of Medicine gave qualified support to human genome editing in 2017 once answers have been found to safety and efficiency problems "but only for serious conditions under stringent oversight."
== History ==
=== 1970s and earlier ===
In 1972, Friedmann and Roblin authored a paper in Science titled "Gene therapy for human genetic disease?". Rogers (1970) was cited for proposing that exogenous good DNA be used to replace the defective DNA in those with genetic defects.
=== 1980s ===
In 1984, a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes.
=== 1990s ===
The first approved gene therapy clinical research in the US took place on 14 September 1990, at the National Institutes of Health (NIH), under the direction of William French Anderson. Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with adenosine deaminase deficiency (ADA-SCID), a severe immune system deficiency. The defective gene of the patient's blood cells was replaced by the functional variant. Ashanti's immune system was partially restored by the therapy. Production of the missing enzyme was temporarily stimulated, but the new cells with functional genes were not generated. She led a normal life only with the regular injections performed every two months. The effects were successful, but temporary.
Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993). The treatment of glioblastoma multiforme, the malignant brain tumor whose outcome is always fatal, was done using a vector expressing antisense IGF-I RNA (clinical trial approved by NIH protocol no.1602 24 November 1993, and by the FDA in 1994). This therapy also represents the beginning of cancer immunogene therapy, a treatment which proves to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena.
In 1992, Claudio Bordignon, working at the Vita-Salute San Raffaele University, performed the first gene therapy procedure using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases. In 2002, this work led to the publication of the first successful gene therapy treatment for ADA-SCID. The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or "bubble boy" disease) from 2000 and 2002, was questioned when two of the ten children treated at the trial's Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the US, the United Kingdom, France, Italy, and Germany.
In 1993, Andrew Gobea was born with SCID following prenatal genetic screening. Blood was removed from his mother's placenta and umbilical cord immediately after birth, to acquire stem cells. The allele that codes for adenosine deaminase (ADA) was obtained and inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses inserted the gene into the stem cell chromosomes. Stem cells containing the working ADA gene were injected into Andrew's blood. Injections of the ADA enzyme were also given weekly. For four years T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.
In 1996, Luigi Naldini and Didier Trono developed a new class of gene therapy vectors based on HIV capable of infecting non-dividing cells that have since then been widely used in clinical and research settings, pioneering lentivirals vector in gene therapy.
Jesse Gelsinger's death in 1999 impeded gene therapy research in the US. As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.
=== 2000s ===
The modified gene therapy strategy of antisense IGF-I RNA (NIH n˚ 1602) using antisense / triple helix anti-IGF-I approach was registered in 2002, by Wiley gene therapy clinical trial - n˚ 635 and 636. The approach has shown promising results in the treatment of six different malignant tumors: glioblastoma, cancers of liver, colon, prostate, uterus, and ovary (Collaborative NATO Science Programme on Gene Therapy USA, France, Poland n˚ LST 980517 conducted by J. Trojan) (Trojan et al., 2012). This anti-gene antisense/triple helix therapy has proven to be efficient, due to the mechanism stopping simultaneously IGF-I expression on translation and transcription levels, strengthening anti-tumor immune and apoptotic phenomena.
==== 2002 ====
Sickle cell disease can be treated in mice. The mice – which have essentially the same defect that causes human cases – used a viral vector to induce production of fetal hemoglobin (HbF), which normally ceases to be produced shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production.
A new gene therapy approach repaired errors in messenger RNA derived from defective genes. This technique has the potential to treat thalassaemia, cystic fibrosis and some cancers.
Researchers created liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.
==== 2003 ====
In 2003, a research team inserted genes into the brain for the first time. They used liposomes coated in a polymer called polyethylene glycol, which unlike viral vectors, are small enough to cross the blood–brain barrier.
Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.
Gendicine is a cancer gene therapy that delivers the tumor suppressor gene p53 using an engineered adenovirus. In 2003, it was approved in China for the treatment of head and neck squamous cell carcinoma.
==== 2006 ====
In March, researchers announced the successful use of gene therapy to treat two adult patients for X-linked chronic granulomatous disease, a disease which affects myeloid cells and damages the immune system. The study is the first to show that gene therapy can treat the myeloid system.
In May, a team reported a way to prevent the immune system from rejecting a newly delivered gene. Similar to organ transplantation, gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as microRNAs. This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.
In August, scientists successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells.
In November, researchers reported on the use of VRX496, a gene-based immunotherapy for the treatment of HIV that uses a lentiviral vector to deliver an antisense gene against the HIV envelope. In a phase I clinical trial, five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were treated. A single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.
==== 2007 ====
In May 2007, researchers announced the first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.
==== 2008 ====
Leber's congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of a small clinical trial in children were published in April. Delivery of recombinant adeno-associated virus (AAV) carrying RPE65 yielded positive results. In May, two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects.
==== 2009 ====
In September researchers were able to give trichromatic vision to squirrel monkeys. In November 2009, researchers halted a fatal genetic disorder called adrenoleukodystrophy in two children using a lentivirus vector to deliver a functioning version of ABCD1, the gene that is mutated in the disorder.
=== 2010s ===
==== 2010 ====
An April paper reported that gene therapy addressed achromatopsia (color blindness) in dogs by targeting cone photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs.
In September it was announced that an 18-year-old male patient in France with beta thalassemia major had been successfully treated. Beta thalassemia major is an inherited blood disease in which beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions. The technique used a lentiviral vector to transduce the human β-globin gene into purified blood and marrow cells obtained from the patient in June 2007. The patient's haemoglobin levels were stable at 9 to 10 g/dL. About a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions were not needed. Further clinical trials were planned. Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.
Cancer immunogene therapy using modified antigene, antisense/triple helix approach was introduced in South America in 2010/11 in La Sabana University, Bogota (Ethical Committee 14 December 2010, no P-004-10). Considering the ethical aspect of gene diagnostic and gene therapy targeting IGF-I, the IGF-I expressing tumors i.e. lung and epidermis cancers were treated (Trojan et al. 2016).
==== 2011 ====
In 2007 and 2008, a man (Timothy Ray Brown) was cured of HIV by repeated hematopoietic stem cell transplantation (see also allogeneic stem cell transplantation, allogeneic bone marrow transplantation, allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor. This cure was accepted by the medical community in 2011. It required complete ablation of existing bone marrow, which is very debilitating.
In August two of three subjects of a pilot study were confirmed to have been cured from chronic lymphocytic leukemia (CLL). The therapy used genetically modified T cells to attack cells that expressed the CD19 protein to fight the disease. In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.
Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction.
In 2011, Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia; it delivers the gene encoding for VEGF. Neovasculogen is a plasmid encoding the CMV promoter and the 165 amino acid form of VEGF.
==== 2012 ====
The FDA approved Phase I clinical trials on thalassemia major patients in the US for 10 participants in July. The study was expected to continue until 2015.
In July 2012, the European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment used Alipogene tiparvovec (Glybera) to compensate for lipoprotein lipase deficiency, which can cause severe pancreatitis. The recommendation was endorsed by the European Commission in November 2012, and commercial rollout began in late 2014. Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012, revised to $1 million in 2015, making it the most expensive medicine in the world at the time. As of 2016, only the patients treated in clinical trials and a patient who paid the full price for treatment have received the drug.
In December 2012, it was reported that 10 of 13 patients with multiple myeloma were in remission "or very close to it" three months after being injected with a treatment involving genetically engineered T cells to target proteins NY-ESO-1 and LAGE-1, which exist only on cancerous myeloma cells.
==== 2013 ====
In March researchers reported that three of five adult subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B cells, cancerous or not. The researchers believed that the patients' immune systems would make normal T cells and B cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease.
Following encouraging Phase I trials, in April, researchers announced they were starting Phase II clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients at several hospitals to combat heart disease. The therapy was designed to increase the levels of SERCA2, a protein in heart muscles, improving muscle function. The U.S. Food and Drug Administration (FDA) granted this a breakthrough therapy designation to accelerate the trial and approval process. In 2016, it was reported that no improvement was found from the CUPID 2 trial.
In July researchers reported promising results for six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 7–32 months. Three of the children had metachromatic leukodystrophy, which causes children to lose cognitive and motor skills. The other children had Wiskott–Aldrich syndrome, which leaves them to open to infection, autoimmune diseases, and cancer. Follow up trials with gene therapy on another six children with Wiskott–Aldrich syndrome were also reported as promising.
In October researchers reported that two children born with adenosine deaminase severe combined immunodeficiency disease (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and that their immune systems were showing signs of full recovery. Another three children were making progress. In 2014, a further 18 children with ADA-SCID were cured by gene therapy. ADA-SCID children have no functioning immune system and are sometimes known as "bubble children".
Also in October researchers reported that they had treated six people with haemophilia in early 2011 using an adeno-associated virus. Over two years later all six were producing clotting factor.
==== 2014 ====
In January researchers reported that six choroideremia patients had been treated with adeno-associated virus with a copy of REP1. Over a six-month to two-year period all had improved their sight. By 2016, 32 patients had been treated with positive results and researchers were hopeful the treatment would be long-lasting. Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of sight.
In March researchers reported that 12 HIV patients had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation (CCR5 deficiency) known to protect against HIV with promising results.
Clinical trials of gene therapy for sickle cell disease were started in 2014.
In February LentiGlobin BB305, a gene therapy treatment undergoing clinical trials for treatment of beta thalassemia gained FDA "breakthrough" status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease.
In March researchers delivered a recombinant gene encoding a broadly neutralizing antibody into monkeys infected with simian HIV; the monkeys' cells produced the antibody, which cleared them of HIV. The technique is named immunoprophylaxis by gene transfer (IGT). Animal tests for antibodies to ebola, malaria, influenza, and hepatitis were underway.
In March, scientists, including an inventor of CRISPR, Jennifer Doudna, urged a worldwide moratorium on germline gene therapy, writing "scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans" until the full implications "are discussed among scientific and governmental organizations".
In December, scientists of major world academies called for a moratorium on inheritable human genome edits, including those related to CRISPR-Cas9 technologies but that basic research including embryo gene editing should continue.
==== 2015 ====
Researchers successfully treated a boy with epidermolysis bullosa using skin grafts grown from his own skin cells, genetically altered to repair the mutation that caused his disease.
In November, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T cells genetically engineered using TALEN to attack cancer cells. One year after the treatment she was still free of her cancer (a highly aggressive form of acute lymphoblastic leukaemia [ALL]). Children with highly aggressive ALL normally have a very poor prognosis and Layla's disease had been regarded as terminal before the treatment.
==== 2016 ====
In April the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed a gene therapy treatment called Strimvelis and the European Commission approved it in June. This treats children born with adenosine deaminase deficiency and who have no functioning immune system. This was the second gene therapy treatment to be approved in Europe.
In October, Chinese scientists reported they had started a trial to genetically modify T cells from 10 adult patients with lung cancer and reinject the modified T cells back into their bodies to attack the cancer cells. The T cells had the PD-1 protein (which stops or slows the immune response) removed using CRISPR-Cas9.
A 2016 Cochrane systematic review looking at data from four trials on topical cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy does not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections. One of the four trials did find weak evidence that liposome-based CFTR gene transfer therapy may lead to a small respiratory improvement for people with CF. This weak evidence is not enough to make a clinical recommendation for routine CFTR gene therapy.
==== 2017 ====
In February Kite Pharma announced results from a clinical trial of CAR-T cells in around a hundred people with advanced non-Hodgkin lymphoma.
In March, French scientists reported on clinical research of gene therapy to treat sickle cell disease.
In August, the FDA approved tisagenlecleucel for acute lymphoblastic leukemia. Tisagenlecleucel is an adoptive cell transfer therapy for B-cell acute lymphoblastic leukemia; T cells from a person with cancer are removed, genetically engineered to make a specific T-cell receptor (a chimeric T cell receptor, or "CAR-T") that reacts to the cancer, and are administered back to the person. The T cells are engineered to target a protein called CD19 that is common on B cells. This is the first form of gene therapy to be approved in the United States. In October, a similar therapy called axicabtagene ciloleucel was approved for non-Hodgkin lymphoma.
In October, biophysicist and biohacker Josiah Zayner claimed to have performed the very first in-vivo human genome editing in the form of a self-administered therapy.
On 13 November, medical scientists working with Sangamo Therapeutics, headquartered in Richmond, California, announced the first ever in-body human gene editing therapy. The treatment, designed to permanently insert a healthy version of the flawed gene that causes Hunter syndrome, was given to 44-year-old Brian Madeux and is part of the world's first study to permanently edit DNA inside the human body. The success of the gene insertion was later confirmed. Clinical trials by Sangamo involving gene editing using zinc finger nuclease (ZFN) are ongoing.
In December the results of using an adeno-associated virus with blood clotting factor VIII to treat nine haemophilia A patients were published. Six of the seven patients on the high dose regime increased the level of the blood clotting VIII to normal levels. The low and medium dose regimes had no effect on the patient's blood clotting levels.
In December, the FDA approved voretigene neparvovec, the first in vivo gene therapy, for the treatment of blindness due to Leber's congenital amaurosis. The price of this treatment is US$850,000 for both eyes.
==== 2019 ====
In May, the FDA approved onasemnogene abeparvovec (Zolgensma) for treating spinal muscular atrophy in children under two years of age. The list price of Zolgensma was set at US$2.125 million per dose, making it the most expensive drug ever.
In May, the EMA approved betibeglogene autotemcel (Zynteglo) for treating beta thalassemia for people twelve years of age and older.
In July, Allergan and Editas Medicine announced phase I/II clinical trial of AGN-151587 for the treatment of Leber congenital amaurosis 10. This is one of the first studies of a CRISPR-based in vivo human gene editing therapy, where the editing takes place inside the human body. The first injection of the CRISPR-Cas System was confirmed in March 2020.
Exagamglogene autotemcel, a CRISPR-based human gene editing therapy, was used for sickle cell and thalassemia in clinical trials.
=== 2020s ===
==== 2020 ====
In May, onasemnogene abeparvovec (Zolgensma) was approved by the European Union for the treatment of spinal muscular atrophy in people who either have clinical symptoms of SMA type 1 or who have no more than three copies of the SMN2 gene, irrespective of body weight or age.
In August, Audentes Therapeutics reported that three out of 17 children with X-linked myotubular myopathy participating the clinical trial of a AAV8-based gene therapy treatment AT132 have died. It was suggested that the treatment, whose dosage is based on body weight, exerts a disproportionately toxic effect on heavier patients, since the three patients who died were heavier than the others. The trial has been put on clinical hold.
On 15 October, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Libmeldy (autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells transduced ex vivo using a lentiviral vector encoding the human arylsulfatase A gene), a gene therapy for the treatment of children with the "late infantile" (LI) or "early juvenile" (EJ) forms of metachromatic leukodystrophy (MLD). The active substance of Libmeldy consists of the child's own stem cells which have been modified to contain working copies of the ARSA gene. When the modified cells are injected back into the patient as a one-time infusion, the cells are expected to start producing the ARSA enzyme that breaks down the build-up of sulfatides in the nerve cells and other cells of the patient's body. Libmeldy was approved for medical use in the EU in December 2020.
On 15 October, Lysogene, a French biotechnological company, reported the death of a patient in who has received LYS-SAF302, an experimental gene therapy treatment for mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A).
==== 2021 ====
In May, a new method using an altered version of HIV as a lentivirus vector was reported in the treatment of 50 children with ADA-SCID obtaining positive results in 48 of them, this method is expected to be safer than retroviruses vectors commonly used in previous studies of SCID where the development of leukemia was usually observed and had already been used in 2019, but in a smaller group with X-SCID.
In June a clinical trial on six patients affected with transthyretin amyloidosis reported a reduction the concentration of missfolded transthretin (TTR) protein in serum through CRISPR-based inactivation of the TTR gene in liver cells observing mean reductions of 52% and 87% among the lower and higher dose groups.This was done in vivo without taking cells out of the patient to edit them and reinfuse them later.
In July results of a small gene therapy phase I study was published reporting observation of dopamine restoration on seven patients between 4 and 9 years old affected by aromatic L-amino acid decarboxylase deficiency (AADC deficiency).
==== 2022 ====
In February, the first ever gene therapy for Tay–Sachs disease was announced, it uses an adeno-associated virus to deliver the correct instruction for the HEXA gene on brain cells which causes the disease. Only two children were part of a compassionate trial presenting improvements over the natural course of the disease and no vector-related adverse events.
In May, eladocagene exuparvovec is recommended for approval by the European Commission.
In July results of a gene therapy candidate for haemophilia B called FLT180 were announced, it works using an adeno-associated virus (AAV) to restore the clotting factor IX (FIX) protein, normal levels of the protein were observed with low doses of the therapy but immunosuppression was necessitated to decrease the risk of vector-related immune responses.
In December, a 13-year girl that had been diagnosed with T-cell acute lymphoblastic leukaemia was successfully treated at Great Ormond Street Hospital (GOSH) in the first documented use of therapeutic gene editing for this purpose, after undergoing six months of an experimental treatment, where all attempts of other treatments failed. The procedure included reprogramming a healthy T-cell to destroy the cancerous T-cells to first rid her of leukaemia, and then rebuilding her immune system using healthy immune cells. The GOSH team used BASE editing and had previously treated a case of acute lymphoblastic leukaemia in 2015 using TALENs.
==== 2023 ====
In May 2023, the FDA approved beremagene geperpavec for the treatment of wounds in people with dystrophic epidermolysis bullosa (DEB) which is applied as a topical gel that delivers a herpes-simplex virus type 1 (HSV-1) vector encoding the collagen type VII alpha 1 chain (COL7A1) gene that is dysfunctional on those affected by DEB . One trial found 65% of the Vyjuvek-treated wounds completely closed while only 26% of the placebo-treated at 24 weeks. It has been also reported its use as an eyedrop for a patient with DEB that had vision loss due to the widespread blistering with good results.
In June 2023, the FDA gave an accelerated approval to Elevidys for Duchenne muscular dystrophy (DMD) only for boys 4 to 5 years old as they are more likely to benefit from the therapy which consists of one-time intravenous infusion of a virus (AAV rh74 vector) that delivers a functioning "microdystrophin" gene (138 kDa) into the muscle cells to act in place of the normal dystrophin (427 kDa) that is found mutated in this disease.
In July 2023, it was reported that it had been developed a new method to affect genetic expressions through direct current.
In December 2023, two gene therapies were approved for sickle cell disease, exagamglogene autotemcel and lovotibeglogene autotemcel.
2024
In November 2024, FDA granted accelerated approval for eladocagene exuparvovec-tneq (Kebilidi, PTC Therapeutics), a direct-to-brain gene therapy for aromatic L-amino acid decarboxylase deficiency. It uses a recombinant adeno-associated virus serotype 2 (rAAV2) to deliver a functioning DOPA decarboxylase (DDC) gene directly into the putamen, increasing the AADC enzyme and restoring dopamine production. It is administered through a stereotactic surgical procedure.
== List of gene therapies ==
Gene therapy for color blindness
Gene therapy for epilepsy
Gene therapy for osteoarthritis
Gene therapy in Parkinson's disease
Gene therapy of the human retina
List of gene therapies
== References ==
== Further reading ==
== External links == | Wikipedia/Gene_therapy |
A drug carrier or drug vehicle is a substrate used in the process of drug delivery which serves to improve the selectivity, effectiveness, and/or safety of drug administration. Drug carriers are primarily used to control the release of drugs into systemic circulation. This can be accomplished either by slow release of a particular drug over a long period of time (typically diffusion) or by triggered release at the drug's target by some stimulus, such as changes in pH, application of heat, and activation by light. Drug carriers are also used to improve the pharmacokinetic properties, specifically the bioavailability, of many drugs with poor water solubility and/or membrane permeability.
A wide variety of drug carrier systems have been developed and studied, each of which has unique advantages and disadvantages. Some of the more popular types of drug carriers include liposomes, polymeric micelles, microspheres, and nanoparticles. Different methods of attaching the drug to the carrier have been implemented, including adsorption, integration into the bulk structure, encapsulation, and covalent bonding. Different types of drug carrier utilize different methods of attachment, and some carriers can even implement a variety of attachment methods.
== Carrier types ==
=== Liposomes ===
Liposomes are structures which consist of at least one lipid bilayer surrounding an aqueous core. This hydrophobic/hydrophilic composition is particularly useful for drug delivery as these carriers can accommodate a number of drugs of varying lipophilicity. Disadvantages associated with using liposomes as drug carriers involve poor control over drug release. Drugs which have high membrane-permeability can readily 'leak' from the carrier, while optimization of in vivo stability can cause drug release by diffusion to be a slow and inefficient process. Much of the current research involving liposomes is focused on improving the delivery of anticancer drugs such as doxorubicin and paclitaxel.
=== Polymeric micelles ===
Polymeric micelles are drug carriers formed by the aggregation of some amphiphile\amphiphilic molecule with an amphiphilic block copolymer. These carriers form at some high concentration specific to the compounds used, called the critical micelle concentration. The addition of an amphiphilic block copolymer effectively lowers this critical micelle concentration by shifting the monomer exchange equilibrium. These carriers are comparable to liposomes, however the lack of an aqueous core makes polymeric micelles less accommodating to a wide variety of drugs.
=== Microspheres ===
Microspheres are hollow, micron-sized carriers often formed via self-assembly of polymeric compounds which are most often used to encapsulate the active drug for delivery. Drug release is often achieved by diffusion through pores in the microsphere structure or by degradation of the microsphere shell. Some of the research currently being done uses advanced assembly techniques, such as precision particle fabrication (PPF), to create microspheres capable of sustained control over drug release.
=== Nanostructures ===
==== Nanodiamonds ====
Nanodiamonds (NDs) are carbon nanoparticles which can vary from ~4-100 nm in diameter. NDs are typically formed in two ways: from micron-sized diamond particles under high-pressure high-temperature conditions, called high-pressure high-temperature nanodiamonds (HPHT NDs) and by shock-wave compression, called detonation nanodiamonds (DNDs). The surfaces of these NDs can be modified by processes such as oxidation and aminification to alter adsorption properties.
=== Nanofibers ===
=== Protein-DNA complexes ===
=== Protein-drug conjugates ===
=== Erythrocytes ===
=== Virosomes ===
=== Dendrimers ===
== Resources ==
The following research papers from IUPAC are in pdf format:
Biodegradable hydrogels for bone regeneration through growth factor release
Development of acid-sensitive copolymer micelles for drug delivery
== References ==
== External links ==
Weighting cancer drugs to make them hit tumors harder at PhysOrg.com
Designing Better Cancer Drugs Insight into Carrier Molecules' Functionality which may yield Safer Cancer Treatments at MIT magazine TechnologyReview.com | Wikipedia/Drug_carrier |
Modelling biological systems is a significant task of systems biology and mathematical biology. Computational systems biology aims to develop and use efficient algorithms, data structures, visualization and communication tools with the goal of computer modelling of biological systems. It involves the use of computer simulations of biological systems, including cellular subsystems (such as the networks of metabolites and enzymes which comprise metabolism, signal transduction pathways and gene regulatory networks), to both analyze and visualize the complex connections of these cellular processes.
An unexpected emergent property of a complex system may be a result of the interplay of the cause-and-effect among simpler, integrated parts (see biological organisation). Biological systems manifest many important examples of emergent properties in the complex interplay of components. Traditional study of biological systems requires reductive methods in which quantities of data are gathered by category, such as concentration over time in response to a certain stimulus. Computers are critical to analysis and modelling of these data. The goal is to create accurate real-time models of a system's response to environmental and internal stimuli, such as a model of a cancer cell in order to find weaknesses in its signalling pathways, or modelling of ion channel mutations to see effects on cardiomyocytes and in turn, the function of a beating heart.
== Standards ==
By far the most widely accepted standard format for storing and exchanging models in the field is the Systems Biology Markup Language (SBML). The SBML.org website includes a guide to many important software packages used in computational systems biology. A large number of models encoded in SBML can be retrieved from BioModels. Other markup languages with different emphases include BioPAX, CellML and MorpheusML.
== Particular tasks ==
=== Cellular model ===
Creating a cellular model has been a particularly challenging task of systems biology and mathematical biology. It involves the use of computer simulations of the many cellular subsystems such as the networks of metabolites, enzymes which comprise metabolism and transcription, translation, regulation and induction of gene regulatory networks.
The complex network of biochemical reaction/transport processes and their spatial organization make the development of a predictive model of a living cell a grand challenge for the 21st century, listed as such by the National Science Foundation (NSF) in 2006.
A whole cell computational model for the bacterium Mycoplasma genitalium, including all its 525 genes, gene products, and their interactions, was built by scientists from Stanford University and the J. Craig Venter Institute and published on 20 July 2012 in Cell.
A dynamic computer model of intracellular signaling was the basis for Merrimack Pharmaceuticals to discover the target for their cancer medicine MM-111.
Membrane computing is the task of modelling specifically a cell membrane.
=== Multi-cellular organism simulation ===
An open source simulation of C. elegans at the cellular level is being pursued by the OpenWorm community. So far the physics engine Gepetto has been built and models of the neural connectome and a muscle cell have been created in the NeuroML format.
=== Protein folding ===
Protein structure prediction is the prediction of the three-dimensional structure of a protein from its amino acid sequence—that is, the prediction of a protein's tertiary structure from its primary structure. It is one of the most important goals pursued by bioinformatics and theoretical chemistry. Protein structure prediction is of high importance in medicine (for example, in drug design) and biotechnology (for example, in the design of novel enzymes). Every two years, the performance of current methods is assessed in the CASP experiment.
=== Human biological systems ===
==== Brain model ====
The Blue Brain Project is an attempt to create a synthetic brain by reverse-engineering the mammalian brain down to the molecular level. The aim of this project, founded in May 2005 by the Brain and Mind Institute of the École Polytechnique in Lausanne, Switzerland, is to study the brain's architectural and functional principles. The project is headed by the Institute's director, Henry Markram. Using a Blue Gene supercomputer running Michael Hines's NEURON software, the simulation does not consist simply of an artificial neural network, but involves a partially biologically realistic model of neurons. It is hoped by its proponents that it will eventually shed light on the nature of consciousness.
There are a number of sub-projects, including the Cajal Blue Brain, coordinated by the Supercomputing and Visualization Center of Madrid (CeSViMa), and others run by universities and independent laboratories in the UK, U.S., and Israel. The Human Brain Project builds on the work of the Blue Brain Project. It is one of six pilot projects in the Future Emerging Technologies Research Program of the European Commission, competing for a billion euro funding.
==== Model of the immune system ====
The last decade has seen the emergence of a growing number of simulations of the immune system.
==== Virtual liver ====
The Virtual Liver project is a 43 million euro research program funded by the German Government, made up of seventy research group distributed across Germany. The goal is to produce a virtual liver, a dynamic mathematical model that represents human liver physiology, morphology and function.
=== Tree model ===
Electronic trees (e-trees) usually use L-systems to simulate growth. L-systems are very important in the field of complexity science and A-life.
A universally accepted system for describing changes in plant morphology at the cellular or modular level has yet to be devised.
The most widely implemented tree generating algorithms are described in the papers "Creation and Rendering of Realistic Trees" and Real-Time Tree Rendering.
=== Ecological models ===
Ecosystem models are mathematical representations of ecosystems. Typically they simplify complex foodwebs down to their major components or trophic levels, and quantify these as either numbers of organisms, biomass or the inventory/concentration of some pertinent chemical element (for instance, carbon or a nutrient species such as nitrogen or phosphorus).
=== Models in ecotoxicology ===
The purpose of models in ecotoxicology is the understanding, simulation and prediction of effects caused by toxicants in the environment. Most current models describe effects on one of many different levels of biological organization (e.g. organisms or populations). A challenge is the development of models that predict effects across biological scales. Ecotoxicology and models discusses some types of ecotoxicological models and provides links to many others.
=== Modelling of infectious disease ===
It is possible to model the progress of most infectious diseases mathematically to discover the likely outcome of an epidemic or to help manage them by vaccination. This field tries to find parameters for various infectious diseases and to use those parameters to make useful calculations about the effects of a mass vaccination programme.
== See also ==
Biological data visualization
Biosimulation
Gillespie algorithm
Molecular modelling software
Stochastic simulation
== Notes ==
== References ==
== Sources ==
Antmann, S. S.; Marsden, J. E.; Sirovich, L., eds. (2009). Mathematical Physiology (2nd ed.). New York, New York: Springer. ISBN 978-0-387-75846-6.
Barnes, D.J.; Chu, D. (2010), Introduction to Modelling for Biosciences, Springer Verlag
An Introduction to Infectious Disease Modelling by Emilia Vynnycky and Richard G White. An introductory book on infectious disease modelling and its applications.
== Further reading ==
== External links ==
The Center for Modeling Immunity to Enteric Pathogens (MIEP) | Wikipedia/Computational_biomodeling |
In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds.
Some polyunsaturated fatty acids are essentials. Polyunsaturated fatty acids are precursors to and are derived from polyunsaturated fats, which include drying oils.
== Nomenclature ==
The position of the carbon-carbon double bonds in carboxylic acid chains in fats is designated by Greek letters. The carbon atom closest to the carboxyl group is the alpha carbon, the next carbon is the beta carbon and so on. In fatty acids the carbon atom of the methyl group at the end of the hydrocarbon chain is called the omega carbon because omega is the last letter of the Greek alphabet. Omega-3 fatty acids have a double bond three carbons away from the methyl carbon, whereas omega-6 fatty acids have a double bond six carbons away from the methyl carbon. The illustration below shows the omega-6 fatty acid, linoleic acid.
Polyunsaturated fatty acids can be classified in various groups by their chemical structure:
methylene-interrupted polyenes
conjugated fatty acids
other PUFAs
Based on the length of their carbon backbone, they are sometimes classified in two groups: All feature pentadiene groups.
short chain polyunsaturated fatty acids (SC-PUFA), with 18 carbon atoms. These are more common. Key members include linoleic acid, α-linolenic acid, and arachidonic acid.
long-chain polyunsaturated fatty acids (LC-PUFA) with 20 or more carbon atoms
== Production ==
PUFAs with 18 carbon atoms, which are the most common variety, are not produced by mammals. Since they have important dietary functions, their biosynthesis has received much attention. Plants produce PUFAs from oleic acid. Key enzymes are called fatty acid desaturases, which introduce additional double bonds. Desaturases convert oleic acid into linoleic acid the precursor to alpha-linolenic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid.
Industrial PUFAs are generally obtained by hydrolysis of fats that contain PUFAs. The process is complicated by the sensitive nature of PUFAs, leading to side reactions and colorization. Thus, steam hydrolysis often fails for this reason. Alkaline hydrolysis of fats followed by acidification is expensive. Lipases, a family of enzymes, show potential as mild and green catalysts for the production of PUFAs from triglycerides.
In general, outside of dietary contexts, PUFAs are undesirable components of vegetable oils, so there is great interest in their removal from, say, olive oil. One technology for lowering the PUFA contact is by selective formation of derivatives with ureas.
== Reactions ==
From the perspective of chemical analysis, PUFA's have high iodine numbers. These high values are simply a reflection of the fact that PUFAs are polyunsaturated. Hydrogenation of PUFAs gives less unsaturated derivatives. For unsaturated products from partial hydrogenation often contain some trans isomers. The trans monounsaturated C20 species elaidic acid can be prepared in this way.
=== Peroxidation ===
Polyunsaturated fatty acids are susceptible to lipid peroxidation, far more so than monounsaturated or saturated analogues. The basis for this reactivity is the weakness of doubly allylic C-H bonds. They are drying oils, i.e. film-forming liquids suitable as painting. One practical consequence is that polyunsaturated fatty acids have poor shelf life, owing to their tendency toward autoxidation, leading, in the case of edibles, to rancidification. Metals accelerate the degradation. A range of reactions with oxygen occur. Products include fatty acid hydroperoxides, epoxy-hydroxy polyunsaturated fatty acids, jasmonates, divinylether fatty acids, and leaf aldehydes. Some of these derivatives are signalling molecules, some are used in plant defense (antifeedants), some are precursors to other metabolites that are used by the plant.
== Types ==
=== Methylene-interrupted polyenes ===
These fatty acids have 2 or more cis double bonds that are separated from each other by a single methylene bridge (−CH2−). This form is also sometimes called a divinylmethane pattern.
The essential fatty acids are all omega-3 and -6 methylene-interrupted fatty acids. See more at Essential fatty acids—Nomenclature
==== Omega-3 ====
==== Omega-6 ====
=== Conjugated fatty acids ===
=== Other polyunsaturated fatty acids ===
== Function and effects ==
The biological effects of the ω-3 and ω-6 fatty acids are largely mediated by their mutual interactions, see Essential fatty acid interactions for detail.
== Health ==
=== Potential benefits ===
Because of their effects in the diet, unsaturated fats (monounsaturated and polyunsaturated) are often referred to as good fats; while saturated fats are sometimes referred to as bad fats. Some fat is needed in the diet, but it is usually considered that fats should not be consumed excessively, unsaturated fats should be preferred, and saturated fats in particular should be limited.
In preliminary research, omega-3 fatty acids in algal oil, fish oil, fish and seafood have been shown to lower the risk of heart attacks. Other preliminary research indicates that omega-6 fatty acids in sunflower oil and safflower oil may also reduce the risk of cardiovascular disease.
Among omega-3 fatty acids, neither long-chain nor short-chain forms were consistently associated with breast cancer risk. High levels of docosahexaenoic acid (DHA), however, the most abundant omega-3 polyunsaturated fatty acid in erythrocyte (red blood cell) membranes, were associated with a reduced risk of breast cancer. DHA is vital for the grey matter structure of the human brain, as well as retinal stimulation and neurotransmission.
Contrary to conventional advice, an evaluation of evidence from 1966–1973 pertaining to the health impacts of replacing dietary saturated fat with linoleic acid found that participants in the group doing so had increased rates of death from all causes, coronary heart disease, and cardiovascular disease. Although this evaluation was disputed by many scientists, it fueled debate over worldwide dietary advice to substitute polyunsaturated fats for saturated fats.
Taking isotope-reinforced polyunsaturated fatty acids, for example deuterated linoleic acid where two atoms of hydrogen substituted with its heavy isotope deuterium, with food (heavy isotope diet) can suppress lipid peroxidation and prevent or treat the associated diseases.
=== Pregnancy ===
Polyunsaturated fat supplementation does not decrease the incidence of pregnancy-related disorders, such as hypertension or preeclampsia, but may increase the length of gestation slightly and decreased the incidence of early premature births.
Expert panels in the United States and Europe recommend that pregnant and lactating women consume higher amounts of polyunsaturated fats than the general population to enhance the DHA status of the fetus and newborn.
=== Cancer ===
Results from observational clinical trials on polyunsaturated fat intake and cancer have been inconsistent and vary by numerous factors of cancer incidence, including gender and genetic risk. Some studies have shown associations between higher intakes and/or blood levels of polyunsaturated fat omega-3s and a decreased risk of certain cancers, including breast and colorectal cancer, while other studies found no associations with cancer risk.
== Dietary sources ==
Polyunsaturated fat can be found mostly in nuts, seeds, fish, seed oils, and oysters. "Unsaturated" refers to the fact that the molecules contain less than the maximum amount of hydrogen (if there were no double bonds). These materials exist as cis or trans isomers depending on the geometry of the double bond.
== Non-dietary applications ==
PUFA's are significant components of alkyd resins, which are used in coatings.
== References ==
== Sources ==
Cyberlipid. "Polyenoic Fatty Acids". Archived from the original on 2018-09-30. Retrieved 2007-01-17.
Gunstone, Frank D. "Lipid Glossary 2" (PDF). Archived from the original (PDF) on 2006-08-13. Retrieved 2007-01-17.
Adlof, R. O. & Gunstone, F. D. (2003-09-17). "Common (non-systematic) Names for Fatty Acids". Archived from the original on 2006-12-06. Retrieved 2007-01-24.
Heinz; Roughan, PG (1983). "Similarities and Differences in Lipid Metabolism of Chloroplasts Isolated from 18:3 and 16:3 Plants". Plant Physiol. 72 (2): 273–279. doi:10.1104/pp.72.2.273. PMC 1066223. PMID 16662992. | Wikipedia/Polyunsaturated_fat |
An industrial park, also known as industrial estate or trading estate, is an area zoned and planned for the purpose of industrial development. An industrial park can be thought of as a more heavyweight version of a business park or office park, which has offices and light industry, rather than heavy industry. Industrial parks are notable for being relatively simple to build; they often feature speedily erected single-space steel sheds, occasionally in bright colours.
== Benefits ==
Industrial parks are usually located on the edges of, or outside, the main residential area of a city, and are normally provided with good transportation access, including road and rail. One such example is the large number of industrial estates located along the River Thames in the Thames Gateway area of London. Industrial parks are usually located close to transport facilities, especially where more than one transport modes coincide, including highways, railroads, airports and ports. Another common feature of a North American industrial park is a water tower, which helps to hold enough water to meet the park's demands and for firefighting purposes, and also advertises the industrial park and locality, as usually the community's name and logo are painted onto its surface.
This idea of setting land aside through this type of zoning has several purposes:
By concentrating dedicated infrastructure in a delimited area, to reduce the per-business cost of that infrastructure. Such infrastructure includes roadways, railroad sidings, ports, high-power electric supplies (often including three-phase electric power), high-end communications cables, large-volume water supplies, and high-volume gas lines.
To attract new business by providing an integrated infrastructure in one location.
Eligibility of Industrial Parks for benefits.
To set apart industrial uses from urban areas to try to reduce the environmental and social impact of the industrial uses.
To provide for localized environmental controls that are specific to the needs of an industrial area.
== Benchmarking ==
Benchmarking helps to rank industrial parks based on various criteria, including performance, investment, environmental protection, social responsibility, and governance (ESG).
For the manufacturing companies located in industrial parks, the performance of industrial park operators is important, as the costs for infrastructure and services charged by the industrial park operator is a serious factor for the competitiveness of the manufacturing companies.
== Criticism ==
Different industrial parks fulfill these criteria to differing degrees. Many small communities have established industrial parks with only access to a nearby highway, and with only the basic utilities and roadways. Public transportation options may be limited or non-existent.
Industrial parks in developing countries such as Pakistan face a myriad of additional difficulties. This includes the availability of a skilled workforce and the clustering together of radically different industrial sectors (pharmaceuticals and heavy engineering, for example), which often leads to unfavorable outcomes for quality centered industries.
== Variations ==
An industrial park specializing in biotechnology is called a biotechnology industrial park. It may also be known as a bio-industrial park or eco-industrial cluster.
Flatted factories exist in cities like Singapore and Hong Kong, where land is scarce. These are typically similar to flats, but house individual industries instead. Flatted factories have cargo lifts and roads that serve each level, providing access to each factory lot.
== Countries ==
=== India ===
India was one of the first countries in Asia to recognize the effectiveness of the Export Processing Zone (EPZ) model in promoting exports, with Asia's first EPZ set up in Kandla in 1965. In order to overcome the shortcomings experienced on account of the multiplicity of controls and clearances; absence of world-class infrastructure, and an unstable fiscal regime and with a view to attract larger foreign investments in India, the Special Economic Zones (SEZs) Policy was announced in April 2000. A special economic zone (SEZ) is a geographical region that has economic laws that are more liberal than a country's domestic economic laws. India has specific laws for its SEZs. The category 'SEZ' covers a broad range of more specific zone types, including free-trade zones (FTZ), export processing zones (EPZ), free zones (FZ), industrial estates (IE), free ports, urban enterprise zones and others. Usually, the goal of a structure is to increase foreign direct investment by foreign investors, typically an international business or a Multi National Corporation (MNC).
Notable SEZs in India
DGDC SEZ, Surat (SURSEZ)
Dholera SEZ, Gujarat
Divi's Laboratories Limited Chippada Village, Visakhapatnam, Andhra Pradesh Pharmaceuticals
DLF Cyber City, Gurgaon Gurgaon, Haryana IT/ITES
HCL ELCOT SEZ – Sholingnalur, Chennai
HCL IT city, Lucknow, Uttar Pradesh IT & Start-Up
Infosys Technologies SEZ Mangaluru Bengaluru, Karnataka IT/ITES
Jindal Steel and Power, Choudwar
Kandla SEZ, Gandhidham, Gujarat{KASEZ}
POSCO India SEZ, Paradeep
Mundra Port & Special Economic Zone, Multi Product
Maharashtra Industrial Development Corporation Ltd., Pune - IT/ITES
Reliance Jamnagar Infrastructure Ltd. Jamnagar Multi Product
Zydus Infrastructure Pvt. Ltd. Sanand, Ahmedabad Pharmaceutical
Larsen & Toubro Limited's IT/ ITeS SEZ at Surat, Gujarat
Calica Group's "3rd eye voice" IT/ITES SEZ, Ahmedabad
Gallops Engineering SEZ, Moraiyya, Near Changodar, Ahmedabad
Vatva Ahmedabad
Infocity IT Park, IT/ITES, Gandhinagar, Gujarat
GIFT SEZ, GIFT CITY, Gandhinagar, Gujarat
DAHEJ SEZ 1 and 2, Tal Vagra, Bharuch
TCS Garima Park IT/ITES SEZ, Gandhinagar
WIPRO Limited Doddakannelli Village, Varthur Hobli, Electronic City, Bengaluru IT
=== Turkey ===
An organized industrial zone (Turkish: Organize Sanayi Bölgesi) is a kind of special economic zone in Turkey. These zones were legislated for between 2000 and 2007, and may bring together related (OIZs for function) industries or just be a special zone for many industries (mixed OIZs).
Not every industry is allowed to operate in organized industrial zones.
== See also ==
Eco-industrial park
Cyberpark
Energy park
Free trade zone
Industrial district
Industrial railway
Mill town
Megasite
== References ==
== External links == | Wikipedia/Industrial_park |
In molecular biology, the protein domain YTH refers to a member of the YTH family that has been shown to selectively remove transcripts of meiosis-specific genes expressed in mitotic cells. They also play a role in the epitranscriptome as reader proteins for m6A.
This protein domain, the YTH-domain, is conserved across all eukaryotes and suggests that the conserved C-terminal region plays a critical role in relaying the cytosolic Ca-signals to the nucleus, thereby regulating gene expression.
== Function/mechanism ==
It has been speculated that in higher order eukaryotic organisms, YTH-family members may be involved in similar mechanisms to suppress gene regulation during gametogenesis or general silencing. The rat protein YT521-B, SWISSPROT, is a tyrosine-phosphorylated nuclear protein, that interacts with the nuclear transcriptosomal component scaffold attachment factor B, and the 68kDa Src substrate associated during mitosis, Sam68. In vivo splicing assays demonstrated that YT521-B modulates alternative splice site selection in a concentration-dependent manner. Additionally, it is also thought that the YTH domain has a role in RNA binding.
The YTH domain proteins also serve as readers for the N6-methyladenosine (m6A) mRNA modification by scanning the mRNA to find the modified bases. The YTH domain proteins YTHDF1, YTHDF2, and YTHDF3 can bind to modified bases and the surrounding bases. These YTH proteins recognize RRACH sequences (with the A being the modified m6A, R being a purine, and H being an A, C, or U) and use these sequences as binding sites, allowing them to “read” the modification. The YTHDF2 proteins remove the adenylation on the m6A, destabilizing the RNA transcript and preventing translation. The YTHDF1 proteins have the opposite effect and promote the initiation of translation through their interactions with the 40 S ribosomal subunit.
== Structure ==
The domain is predicted to be a mixed alpha/beta-fold containing four alpha helices and six beta strands. Crystallography studies of these YTH domain proteins show that they have a common hydrophobic region that has been proven to participate in the proteins binding to m6A since mutations in this region decrease binding affinity.
== Plant ==
In plant cells environmental stimuli, which light, pathogens, hormones, and abiotic stresses, elicit changes in the cytosolic calcium levels but little is known of the cytosolic-nuclear Ca-signaling pathway; where gene regulation occurs to respond appropriately to the stress. It has been demonstrated that two novel Arabidopsis thaliana (Mouse-ear cress) proteins, (ECT1 and ECT2), specifically associated with Calcineurin B-Like-Interacting Protein Kinase1 (CIPK1), a member of Ser/Thr protein kinases that interact with the calcineurin B-like Ca-binding proteins. These two proteins contain a very similar C-terminal region (180 amino acids in length, 81% similarity), which is required and sufficient for both interaction with CIPK1 and translocation to the nucleus.
== References == | Wikipedia/YTH_protein_domain |
A chromoprotein is a conjugated protein that contains a pigmented prosthetic group (or cofactor). A common example is haemoglobin, which contains a heme cofactor, which is the iron-containing molecule that makes oxygenated blood appear red. Other examples of chromoproteins include other hemochromes, cytochromes, phytochromes and flavoproteins.
In hemoglobin there exists a chromoprotein (tetramer MW:4 x 16.125 =64.500), namely heme, consisting of Fe++ four pyrrol rings.
A single chromoprotein can act as both a phytochrome and a phototropin due to the presence and processing of multiple chromophores. Phytochrome in ferns contains PHY3 which contains an unusual photoreceptor with a dual-channel possessing both phytochrome (red-light sensing) and phototropin (blue-light sensing) and this helps the growth of fern plants at low sunlight.
The GFP protein family includes both fluorescent proteins and non-fluorescent chromoproteins. Through mutagenesis or irradiation, the non-fluorescent chromoproteins can be converted to fluorescent chromoproteins. An example of such converted chromoprotein is "kindling fluorescent proteins" or KFP1 which was converted from a mutated non-fluorescent Anemonia sulcata chromoprotein to a fluorescent chromoprotein.
Sea anemones contain purple chromoprotein shCP with its GFP-like chromophore in the trans-conformation. The chromophore is derived from Glu-63, Tyr-64 and Gly-65 and the phenolic group of Tyr-64 plays a vital role in the formation of a conjugated system with the imidazolidone moiety resulting a high absorbance in the absorption spectrum of chromoprotein in the excited state. The replacement of Tyrosine with other amino acids leads to the alteration of optical and non-planer properties of the chromoprotein. Fluorescent proteins such as anthrozoa chromoproteins emit long wavelengths
14 chromoproteins were engineered to be expressed in E. coli for synthetic biology. However, chromoproteins bring high toxicities to their E. coli hosts, resulting in the loss of colors. mRFP1, the monomeric red fluorescent protein, which also displays distinguishable color under ambient light, was found to be less toxic. Color-changing mutagenesis on amino acids 64–65 of the mRFP1 fluorophore was done to acquire different colors.
Chromoproteins are valuable in synthetic biology, genetic engineering, and biotechnology as visible markers for tracking gene expression, assaying cellular functions and creating colorful biosensors.
== References == | Wikipedia/Chromoprotein |
A domain of unknown function (DUF) is a protein domain that has no characterised function. These families have been collected together in the Pfam database using the prefix DUF followed by a number, with examples being DUF2992 and DUF1220. As of 2019, there are almost 4,000 DUF families within the Pfam database representing over 22% of known families. Some DUFs are not named using the nomenclature due to popular usage but are nevertheless DUFs.
The DUF designation is tentative, and such families tend to be renamed to a more specific name (or merged to an existing domain) after a function is identified.
== History ==
The DUF naming scheme was introduced by Chris Ponting, through the addition of DUF1 and DUF2 to the SMART database. These two domains were found to be widely distributed in bacterial signaling proteins. Subsequently, the functions of these domains were identified and they have since been renamed as the GGDEF domain and EAL domain respectively.
== Characterisation ==
Structural genomics programmes have attempted to understand the function of DUFs through structure determination. The structures of over 250 DUF families have been solved. This (2009) work showed that about two thirds of DUF families had a structure similar to a previously solved one and therefore likely to be divergent members of existing protein superfamilies, whereas about one third possessed a novel protein fold.
Some DUF families share remote sequence homology with domains that has characterized function. Computational work can be used to link these relationships. A 2015 work was able to assign 20% of the DUFs to characterized structural superfamilies. Pfam also continuously perform the (manually-verified) assignment in "clan" superfamily entries.
== Frequency and conservation ==
More than 20% of all protein domains were annotated as DUFs in 2013. About 2,700 DUFs are found in bacteria compared with just over 1,500 in eukaryotes. Over 800 DUFs are shared between bacteria and eukaryotes, and about 300 of these are also present in archaea. A total of 2,786 bacterial Pfam domains even occur in animals, including 320 DUFs.
== Role in biology ==
Many DUFs are highly conserved, indicating an important role in biology. However, many such DUFs are not essential, hence their biological role often remains unknown. For instance, DUF143 is present in most bacteria and eukaryotic genomes. However, when it was deleted in Escherichia coli no obvious phenotype was detected. Later it was shown that the proteins that contain DUF143, are ribosomal silencing factors that block the assembly of the two ribosomal subunits. While this function is not essential, it helps the cells to adapt to low nutrient conditions by shutting down protein biosynthesis. As a result, these proteins and the DUF only become relevant when the cells starve. It is thus believed that many DUFs (or proteins of unknown function, PUFs) are only required under certain conditions.
== Essential DUFs ==
Goodacre et al. identified 238 DUFs in 355 essential proteins (in 16 model bacterial species), most of which represent single-domain proteins, clearly establishing the biological essentiality of DUFs. These DUFs are called "essential DUFs" or eDUFs.
== External links ==
List of Pfam families beginning with the letter D, including DUF families
== References == | Wikipedia/Domain_of_unknown_function |
In biochemistry, globular proteins or spheroproteins are spherical ("globe-like") proteins and are one of the common protein types (the others being fibrous, disordered and membrane proteins). Globular proteins are somewhat water-soluble (forming colloids in water), unlike the fibrous or membrane proteins. There are multiple fold classes of globular proteins, since there are many different architectures that can fold into a roughly spherical shape.
The term globin can refer more specifically to proteins including the globin fold.
== Globular structure and solubility ==
The term globular protein is quite old (dating probably from the 19th century) and is now somewhat archaic given the hundreds of thousands of proteins and more elegant and descriptive structural motif vocabulary. The globular nature of these proteins can be determined without the means of modern techniques, but only by using ultracentrifuges or dynamic light scattering techniques.
The spherical structure is induced by the protein's tertiary structure. The molecule's apolar (hydrophobic) amino acids are bounded towards the molecule's interior whereas polar (hydrophilic) amino acids are bound outwards, allowing dipole–dipole interactions with the solvent, which explains the molecule's solubility.
Globular proteins are only marginally stable because the free energy released when the protein folded into its native conformation is relatively small. This is because protein folding requires entropic cost. As a primary sequence of a polypeptide chain can form numerous conformations, native globular structure restricts its conformation to a few only. It results in a decrease in randomness, although non-covalent interactions such as hydrophobic interactions stabilize the structure.
=== Protein folding ===
Although it is still unknown how proteins fold up naturally, new evidence has helped advance understanding. Part of the protein folding problem is that several non-covalent, weak interactions are formed, such as hydrogen bonds and Van der Waals interactions. Via several techniques, the mechanism of protein folding is currently being studied. Even in the protein's denatured state, it can be folded into the correct structure.
Globular proteins seem to have two mechanisms for protein folding, either the diffusion-collision model or nucleation condensation model, although recent findings have shown globular proteins, such as PTP-BL PDZ2, that fold with characteristic features of both models. These new findings have shown that the transition states of proteins may affect the way they fold. The folding of globular proteins has also recently been connected to treatment of diseases, and anti-cancer ligands have been developed which bind to the folded but not the natural protein. These studies have shown that the folding of globular proteins affects its function.
By the second law of thermodynamics, the free energy difference between unfolded and folded states is contributed by enthalpy and entropy changes. As the free energy difference in a globular protein that results from folding into its native conformation is small, it is marginally stable, thus providing a rapid turnover rate and effective control of protein degradation and synthesis.
== Role ==
Unlike fibrous proteins which only play a structural function, globular proteins can act as:
Enzymes, by catalyzing organic reactions taking place in the organism in mild conditions and with a great specificity. Different esterases fulfill this role.
Messengers, by transmitting messages to regulate biological processes. This function is done by hormones, i.e. insulin etc.
Transporters of other molecules through membranes
Stocks of amino acids.
Regulatory roles are also performed by globular proteins rather than fibrous proteins.
Structural proteins, e.g., actin and tubulin, which are globular and soluble as monomers, but polymerize to form long, stiff fibers
== Members ==
Among the most known globular proteins is hemoglobin, a member of the globin protein family. Other globular proteins are the alpha, beta and gamma (IgA, IgD, IgE, IgG and IgM) globulin. See protein electrophoresis for more information on the different globulins. Nearly all enzymes with major metabolic functions are globular in shape, as well as many signal transduction proteins.
Albumins are also globular proteins, although, unlike all of the other globular proteins, they are completely soluble in water. They are not soluble in oil.
== References == | Wikipedia/Globular_protein |
Phosphoribosylglycinamide formyltransferase (EC 2.1.2.2), also known as glycinamide ribonucleotide transformylase (GAR Tfase), is an enzyme with systematic name 10-formyltetrahydrofolate:5'-phosphoribosylglycinamide N-formyltransferase. This enzyme catalyses the following chemical reaction
10-formyltetrahydrofolate + N1-(5-phospho-D-ribosyl)glycinamide
⇌
{\displaystyle \rightleftharpoons }
tetrahydrofolate + N2-formyl-N1-(5-phospho-D-ribosyl)glycinamide
This tetrahydrofolate (THF)–dependent enzyme catalyzes a nucleophilic acyl substitution of the formyl group from 10-formyltetrahydrofolate (fTHF) to N1-(5-phospho-D-ribosyl)glycinamide (GAR) to form N2-formyl-N1-(5-phospho-D-ribosyl)glycinamide (fGAR) as shown above. This reaction plays an important role in the formation of purine through the de novo purine biosynthesis pathway. This pathway creates inosine monophosphate (IMP), a precursor to adenosine monophosphate (AMP) and guanosine monophosphate (GMP). AMP is a building block for important energy carriers such as ATP, NAD+ and FAD, and signaling molecules such as cAMP. GARTfase's role in de novo purine biosynthesis makes it a target for anti-cancer drugs and its overexpression during postnatal development has been connected to Down syndrome. There are two known types of genes encoding GAR transformylase in Escherichia coli: purN and purT, while only purN is found in humans. Many residues in the active site are conserved across bacterial, yeast, avian and human enzymes.
== Enzyme structure ==
In humans, GARTfase is part of trifunctional enzyme which also includes glycinamide ribonucleotide synthase (GARS) and aminoimidazole ribonucleotide synthetase (AIRS). This protein (110kDa) catalyzes steps 2, 3 and 5 of de novo purine biosynthesis. The proximity of these enzyme units and flexibility of the protein serves to increase pathway throughput. GARTfase is located on the C-terminal end of the protein.
Human GARTfase has been crystallized by vapor-diffusion sitting drop method and imaged at the Stanford Synchrotron Radiation Laboratory (SSRL) by at least two groups.
The structure can be described by two subdomains which are connected by a seven-stranded beta sheet. The N-terminal domain consists of a Rossman type mononucleotide fold, with a four strand part of the beta sheet surrounded on each side by two alpha helices. The beta sheet continues into the C-terminal domain, where on one side it is covered by a long alpha helix and on the other it is partially exposed to solvent. It is the cleft between the two subdomains where the active site lies.
The cleft consists of the GAR binding site and the folate-binding pocket. The folate-binding pocket is delineated by pteridine-binding cleft, the formyl transfer region and the benzoylglutamate region which bind the pteridine head and a benzoylglutamate tail connected by a formyl bound nitrogen of fTHF. This folate-binding region has been the subject of much research because its inhibition by small molecules has led to the discovery of antineoplastic drugs. The folate-binding loop has been shown to change conformation depending on the pH of solution and as such human GAR transformylase shows highest activity around pH 7.5–8. Lower pH (~4.2) conditions change the conformation of the substrate (GAR) binding loops as well.
== Mechanism ==
=== Mechanism of purN GARTfase ===
Klein et al. first suggested a water-molecule-assisted mechanism. A single water molecule possibly held in place by hydrogen bonding with the carboxylate group of the persistent Asp144 residue transfers protons from the GAR-N to the THF-N. The nucleophilic nitrogen on the terminal amino group of GAR attacks the carbonyl carbon of the formyl group on THF pushing negative charge onto the oxygen. Klein suggests that His108 stabilizes the transition state by hydrogen bonding with the negatively charged oxygen and that the reformation of the carbonyl double bond results in breaking the THF-N - formyl bond. Calculations by Qiao et al. suggest that the water assisted stepwise proton transfer from Gar-N to THF-N is 80-100 kj/mol more favorable than the concerted transfer suggested by Klein. The mechanism shown is suggested by Qiao et al., who admittedly did not consider surrounding residues in their calculations. Much of the early active site mapping on GAR TFase was determined with the bacterial enzyme owing to the quantity available from its overexpression in E. coli. Using a bromoacetyl dideazafolate affinity analog James Inglese and colleagues first identified Asp144 as an active site residue likely involved in the formyl transfer mechanism.
=== Mechanism of purT GARTfase ===
Studies of the purT variant of GAR transformylase in E. coli found that the reaction proceeds through a formyl phosphate intermediate. While the in vitro reaction can proceed without THF, overall the in vivo reaction is the same.
== Involvement in de novo purine biosynthesis ==
GART catalyzes the third step in de novo purine biosynthesis, the formation of N2-formyl-N1-(5-phospho-D-ribosyl)glycinamide (fGAR) by formyl addition to N1-(5-phospho-D-ribosyl)glycinamide (GAR). In E. coli, the purN enzyme is a 23 kDa protein but in humans it is part of a trifunctional protein of 110 kDa which includes AIRS and GARS functionalities. This protein catalyzes three different steps of the de novo purine pathway.
== Disease relevance ==
=== Cancer target ===
Due to their increased growth rate and metabolic requirements, cancer cells rely on de novo nucleotide biosynthesis to achieve levels of AMP and GMP necessary. Being able to block any of the steps of the de novo purine pathway would present significant reduction in tumor growth. Studies have been done both on the substrate binding and folate binding site to find inhibitors.
=== Down syndrome ===
GARTfase is suspected to be connected with Down syndrome. The gene encoding the trifunctional protein human GARS-AIRS-GART is located on chromosome 21q22.1, in the Down syndrome critical region. The protein is overexpressed in the cerebellum during the postnatal development of individuals with Down syndrome. Typically, this protein is undetectable in cerebellum shortly after birth, but found in high levels in prenatal development.
== See also ==
Trifunctional purine biosynthetic protein adenosine-3
== References ==
== External links ==
Phosphoribosylglycinamide+formyltransferase at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/GAR_transformylase |
Families of Structurally Similar Proteins or FSSP is a database of structurally superimposed proteins generated using the "Distance-matrix ALIgnment" (DALI) algorithm.The database currently contains an extended structural family for each of 330 representative protein chains. Each data set contains structural alignments of one search structure with all other structurally significantly similar proteins in the representative set (remote homologs, < 30% sequence identity), as well as all structures in the Protein Data Bank with 70-30% sequence identity relative to the search structure (medium homologs). Very close homologs (above 70% sequence identity) are excluded as they rarely have marked structural differences. The alignments of remote homologs are the result of pairwise all-against-all structural comparisons in the set of 330 representative protein chains. All such comparisons are based purely on the 3D co-ordinates of the proteins and are derived by automatic (objective) structure comparison programs. The significance of structural similarity is estimated based on statistical criteria. The FSSP database is available electronically from the EMBL file server and by anonymous ftp (file transfer protocol). The database is helpful for the comparison of protein structures.
== See also ==
CATH
SCOP
== References ==
== External links ==
FSSP Search page at EBI | Wikipedia/Families_of_structurally_similar_proteins |
Phycobiliproteins are water-soluble proteins present in cyanobacteria and certain algae (rhodophytes, cryptomonads, glaucocystophytes). They capture light energy, which is then passed on to chlorophylls during photosynthesis. Phycobiliproteins are formed of a complex between proteins and covalently bound phycobilins that act as chromophores (the light-capturing part). They are most important constituents of the phycobilisomes.
== Major phycobiliproteins ==
== Characteristics ==
Phycobiliproteins demonstrate superior fluorescent properties compared to small organic fluorophores, especially when high sensitivity or multicolor detection required :
Broad and high absorption of light suits many light sources
Very intense emission of light: 10-20 times brighter than small organic fluorophores
Relative large Stokes shift gives low background, and allows multicolor detections.
Excitation and emission spectra do not overlap compared to conventional organic dyes.
Can be used in tandem (simultaneous use by FRET) with conventional chromophores (i.e. PE and FITC, or APC and SR101 with the same light source).
Longer fluorescence retention period.
High water solubility
== Applications ==
Phycobiliproteins allow very high detection sensitivity, and can be used in various fluorescence based techniques fluorimetric microplate assays Archived 2018-03-18 at the Wayback Machine, FISH and multicolor detection.
They are under development for use in artificial photosynthesis, limited by the relatively low conversion efficiency of 4-5%.
== References == | Wikipedia/Phycobiliprotein |
A protein family is a group of evolutionarily related proteins. In many cases, a protein family has a corresponding gene family, in which each gene encodes a corresponding protein with a 1:1 relationship. The term "protein family" should not be confused with family as it is used in taxonomy.
Proteins in a family descend from a common ancestor and typically have similar three-dimensional structures, functions, and significant sequence similarity. Sequence similarity (usually amino-acid sequence) is one of the most common indicators of homology, or common evolutionary ancestry. Some frameworks for evaluating the significance of similarity between sequences use sequence alignment methods. Proteins that do not share a common ancestor are unlikely to show statistically significant sequence similarity, making sequence alignment a powerful tool for identifying the members of protein families. Families are sometimes grouped together into larger clades called superfamilies based on structural similarity, even if there is no identifiable sequence homology.
Currently, over 60,000 protein families have been defined, although ambiguity in the definition of "protein family" leads different researchers to highly varying numbers.
== Terminology and usage ==
The term protein family has broad usage and can be applied to large groups of proteins with barely detectable sequence similarity as well as narrow groups of proteins with near identical sequence, function, and structure. To distinguish between these cases, a hierarchical terminology is in use. At the highest level of classification are protein superfamilies, which group distantly related proteins, often based on their structural similarity. Next are protein families, which refer to proteins with a shared evolutionary origin exhibited by significant sequence similarity. Subfamilies can be defined within families to denote closely related proteins that have similar or identical functions. For example, a superfamily like the PA clan of proteases has less sequence conservation than the C04 family within it.
== Protein domains and motifs ==
Protein families were first recognised when most proteins that were structurally understood were small, single-domain proteins such as myoglobin, hemoglobin, and cytochrome c. Since then, many proteins have been found with multiple independent structural and functional units called domains. Due to evolutionary shuffling, different domains in a protein have evolved independently. This has led to a focus on families of protein domains. Several online resources are devoted to identifying and cataloging these domains.
Different regions of a protein have differing functional constraints. For example, the active site of an enzyme requires certain amino-acid residues to be precisely oriented. A protein–protein binding interface may consist of a large surface with constraints on the hydrophobicity or polarity of the amino-acid residues. Functionally constrained regions of proteins evolve more slowly than unconstrained regions such as surface loops, giving rise to blocks of conserved sequence when the sequences of a protein family are compared (see multiple sequence alignment). These blocks are most commonly referred to as motifs, although many other terms are used (blocks, signatures, fingerprints, etc.). Several online resources are devoted to identifying and cataloging protein motifs.
== Evolution of protein families ==
According to current consensus, protein families arise in two ways. First, the separation of a parent species into two genetically isolated descendant species allows a gene/protein to independently accumulate variations (mutations) in these two lineages. This results in a family of orthologous proteins, usually with conserved sequence motifs. Second, a gene duplication may create a second copy of a gene (termed a paralog). Because the original gene is still able to perform its function, the duplicated gene is free to diverge and may acquire new functions (by random mutation).
Certain gene/protein families, especially in eukaryotes, undergo extreme expansions and contractions in the course of evolution, sometimes in concert with whole genome duplications. Expansions are less likely, and losses more likely, for intrinsically disordered proteins and for protein domains whose hydrophobic amino acids are further from the optimal degree of dispersion along the primary sequence. This expansion and contraction of protein families is one of the salient features of genome evolution, but its importance and ramifications are currently unclear.
== Use and importance of protein families ==
As the total number of sequenced proteins increases and interest expands in proteome analysis, an effort is ongoing to organize proteins into families and to describe their component domains and motifs. Reliable identification of protein families is critical to phylogenetic analysis, functional annotation, and the exploration of the diversity of protein function in a given phylogenetic branch. The Enzyme Function Initiative uses protein families and superfamilies as the basis for development of a sequence/structure-based strategy for large scale functional assignment of enzymes of unknown function. The algorithmic means for establishing protein families on a large scale are based on a notion of similarity.
== Protein family resources ==
Many biological databases catalog protein families and allow users to match query sequences to known families. These include:
Pfam - Protein families database of alignments and HMMs
PROSITE - Database of protein domains, families and functional sites
PIRSF - SuperFamily Classification System
PASS2 - Protein Alignment as Structural Superfamilies v2 - PASS2@NCBS
SUPERFAMILY - Library of HMMs representing superfamilies and database of (superfamily and family) annotations for all completely sequenced organisms
SCOP and CATH - Classifications of protein structures into superfamilies, families and domains
Similarly, many database-searching algorithms exist, for example:
BLAST - DNA sequence similarity search
BLASTp - Protein sequence similarity search
OrthoFinder - Method for clustering proteins into families (orthogroups)
== See also ==
=== Protein families ===
== References ==
== External links ==
Media related to Protein families at Wikimedia Commons | Wikipedia/Protein_families |
Protein subfamily is a level of protein classification, based on their close evolutionary relationship. It is below the larger levels of protein superfamily and protein family.
Proteins typically share greater sequence and function similarities with other subfamily members than they do with members of their wider family. For example, in the Structural Classification of Proteins database classification system, members of a subfamily share the same interaction interfaces and interaction partners. These are stricter criteria than for a family, where members have similar structures, but may be more distantly related and so have different interfaces. Subfamilies are assigned by a variety of methods, including sequence similarity, motifs linked to function, or phylogenetic clade. There is no exact and consistent distinction between a subfamily and a family. The same group of proteins may sometimes be described as a family or a subfamily, depending on the context.
== References ==
== External links ==
SCOP DB at Cambridge UK
CATH protein structure DB | Wikipedia/Protein_subfamily |
The Structural Classification of Proteins (SCOP) database is a largely manual classification of protein structural domains based on similarities of their structures and amino acid sequences. A motivation for this classification is to determine the evolutionary relationship between proteins. Proteins with the same shapes but having little sequence or functional similarity are placed in different superfamilies, and are assumed to have only a very distant common ancestor. Proteins having the same shape and some similarity of sequence and/or function are placed in "families", and are assumed to have a closer common ancestor.
Similar to CATH and Pfam databases, SCOP provides a classification of individual structural domains of proteins, rather than a classification of the entire proteins which may include a significant number of different domains.
The SCOP database is freely accessible on the internet. SCOP was created in 1994 in the Centre for Protein Engineering and the Laboratory of Molecular Biology. It was maintained by Alexey G. Murzin and his colleagues in the Centre for Protein Engineering until its closure in 2010 and subsequently at the Laboratory of Molecular Biology in Cambridge, England.
The work on SCOP 1.75 has been discontinued in 2014. Since then SCOPe team from UC Berkeley has been responsible for updating the database in a compatible manner, with a combination of automated and manual methods. As of April 2019, the latest release is SCOPe 2.07 (March 2018).
The new Structural Classification of Proteins version 2 (SCOP2) database was released at the beginning of 2020. The new update featured an improved database schema, a new API and modernised web interface. This was the most significant update by the Cambridge group since SCOP 1.75 and builds on the advances in schema from the SCOP 2 prototype.
== Hierarchical organisation ==
The source of protein structures is the Protein Data Bank. The unit of classification of structure in SCOP is the protein domain. What the SCOP authors mean by "domain" is suggested by their statement that small proteins and most medium-sized ones have just one domain, and by the observation that human hemoglobin, which has an α2β2 structure, is assigned two SCOP domains, one for the α and one for the β subunit.
The shapes of domains are called "folds" in SCOP. Domains belonging to the same fold have the same major secondary structures in the same arrangement with the same topological connections. 1195 folds are given in SCOP version 1.75. Short descriptions of each fold are given. For example, the "globin-like" fold is described as core: 6 helices; folded leaf, partly opened. The fold to which a domain belongs is determined by inspection, rather than by software.
The levels of SCOP version 1.75 are as follows.
Class: Types of folds, e.g., beta sheets.
Fold: The different shapes of domains within a class.
Superfamily: The domains in a fold are grouped into superfamilies, which have at least a distant common ancestor.
Family: The domains in a superfamily are grouped into families, which have a more recent common ancestor.
Protein domain: The domains in families are grouped into protein domains, which are essentially the same protein.
Species: The domains in "protein domains" are grouped according to species.
Domain: part of a protein. For simple proteins, it can be the entire protein.
=== Classes ===
The broadest groups on SCOP version 1.75 are the protein fold classes. These classes group structures with similar secondary structure composition, but different overall tertiary structures and evolutionarily origins. This is the top level "root" of the SCOP hierarchical classification.
All alpha proteins [46456] (284): Domains consisting of α-helices
All beta proteins [48724] (174): Domains consisting of β-sheets
Alpha and beta proteins (a/b) [51349] (147): Mainly parallel beta sheets (beta-alpha-beta units)
Alpha and beta proteins (a+b) [53931] (376): Mainly antiparallel beta sheets (segregated alpha and beta regions)
Multi-domain proteins (alpha and beta) [56572] (66): Folds consisting of two or more domains belonging to different classes
membrane and cell surface proteins and peptides [56835] (58): Does not include proteins in the immune system
Small proteins [56992] (90): Usually dominated by metal ligand, cofactor, and/or disulfide bridges
coiled-coil proteins [57942] (7): Not a true class
Low resolution protein structures [58117] (26): Peptides and fragments. Not a true class
Peptides [58231] (121): peptides and fragments. Not a true class.
Designed proteins [58788] (44): Experimental structures of proteins with essentially non-natural sequences. Not a true class
The number in brackets, called a "sunid", is a SCOP unique integer identifier for each node in the SCOP hierarchy. The number in parentheses indicates how many elements are in each category. For example, there are 284 folds in the "All alpha proteins" class. Each member of the hierarchy is a link to the next level of the hierarchy.
=== Folds ===
Each class contains a number of distinct folds. This classification level indicates similar tertiary structure, but not necessarily evolutionary relatedness. For example, the "All-α proteins" class contains >280 distinct folds, including: Globin-like (core: 6 helices; folded leaf, partly opened), long alpha-hairpin (2 helices; antiparallel hairpin, left-handed twist) and Type I dockerin domains (tandem repeat of two calcium-binding loop-helix motifs, distinct from the EF-hand).
=== Superfamilies ===
Domains within a fold are further classified into superfamilies. This is a largest grouping of proteins for which structural similarity is sufficient to indicate evolutionary relatedness and therefore share a common ancestor. However, this ancestor is presumed to be distant, because the different members of a superfamily have low sequence identities. For example, the two superfamilies of the "Globin-like" fold are: the Globin superfamily and alpha-helical ferredoxin superfamily (contains two Fe4-S4 clusters).
=== Families ===
Protein families are more closely related than superfamilies. Domains are placed in the same family if that have either:
>30% sequence identity
some sequence identity (e.g., 15%) and perform the same function
The similarity in sequence and structure is evidence that these proteins have a closer evolutionary relationship than do proteins in the same superfamily. Sequence tools, such as BLAST, are used to assist in placing domains into superfamilies and families. For example, the four families in the "globin-like" superfamily of the "globin-like" fold are truncated hemoglobin (lack the first helix), nerve tissue mini-hemoglobin (lack the first helix but otherwise is more similar to conventional globins than the truncated ones), globins (Heme-binding protein), and phycocyanin-like phycobilisome proteins (oligomers of two different types of globin-like subunits containing two extra helices at the N-terminus binds a bilin chromophore). Families in SCOP are each assigned a concise classification string, sccs, where the letter identifies the class to which the domain belongs; the following integers identify the fold, superfamily, and family, respectively (e.g., a.1.1.2 for the "Globin" family).
=== PDB entry domains ===
A "TaxId" is the taxonomy ID number and links to the NCBI taxonomy browser, which provides more information about the species to which the protein belongs. Clicking on a species or isoform brings up a list of domains. For example, the "Hemoglobin, alpha-chain from Human (Homo sapiens)" protein has >190 solved protein structures, such as 2dn3 (complexed with cmo), and 2dn1 (complexed with hem, mbn, oxy). Clicking on the PDB numbers is supposed to display the structure of the molecule, but the links are currently broken (links work in pre-SCOP).
== Example ==
Most pages in SCOP contain a search box. Entering "trypsin +human" retrieves several proteins, including the protein trypsinogen from humans. Selecting that entry displays a page that includes the "lineage", which is at the top of most SCOP pages.
Human trypsonogen lineage
Root: scop
Class: All beta proteins [48724]
Fold: Trypsin-like serine proteases [50493]
barrel, closed; n=6, S=8; greek-key
duplication: consists of two domains of the same fold
Superfamily: Trypsin-like serine proteases [50494]
Family: Eukaryotic proteases [50514]
Protein: Trypsin(ogen) [50515]
Species: Human (Homo sapiens) [TaxId: 9606] [50519]
Searching for "Subtilisin" returns the protein, "Subtilisin from Bacillus subtilis, carlsberg", with the following lineage.
Subtilisin from Bacillus subtilis, carlsberg lineage
Root: scop
Class: Alpha and beta proteins (a/b) [51349]
Mainly parallel beta sheets (beta-alpha-beta units)
Fold: Subtilisin-like [52742]
3 layers: a/b/a, parallel beta-sheet of 7 strands, order 2314567; left-handed crossover connection between strands 2 & 3
Superfamily: Subtilisin-like [52743]
Family: Subtilases [52744]
Protein: Subtilisin [52745]
Species: Bacillus subtilis, carlsberg [TaxId: 1423] [52746]
Although both of these proteins are proteases, they do not even belong to the same fold, which is consistent with them being an example of convergent evolution.
== Comparison to other classification systems ==
SCOP classification is more dependent on manual decisions than the semi-automatic classification by CATH, its chief rival. Human expertise is used to decide whether certain proteins are evolutionary related and therefore should be assigned to the same superfamily, or their similarity is a result of structural constraints and therefore they belong to the same fold. Another database, FSSP, is purely automatically generated (including regular automatic updates) but offers no classification, allowing the user to draw their own conclusion as to the significance of structural relationships based on the pairwise comparisons of individual protein structures.
=== SCOP successors ===
By 2009, the original SCOP database manually classified 38,000 PDB entries into a strictly hierarchical structure. With the accelerating pace of protein structure publications, the limited automation of classification could not keep up, leading to a non-comprehensive dataset. The Structural Classification of Proteins extended (SCOPe) database was released in 2012 with far greater automation of the same hierarchical system and is full backwards compatible with SCOP version 1.75. In 2014, manual curation was reintroduced into SCOPe to maintain accurate structure assignment. As of February 2015, SCOPe 2.05 classified 71,000 of the 110,000 total PDB entries.
SCOP2 prototype was a beta version of Structural classification of proteins and classification system that aimed to more the evolutionary complexity inherent in protein structure evolution.
It is therefore not a simple hierarchy, but a directed acyclic graph network connecting protein superfamilies representing structural and evolutionary relationships such as circular permutations, domain fusion and domain decay. Consequently, domains are not separated by strict fixed boundaries, but rather are defined by their relationships to the most similar other structures. The prototype was used for the development of the SCOP version 2 database. The SCOP version 2, release January 2020, contains 5134 families and 2485 superfamilies compared to 3902 families and 1962 superfamilies in SCOP 1.75. The classification levels organise more than 41 000 non-redundant domains that represent more than 504 000 protein structures.
The Evolutionary Classification of Protein Domains (ECOD) database released in 2014 is a similar to SCOPe expansion of SCOP version 1.75. Unlike the compatible SCOPe, it renames the class-fold-superfamily-family hierarchy into an architecture-X-homology-topology-family (A-XHTF) grouping, with the last level mostly defined by Pfam and supplemented by HHsearch clustering for uncategorized sequences. ECOD has the best PDB coverage of all three successors: it covers every PDB structure, and is updated biweekly. The direct mapping to Pfam has proven useful to Pfam curators who use the homology-level category to supplement their "clan" grouping.
== See also ==
Structural alignment
CATH
FSSP
SUPERFAMILY
Pfam
== References ==
== External links ==
Structural Classification of Proteins (SCOP 2) - Manual classification of representative domains, regularly updated by the SCOP authors
Structural Classification of Proteins (SCOP 1.75) - Legacy SCOP 1.75 site, no longer updated
Structural Classification of Proteins extended (SCOPe) - The more automated successor of SCOP version 1.75
Evolutionary Classification of Protein Domains (ECOD) - Evolutionary classification based on SCOP version 1.75 and Pfam
Structural Classification of Proteins 2 (SCOP2 prototype) - Legacy site of the SCOP 2 prototype, no longer updated
SUPERFAMILY - Library of HMMs representing SCOP superfamilies and database of (superfamily and family) annotations for all completely sequenced organisms
Protein Structure Classification - a book chapter that discusses different protein classifications in detail. | Wikipedia/Structural_Classification_of_Proteins_database |
Photoreceptor proteins are light-sensitive proteins involved in the sensing and response to light in a variety of organisms. Some examples are rhodopsin in the photoreceptor cells of the vertebrate retina, phytochrome in plants, and bacteriorhodopsin and bacteriophytochromes in some bacteria. They mediate light responses as varied as visual perception, phototropism and phototaxis, as well as responses to light-dark cycles such as circadian rhythm and other photoperiodisms including control of flowering times in plants and mating seasons in animals.
== Structure ==
Photoreceptor proteins typically consist of a protein attached to a non-protein chromophore (sometimes referred as photopigment, even so photopigment may also refer to the photoreceptor as a whole). The chromophore reacts to light via photoisomerization or photoreduction, thus initiating a change of the receptor protein which triggers a signal transduction cascade. Chromophores found in photoreceptors include retinal (retinylidene proteins, for example rhodopsin in animals), flavin (flavoproteins, for example cryptochrome in plants and animals) and bilin (biliproteins, for example phytochrome in plants). The plant protein UVR8 is exceptional amongst photoreceptors in that it contains no external chromophore. Instead, UVR8 absorbs light through tryptophan residues within its protein coding sequence.
== Photoreceptors in animals ==
Melanopsin: in vertebrate retina, mediates pupillary reflex, involved in regulation of circadian rhythms
Photopsin: reception of various colors of light in the cone cells of vertebrate retina
Rhodopsin: green-blue light reception in the rod cells of vertebrate retina
Protein Kinase C: mediates photoreceptor deactivation, and retinal degeneration
OPN5: sensitive to UV-light
== Photoreceptors in plants ==
UVR8: UV-B light reception
Cryptochrome: blue and UV-A light reception
Phototropin: blue and UV-A light perception (to mediate phototropism and chloroplast movement)
Zeitlupe: blue light entrainment of the circadian clock
Phytochrome: red and far-red light reception
All the photoreceptors listed above allow plants to sense light with wavelengths range from 280 nm (UV-B) to 750 nm (far-red light). Plants use light of different wavelengths as environmental cues to both alter their position and to trigger important developmental transitions. The most prominent wavelength responsible for plant mechanisms is blue light, which can trigger cell elongation, plant orientation, and flowering. One of the most important processes regulated by photoreceptors is known as photomorphogenesis. When a seed germinates underground in the absence of light, its stem rapidly elongates upwards. When it breaks through the surface of the soil, photoreceptors perceive light. The activated photoreceptors cause a change in developmental program; the plant starts producing chlorophyll and switches to photosynthetic growth.
== Photoreceptors in phototactic flagellates ==
(Also see: Eyespot apparatus)
Channelrhodopsin: in unicellular algae, mediates phototaxis
Chlamyopsin and volvoxopsin
Flavoproteins
== Photoreceptors in archaea and bacteria ==
Bacteriophytochrome
sensory bacteriorhodopsin
Halorhodopsin
Proteorhodopsin
Cyanobacteriochrome
== Photoreception and signal transduction ==
Visual cycle
Visual phototransduction
== Responses to photoreception ==
Visual perception
Phototropism
Phototaxis
Circadian rhythm (body clock)
Photoperiodism
== See also ==
Biliproteins
Photomolecular biology
== References == | Wikipedia/Photoreceptor_protein |
Biliproteins are pigment protein compounds that are located in photosynthesising organisms such as algae, and sometimes also in certain insects. They refer to any protein that contains a bilin chromophore. In plants and algae, the main function of biliproteins is to make the process of light accumulation required for photosynthesis more efficient; while in insects they play a role in growth and development. Some of their properties: including light-receptivity, light-harvesting and fluorescence have made them suitable for applications in bioimaging and as indicators; while other properties such as anti-oxidation, anti-aging and anti-inflammation in phycobiliproteins have given them potential for use in medicine, cosmetics and food technology. While research on biliproteins dates back as far as 1950, it was hindered due to issues regarding biliprotein structure, lack of methods available for isolating individual biliprotein components, as well as limited information on lyase reactions (which are needed to join proteins with their chromophores). Research on biliproteins has also been primarily focused on phycobiliproteins; but advances in technology and methodology, along with the discovery of different types of lyases, has renewed interest in biliprotein research, allowing new opportunities for investigating biliprotein processes such as assembly/disassembly and protein folding.
== Functions ==
=== In plants and algae ===
Biliproteins found in plants and algae serve as a system of pigments whose purpose is to detect and absorb light needed for photosynthesis. The absorption spectra of biliproteins complements that of other photosynthetic pigments such as chlorophyll or carotene. The pigments detect and absorb energy from sunlight; the energy later being transferred to chlorophyll via internal energy transfer. According to a 2002 article written by Takashi Hirata et al., the chromophores of certain phycobiliproteins are responsible for antioxidant activities in these biliproteins, and phycocyanin also possesses anti-inflammatory qualities due to its inhibitory apoprotein. When induced by both collagen and adenosine triphosphate (ADP), the chromophore phycocyanobilin suppresses platelet aggregation in phycocyanin, its corresponding phycobiliprotein.
=== In insects ===
In insects, biliprotein lipocalins generally function to facilitate the changing of colours during camouflage, but other roles of biliproteins in insects have also been found. Functions such as preventing cellular damage, regulating guanylyl cyclase with biliverdin, among other roles associated with metabolic maintenance, have been hypothesised but yet to be proven. In the tobacco hornworm, the biliprotein insecticyanin (INS) was found to play a crucial part in embryonic development, as the absorption of INS into the moth eggs was observed.
== Structure ==
The structure of biliproteins is typically characterised by bilin chromophores arranged in linear tetrapyrrolic formation, and the bilins are covalently bound to apoproteins via thioether bonds. Each type of biliprotein has a unique bilin that belongs to it (e.g. phycoerythrobilin is the chromophore of phycoerythrin and phycocyanobilin is the chromophore of phycocyanin). The bilin chromophores are formed by the oxidative cleavage of a haem ring and catalysed by haem oxygenases at one of four methine bridges, allowing four possible bilin isomers to occur. In all organisms known to have biliproteins, cleavage usually occurs at the α-bridge, generating biliverdin IXα.
Phycobiliproteins are grouped together in separate clusters, approximately 40nm in diameter, known as phycobilisomes. The structural changes involved in deriving bilins from their biliverdin IXα isomer determine the spectral range of light absorption.
The structure of biliproteins in insects differ slightly than those in plants and algae; they have a crystal structure and their chromophores are not covalently bound to the apoproteins. Unlike phycobiliproteins whose chromophores are held in an extended arrangement by specific interactions between chromophores and proteins, the chromophore in insect biliproteins has a cyclic helical crystal structure in the protein-bound state, as found in studies of the biliprotein extracted from the large white butterfly.
== Classes of biliproteins ==
=== Phycobiliproteins ===
Phycobiliproteins are found in cyanobacteria (also known as blue-green algae) and algae groups such as rhodophyta (red algae) and cryptophytes. Major phycobiliproteins include variations of phycocyanin (blue-pigment), variations of phycoerythrin (red pigment), and allophycocyanin (light-blue pigment); each of them possessing different spectral properties. These water-soluble biliproteins are not essential for the functioning of cells. Some special qualities of phycobiliproteins include antioxidant properties and high fluorescence, and it is their chromophores that give these proteins their strong pigment. Phycobiliproteins are classified into two categories based on their amino-terminal sequences: "α-type" and "β-type" sequences. In biliproteins where the number of bilins on the two subunits is unequal, the subunit with more bilins has a β-type amino sequence.
==== Phycochromes ====
Phycochromes are a subclass of phycobiliprotein that was initially recognised only as light sensory pigments in cyanobacteria. They are now deemed to constitute of all possible photoreversibly photochromic pigments, regardless of function. They are also found in red algae. In a series of journal articles written by G.S. and L.O. Björn, it was reported that phycochromes a, b, c and d were discovered by scientists who fractionated samples of blue-green algae using electrofocusing. The fractions with isoelectric points at or around 4.6 seemed analogous to phytochromes in that they possessed photochromic properties, yet were sensitive to light of shorter wavelengths. All four phycochromes except phycochrome c were extracted from the blue-green algae Tolypothrix distorta; whereas phycochrome a was also found in Phormidium luridum, Nostoc muscorum 1453/12 and Anacystis nidulans; and phycochrome c was extracted from Nostoc muscorum A and Tolypothrix tenuis.
=== Phytochromes ===
Phytochromes (also known as phys) were initially discovered in green plants in 1945. The photoreversible pigment was later found in fungi, mosses, and other algae groups due to the development of whole-genome sequencing, as explained in Peter H. Quail's 2010 journal article Phytochromes. As described in Hugo Scheer's 1981 journal article Biliproteins, phytochromes function as a sensor of light intensity in ‘high-energy’ reactions, i.e. in higher plants (e.g. underground seedlings), during transformation of heterotrophic blanching growth to autotrophic photosynthetic growth. They carry out this function by monitoring the various parameters of light signals (such as presence/absence, colour, intensity and photoperiodicity). This information is then transduced via intracellular signaling pathways that trigger responses specific to the organism and its development state on both cellular and molecular levels, as explained by Quail. Phytochromes are also responsible for regulating many aspects of a plant's growth, development and reproduction throughout its lifecycle.
=== Lipocalins (Insect biliproteins) ===
The lipocalins that have been identified as biliproteins have been found in a wide variety of insects, but mainly in the order Lepidoptera. Scientists have discovered them in the large white butterfly and a number of moth and silkmoth species, including the ailanthus and domestic silkmoths, giant silkworm moth, tobacco hawk moth, honeycomb moth, and the puss moth. The biliproteins associated with these insect species are the bilin-binding proteins, biliverdin-binding proteins, bombyrin, lipocalins 1 and 4, insecticyanin, gallerin and CV-bilin respectively. The biliproteins found in the tobacco hawk moth and pussmoth make up a major part of the insects’ haemolymph fluids.
The biliproteins that have been found in other insect orders apart from Lepidoptera still have unknown sequences, and so their lipocalin nature is still open.
== Comparison of biliproteins from different organisms ==
In a 1988 study conducted by Hugo Scheer and Harmut Kayser, biliproteins were extracted from the large white butterfly and puss moth and their respective properties were examined. Their properties were compared to those of plant and algae biliproteins, and their distinguishing features were taken into account.
Unlile plant and algae biliproteins whose bilins are generally only derived from the IXα biliverdin isomer, the bilins of insect biliproteins are also derived from the IXγ isomer, which is almost exclusively found in Lepidoptera. The study cited from M. Bois-Choussy and M. Barbier that these IXγ-series bile pigments are derived from cleavage of the porphyrin precursors at the C-15 (formerly γ) methine bridge, which is uncharacteristic of other mammalian and plant biliproteins. When the scientists examined biliproteins from both the large white butterfly and puss moth, they found that their polypeptides had a low α-helix content in comparison to phycobiliproteins.
It was hypothesised that the role of biliproteins in insects would also have a role related to light-absorption similar to that in plant and algae biliproteins. However, when the photochemical properties required for light-absorption were found absent in the biliprotein of the large white butterfly, this hypothesis was eliminated, followed by the assumption that those photochemical properties also do not occur in any other insect biliproteins.
Based on these examinations, it was concluded that insect biliproteins are only loosely related to those from plants and algae, due to the large number of differences they have regarding structure, chemical composition, derivation of bilins and general functions.
== Applications ==
=== Bioimaging ===
Fluorescent proteins have had a substantial impact on bioimaging, which is why biliproteins have made suitable candidates for the application, due to their properties of fluorescence, light-harvesting, light-sensitivity and photoswitching (the latter occurring only in phytochromes). Phycobiliproteins, which are highly fluorescent, have been used in external applications of bioimaging since the early 1980s. That application requires the bilin chromophore to be synthesised from haem, after which a lyase is needed to covalently bond the bilin to its corresponding apoprotein. An alternative method of uses phytochromes instead; some phytochromes only require one enzyme, haem oxygenase, for synthesising chromophores. Another benefit of using phytochromes is that they bind to their bilins autocatalytically. While there are photochromic pigments with poor fluorescence, this problem has been alleviated by engineering protein variants that reduce photochemistry and enhance fluorescence.
=== Food, medicine and cosmetics ===
Properties of phycobiliproteins, such as their natural antioxidant, anti-inflammatory, food colourant, strong pigment and anti-aging activities, have given them considerable potential for use in food, cosmetics and medicinal applications. They have also proven to be therapeutic in treating diseases such as Alzheimer's disease and cancer. Given their large range of applications and potential uses, researchers have been trying to find and develop ways to produce and purify phycobiliproteins to meet the growing demand for them. One such phycobiliprotein is C-phycocyanin (C-PC), which is found in spirulina. A limiting factor of C-PC's usage in these applications is its protein stability, given that in its natural form, C-PC is highly sensitive to light and heat when in aqueous solution, due to its photosensitive phycocyanobilin (PCB) chromophore, which also makes it prone to free-radical oxidation. Like other natural food colourants, C-PC is also sensitive to acidic conditions and oxidant exposure. This has prompted studies to develop methods of stabilising C-PC/PCB and expand their applications to other food systems.
More details on the applications of phycocyanin in food and medicine can be found here.
=== Indicator of drinking water quality ===
The fluorescence signals emitted from phycoerythrin and phycocyanin have made them suitable for use as indicators to detect cyanotoxins such as microcystins in drinking water. A study examined the nature of the biliproteins' fluorescence signals regarding their real-time character, sensitivity and the biliproteins' behaviour in different treatment stages (of water) in comparison to microcystins. The fluorescence signals' real-time character was confirmed by fluorescence measurements, as they can be carried out without having to pre-concentrate the biliproteins. If the ratio of biliprotein to microcystin is above 1, the fluorescence signals can estimate very low concentrations of microcystins. A test conducted in 2009 compared the behaviour of both biliproteins and selected microcystins MC-LR and MC-RR during water treatment. The test results showed that the biliproteins have an early warning function against microcystins in conventional treatment stages that use pre-oxidation with permanganate, activated carbon and chlorination. However, the early warning function does not occur when chlorine dioxide is used as a pre-oxidant or final disinfectant. It is important for the biliprotein/toxin ratio of raw water to be known in order to use the biliproteins for control measurements in drinking water treatment.
== See also ==
Chromoproteins
Photoreceptor protein
== References ==
== Further reading ==
Björn, G. S.; Björn, L. O. (1976). "Photochromic Pigments from Blue-Green Algae: Phycochromes a, b, and C". Physiologia Plantarum. 36 (4): 297–304. Bibcode:1976PPlan..36..297B. doi:10.1111/j.1399-3054.1976.tb02246.x..
Björn, G. S. (1978). "Phycochrome d, a New Photochromic Pigment from the Blue-Green Alga, Tolypothrix distorta". Physiologia Plantarum. 42 (3): 321–323. Bibcode:1978PPlan..42..321B. doi:10.1111/j.1399-3054.1978.tb04089.x..
Shropshire, W. & Mohr, H. (1983). Photomorphogenesis (1st ed.). Berlin, Heidelberg: Springer. ISBN 978-3-642-68918-5.
Scheer, Hugo; Yang, Xiaojing; Zhao, Kai-Hong (2015). "Biliproteins and their Applications in Bioimaging". Procedia Chemistry. 14: 176–185. doi:10.1016/j.proche.2015.03.026.
Stanic-Vucinic, D.; Minic, S.; Nikolic, M. R.; Velickovic, T. C. (2018). "7. Spirulina Phycobiliproteins as Food Components and Complements". In Jacob-Lopes, Eduardo (ed.). Microalgal Biotechnology. Norderstedt, Germany: Books on Demand. pp. 129–148. ISBN 978-1-78923-333-9.
Moldaenke, Christian; Imhof, Lutz; Bornmann, Katrin; Petzoldt, Heike; Schmidt, Wido (2009). "Use of cyanopigment determination as an indicator of cyanotoxins in drinking water". Water Science and Technology. 59 (8): 1531–1540. Bibcode:2009WSTec..59.1531S. doi:10.2166/wst.2009.448. PMID 19403966. | Wikipedia/Biliprotein |
Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the cell. Proteins can be targeted to the inner space of an organelle, different intracellular membranes, the plasma membrane, or to the exterior of the cell via secretion. Information contained in the protein itself directs this delivery process. Correct sorting is crucial for the cell; errors or dysfunction in sorting have been linked to multiple diseases.
== History ==
In 1970, Günter Blobel conducted experiments on protein translocation across membranes. Blobel, then an assistant professor at Rockefeller University, built upon the work of his colleague George Palade. Palade had previously demonstrated that non-secreted proteins were translated by free ribosomes in the cytosol, while secreted proteins (and target proteins, in general) were translated by ribosomes bound to the endoplasmic reticulum (ER). Candidate explanations at the time postulated a processing difference between free and ER-bound ribosomes, but Blobel hypothesized that protein targeting relied on characteristics inherent to the proteins, rather than a difference in ribosomes. Supporting his hypothesis, Blobel discovered that many proteins have a short amino acid sequence at one end that functions like a postal code specifying an intracellular or extracellular destination. He described these short sequences (generally 13 to 36 amino acids residues) as signal peptides or signal sequences and was awarded the 1999 Nobel prize in Physiology for the same.
== Signal peptides ==
Signal peptides serve as targeting signals, enabling cellular transport machinery to direct proteins to specific intracellular or extracellular locations. While no consensus sequence has been identified for signal peptides, many nonetheless possess a characteristic tripartite structure:
A positively charged, hydrophilic region near the N-terminal.
A span of 10 to 15 hydrophobic amino acids near the middle of the signal peptide.
A slightly polar region near the C-terminal, typically favoring amino acids with smaller side chains at positions approaching the cleavage site.
After a protein has reached its destination, the signal peptide is generally cleaved by a signal peptidase. Consequently, most mature proteins do not contain signal peptides. While most signal peptides are found at the N-terminal, in peroxisomes the targeting sequence is located on the C-terminal extension. Unlike signal peptides, signal patches are composed by amino acid residues that are discontinuous in the primary sequence but become functional when folding brings them together on the protein surface. Unlike most signal sequences, signal patches are not cleaved after sorting is complete. In addition to intrinsic signaling sequences, protein modifications like glycosylation can also induce targeting to specific intracellular or extracellular regions.
== Protein translocation ==
Since the translation of mRNA into protein by a ribosome takes place within the cytosol, proteins destined for secretion or a specific organelle must be translocated. This process can occur during translation, known as co-translational translocation, or after translation is complete, known as post-translational translocation.
=== Co-translational translocation ===
Most secretory and membrane-bound proteins are co-translationally translocated. Proteins that reside in the endoplasmic reticulum (ER), golgi or endosomes also use the co-translational translocation pathway. This process begins while the protein is being synthesized on the ribosome, when a signal recognition particle (SRP) recognizes an N-terminal signal peptide of the nascent protein. Binding of the SRP temporarily pauses synthesis while the ribosome-protein complex is transferred to an SRP receptor on the ER in eukaryotes, and the plasma membrane in prokaryotes. There, the nascent protein is inserted into the translocon, a membrane-bound protein conducting channel composed of the Sec61 translocation complex in eukaryotes, and the homologous SecYEG complex in prokaryotes. In secretory proteins and type I transmembrane proteins, the signal sequence is immediately cleaved from the nascent polypeptide once it has been translocated into the membrane of the ER (eukaryotes) or plasma membrane (prokaryotes) by signal peptidase. The signal sequence of type II membrane proteins and some polytopic membrane proteins are not cleaved off and therefore are referred to as signal anchor sequences. Within the ER, the protein is first covered by a chaperone protein to protect it from the high concentration of other proteins in the ER, giving it time to fold correctly. Once folded, the protein is modified as needed (for example, by glycosylation), then transported to the Golgi for further processing and goes to its target organelles or is retained in the ER by various ER retention mechanisms.
The amino acid chain of transmembrane proteins, which often are transmembrane receptors, passes through a membrane one or several times. These proteins are inserted into the membrane by translocation, until the process is interrupted by a stop-transfer sequence, also called a membrane anchor or signal-anchor sequence. These complex membrane proteins are currently characterized using the same model of targeting that has been developed for secretory proteins. However, many complex multi-transmembrane proteins contain structural aspects that do not fit this model. Seven transmembrane G-protein coupled receptors (which represent about 5% of the genes in humans) mostly do not have an amino-terminal signal sequence. In contrast to secretory proteins, the first transmembrane domain acts as the first signal sequence, which targets them to the ER membrane. This also results in the translocation of the amino terminus of the protein into the ER membrane lumen. This translocation, which has been demonstrated with opsin with in vitro experiments, breaks the usual pattern of "co-translational" translocation which has always held for mammalian proteins targeted to the ER. A great deal of the mechanics of transmembrane topology and folding remains to be elucidated.
=== Post-translational translocation ===
Even though most secretory proteins are co-translationally translocated, some are translated in the cytosol and later transported to the ER/plasma membrane by a post-translational system. In prokaryotes this process requires certain cofactors such as SecA and SecB and is facilitated by Sec62 and Sec63, two membrane-bound proteins. The Sec63 complex, which is embedded in the ER membrane, causes hydrolysis of ATP, allowing chaperone proteins to bind to an exposed peptide chain and slide the polypeptide into the ER lumen. Once in the lumen the polypeptide chain can be folded properly. This process only occurs in unfolded proteins located in the cytosol.
In addition, proteins targeted to other cellular destinations, such as mitochondria, chloroplasts, or peroxisomes, use specialized post-translational pathways. Proteins targeted for the nucleus are also translocated post-translationally through the addition of a nuclear localization sequence (NLS) that promotes passage through the nuclear envelope via nuclear pores.
== Sorting of proteins ==
=== Mitochondria ===
While some proteins in the mitochondria originate from mitochondrial DNA within the organelle, most mitochondrial proteins are synthesized as cytosolic precursors containing uptake peptide signals. Unfolded proteins bound by cytosolic chaperone hsp70 that are targeted to the mitochondria may be localized to four different areas depending on their sequences. They may be targeted to the mitochondrial matrix, the outer membrane, the intermembrane space, or the inner membrane. Defects in any one or more of these processes has been linked to health and disease.
==== Mitochondrial matrix ====
Proteins destined for the mitochondrial matrix have specific signal sequences at their beginning (N-terminus) that consist of a string of 20 to 50 amino acids. These sequences are designed to interact with receptors that guide the proteins to their correct location inside the mitochondria. The sequences have a unique structure with clusters of water-loving (hydrophilic) and water-avoiding (hydrophobic) amino acids, giving them a dual nature known as amphipathic. These amphipathic sequences typically form a spiral shape (alpha-helix) with the charged amino acids on one side and the hydrophobic ones on the opposite side. This structural feature is essential for the sequence to function correctly in directing proteins to the matrix. If mutations occur that mess with this dual nature, the protein often fails to reach its intended destination, although not all changes to the sequence have this effect. This indicates the importance of the amphipathic property for the protein to be correctly targeted to the mitochondrial matrix.Proteins targeted to the mitochondrial matrix first involves interactions between the matrix targeting sequence located at the N-terminus and the outer membrane import receptor complex TOM20/22. In addition to the docking of internal sequences and cytosolic chaperones to TOM70. Where TOM is an abbreviation for translocase of the outer membrane. Binding of the matrix targeting sequence to the import receptor triggers a handoff of the polypeptide to the general import core (GIP) known as TOM40. The general import core (TOM40) then feeds the polypeptide chain through the intermembrane space and into another translocase complex TIM17/23/44 located on the inner mitochondrial membrane. This is accompanied by the necessary release of the cytosolic chaperones that maintain an unfolded state prior to entering the mitochondria. As the polypeptide enters the matrix, the signal sequence is cleaved by a processing peptidase and the remaining sequences are bound by mitochondrial chaperones to await proper folding and activity. The push and pull of the polypeptide from the cytosol to the intermembrane space and then the matrix is achieved by an electrochemical gradient that is established by the mitochondrion during oxidative phosphorylation. In which a mitochondrion active in metabolism has generated a negative potential inside the matrix and a positive potential in the intermembrane space. It is this negative potential inside the matrix that directs the positively charged regions of the targeting sequence into its desired location.
==== Mitochondrial inner membrane ====
Targeting of mitochondrial proteins to the inner membrane may follow 3 different pathways depending upon their overall sequences, however, entry from the outer membrane remains the same using the import receptor complex TOM20/22 and TOM40 general import core. The first pathway for proteins targeted to the inner membrane follows the same steps as those designated to the matrix where it contains a matrix targeting sequence that channels the polypeptide to the inner membrane complex containing the previously mentioned translocase complex TIM17/23/44. However, the difference is that the peptides that are designated to the inner membrane and not the matrix contain an upstream sequence called the stop-transfer-anchor sequence. This stop-transfer-anchor sequence is a hydrophobic region that embeds itself into the phospholipid bilayer of the inner membrane and prevents translocation further into the mitochondrion. The second pathway for proteins targeted to the inner membrane follows the matrix localization pathway in its entirety. However, instead of a stop-transfer-anchor sequence, it contains another sequence that interacts with an inner membrane protein called Oxa-1 once inside the matrix that will embed it into the inner membrane. The third pathway for mitochondrial proteins targeted to the inner membrane follow the same entry as the others into the outer membrane, however, this pathway utilizes the translocase complex TIM22/54 assisted by complex TIM9/10 in the intermembrane space to anchor the incoming peptide into the membrane. The peptides for this last pathway do not contain a matrix targeting sequence, but instead contain several internal targeting sequences.
==== Mitochondrial intermembrane space ====
If instead the precursor protein is designated to the intermembrane space of the mitochondrion, there are two pathways this may occur depending on the sequences being recognized. The first pathway to the intermembrane space follows the same steps for an inner membrane targeted protein. However, once bound to the inner membrane the C-terminus of the anchored protein is cleaved via a peptidase that liberates the preprotein into the intermembrane space so it can fold into its active state. One of the greatest examples for a protein that follows this pathway is cytochrome b2, that upon being cleaved will interact with a heme cofactor and become active. The second intermembrane space pathway does not utilize any inner membrane complexes and therefor does not contain a matrix targeting signal. Instead, it enters through the general import core TOM40 and is further modified in the intermembrane space to achieve its active conformation. TIM9/10 is an example of a protein that follows this pathway in order to be in the location it needs to be to assist in inner membrane targeting.
==== Mitochondrial outer membrane ====
Outer membrane targeting simply involves the interaction of precursor proteins with the outer membrane translocase complexes that embeds it into the membrane via internal-targeting sequences that are to form hydrophobic alpha helices or beta barrels that span the phospholipid bilayer. This may occur by two different routes depending on the preprotein internal sequences. If the preprotein contains internal hydrophobic regions capable of forming alpha helices, then the preprotein will utilize the mitochondrial import complex (MIM) and be transferred laterally to the membrane. For preproteins containing hydrophobic internal sequences that correlate to beta-barrel forming proteins, they will be imported from the aforementioned outer membrane complex TOM20/22 to the intermembrane space. In which they will interact with TIM9/10 intermembrane-space protein complex that transfers them to sorting and assembly machinery (SAM) that is present in the outer membrane that laterally displaces the targeted protein as a beta-barrel.
=== Chloroplasts ===
Chloroplasts are similar to mitochondria in that they contain their own DNA for production of some of their components. However, the majority of their proteins are obtained via post-translational translocation and arise from nuclear genes. Proteins may be targeted to several sites of the chloroplast depending on their sequences such as the outer envelope, inner envelope, stroma, thylakoid lumen, or the thylakoid membrane. Proteins are targeted to Thylakoids by mechanisms related to Bacterial Protein Translocation. Proteins targeted to the envelope of chloroplasts usually lack cleavable sorting sequence and are laterally displaced via membrane sorting complexes. General import for the majority of preproteins requires translocation from the cytosol through the Toc and Tic complexes located within the chloroplast envelope. Where Toc is an abbreviation for the translocase of the outer chloroplast envelope and Tic is the translocase of the inner chloroplast envelope. There is a minimum of three proteins that make up the function of the Toc complex. Two of which, referred to as Toc159 and Toc34, are responsible for the docking of stromal import sequences and both contain GTPase activity. The third known as Toc 75, is the actual translocation channel that feeds the recognized preprotein by Toc159/34 into the chloroplast.
==== Stroma ====
Targeting to the stroma requires the preprotein to have a stromal import sequence that is recognized by the Tic complex of the inner envelope upon being translocated from the outer envelope by the Toc complex. The Tic complex is composed of at least five different Tic proteins that are required to form the translocation channel across the inner envelope. Upon being delivered to the stroma, the stromal import sequence is cleaved off via a signal peptidase. This delivery process to the stroma is currently known to be driven by ATP hydrolysis via stromal HSP chaperones, instead of the transmembrane electrochemical gradient that is established in mitochondria to drive protein import. Further intra-chloroplast sorting depends on additional target sequences such as those designated to the thylakoid membrane or the thylakoid lumen.
==== Thylakoid lumen ====
If a protein is to be targeted to the thylakoid lumen, this may occur via four differently known routes that closely resemble bacterial protein transport mechanisms. The route that is taken depends upon the protein delivered to the stroma being in either an unfolded or metal-bound folded state. Both of which will still contain a thylakoid targeting sequence that is also cleaved upon entry to the lumen. While protein import into the stroma is ATP-driven, the pathway for metal-bound proteins in a folded state to the thylakoid lumen has been shown to be driven by a pH gradient.
==== Thylakoid membrane ====
Proteins bound for the membrane of the thylakoid will follow up to four known routes that are illustrated in the corresponding figure shown. They may follow a co-translational insertion route that utilizes stromal ribosomes and the SecY/E transmembrane complex, the SRP-dependent pathway, the spontaneous insertion pathway, or the GET pathway. The last of the three are post-translational pathways originating from nuclear genes and therefor constitute the majority of proteins targeted to the thylakoid membrane. According to recent review articles in the journal of biochemistry and molecular biology, the exact mechanisms are not yet fully understood.
=== Both chloroplasts and mitochondria ===
Many proteins are needed in both mitochondria and chloroplasts. In general the dual-targeting peptide is of intermediate character to the two specific ones. The targeting peptides of these proteins have a high content of basic and hydrophobic amino acids, a low content of negatively charged amino acids. They have a lower content of alanine and a higher content of leucine and phenylalanine. The dual targeted proteins have a more hydrophobic targeting peptide than both mitochondrial and chloroplastic ones. However, it is tedious to predict if a peptide is dual-targeted or not based on its physio-chemical characteristics.
=== Nucleus ===
The nucleus of a cell is surrounded by a nuclear envelope consisting of two layers, with the inner layer providing structural support and anchorage for chromosomes and the nuclear lamina. The outer layer is similar to the endoplasmic reticulum (ER) membrane. This envelope contains nuclear pores, which are complex structures made from around 30 different proteins. These pores act as selective gates that control the flow of molecules into and out of the nucleus.
While small molecules can pass through these pores without issue, larger molecules, like RNA and proteins destined for the nucleus, must have specific signals to be allowed through. These signals are known as nuclear localization signals, usually comprising short sequences rich in positively charged amino acids like lysine or arginine.
Proteins called nuclear import receptors recognize these signals and guide the large molecules through the nuclear pores by interacting with the disordered, mesh-like proteins that fill the pore. The process is dynamic, with the receptor moving the molecule through the meshwork until it reaches the nucleus.
Once inside, a GTPase enzyme called Ran, which can exist in two different forms (one bound to GTP and the other to GDP), facilitates the release of the cargo inside the nucleus and recycles the receptor back to the cytosol. The energy for this transport comes from the hydrolysis of GTP by Ran. Similarly, nuclear export receptors help move proteins and RNA out of the nucleus using a different signal and also harnessing Ran's energy conversion.
Overall, the nuclear pore complex works efficiently to transport macromolecules at high speed, allowing proteins to move in their folded state and ribosomal components as complete particles, which is distinct from how proteins are transported into most other organelles.
=== Endoplasmic reticulum ===
The endoplasmic reticulum (ER) plays a key role in protein synthesis and distribution in eukaryotic cells. It's a vast network of membranes where proteins are processed and sorted to various destinations, including the ER itself, the cell surface, and other organelles like the Golgi apparatus, endosomes, and lysosomes. Unlike other organelle-targeted proteins, those headed for the ER start to be transferred across its membrane while they're still being made.
==== Protein synthesis and sorting ====
There are two types of proteins that move to the ER: water-soluble proteins, which completely cross into the ER lumen, and transmembrane proteins, which partly cross and embed themselves within the ER membrane. These proteins find their way to the ER with the help of an ER signal sequence, a short stretch of hydrophobic amino acids.
Proteins entering the ER are synthesized by ribosomes. There are two sets of ribosomes in the cell: those bound to the ER (making it look 'rough') and those floating freely in the cytosol. Both sets are identical but differ in the proteins they synthesize at a given moment. Ribosomes that are making proteins with an ER signal sequence attach to the ER membrane and start the translocation process. This process is energy-efficient because the growing protein chain itself pushes through the ER membrane as it elongates.
As the mRNA is translated into a protein, multiple ribosomes may attach to it, creating a structure called a polyribosome. If the mRNA is coding for a protein with an ER signal sequence, the polyribosome attaches to the ER membrane, and the protein begins to enter the ER while it is still being synthesized.
===== Guided entry of soluble proteins =====
In the process of protein synthesis within eukaryotic cells, soluble proteins that are destined for the endoplasmic reticulum (ER) or for secretion out of the cell are guided to the ER by a two-part system. Firstly, a signal-recognition particle (SRP) in the cytosol attaches to the emerging protein's ER signal sequence and the ribosome itself. Secondly, an SRP receptor located in the ER membrane recognizes and binds to the SRP. This interaction temporarily slows down protein synthesis until the SRP and ribs complex binds to the SRP receptor on the ER.
Once this binding occurs, the SRP is released, and the ribosome is transferred to a protein translocator in the ER membrane, allowing protein synthesis to continue. The polypeptide chain of the protein is then threaded through a channel in the translocator into the ER lumen. The signal sequence of the protein, typically at the beginning (N-terminus) of the polypeptide chain, plays a dual role. It not only targets the ribosome to the ER but also triggers the opening of the translocator. As the protein is fed through the translocator, the signal sequence stays attached, allowing the rest of the protein to move through as a loop. A signal peptidase inside the ER then cuts off the signal sequence, which is subsequently discarded into the lipid bilayer of the ER membrane and broken down.
Finally, once the last part of the protein (the C-terminus) passes through the translocator, the entire soluble protein is released into the ER lumen, where it can then fold and undergo further modifications or be transported to its final destination.
====== Mechanisms of transmembrane protein integration ======
Transmembrane proteins, which are partly integrated into the ER membrane rather than released into the ER lumen, have a complex assembly process. The initial stages are similar to soluble proteins: a signal sequence starts the insertion into the ER membrane. However, this process is interrupted by a stop-transfer sequence—a string of hydrophobic amino acids—which causes the translocator to halt and release the protein laterally into the membrane. This results in a single-pass transmembrane protein with one end inside the ER lumen and the other in the cytosol, and this orientation is permanent.
Some transmembrane proteins use an internal signal (start-transfer sequence) instead of one at the N-terminus, and unlike the initial signal sequence, this start-transfer sequence isn't removed. It begins the transfer process, which continues until a stop-transfer sequence is encountered, at which point both sequences become anchored in the membrane as alpha-helical segments.
In more complex proteins that span the membrane multiple times, additional pairs of start- and stop-transfer sequences are used to weave the protein into the membrane in a fashion akin to a sewing machine. Each pair allows a new segment to cross the membrane and adds to the protein's structure, ensuring it is properly embedded with the correct arrangement of segments inside and outside the ER membrane.
=== Peroxisomes ===
Peroxisomes contain a single phospholipid bilayer that surrounds the peroxisomal matrix containing a wide variety of proteins and enzymes that participate in anabolism and catabolism. Peroxisomes are specialized cell organelles that carry out specific oxidative reactions using molecular oxygen. Their primary function is to remove hydrogen atoms from organic molecules, a process that results in the production of hydrogen peroxide (H2O2). Within peroxisomes, an enzyme called catalase plays a critical role. It uses the hydrogen peroxide generated in the earlier reaction to oxidize various other substances, including phenols, formic acid, formaldehyde, and alcohol. This is known as the "peroxidative" reaction.
Peroxisomes are particularly important in liver and kidney cells for detoxifying harmful substances that enter the bloodstream. For example, they are responsible for oxidizing about 25% of the ethanol we consume into acetaldehyde. Additionally, catalase within peroxisomes can break down excess hydrogen peroxide into water and oxygen and thus preventing potential damage from the build-up of H2O2. Since it contains no internal DNA like that of the mitochondria or chloroplast all peroxisomal proteins are encoded by nuclear genes. To date there are two types of known Peroxisome Targeting Signals (PTS):
Peroxisome targeting signal 1 (PTS1): a C-terminal tripeptide with a consensus sequence (S/A/C)-(K/R/H)-(L/A). The most common PTS1 is serine-lysine-leucine (SKL). The initial research that led to the discovery of this consensus observed that when firefly luciferase was expressed in cultured insect cells it was targeted to the peroxisome. By testing a variety of mutations in the gene encoding the expressed luciferase, the consensus sequence was then determined. It has also been found that by adding this C-terminal sequence of SKL to a cytosolic protein that it becomes targeted for transport to the peroxisome. The majority of peroxisomal matrix proteins possess this PTS1 type signal.
Peroxisome targeting signal 2 (PTS2): a nonapeptide located near the N-terminus with a consensus sequence (R/K)-(L/V/I)-XXXXX-(H/Q)-(L/A/F) (where X can be any amino acid).
There are also proteins that possess neither of these signals. Their transport may be based on a so-called "piggy-back" mechanism: such proteins associate with PTS1-possessing matrix proteins and are translocated into the peroxisomal matrix together with them.
In the case of cytosolic proteins that are produced with the PTS1 C-terminal sequence, its path to the peroxisomal matrix is dependent upon binding to another cytosolic protein called pex5 (peroxin 5). Once bound, pex5 interacts with a peroxisomal membrane protein pex14 to form a complex. When the pex5 protein with bound cargo interacts with the pex14 membrane protein, the complex induces the release of the targeted protein into the matrix. Upon releasing the cargo protein into the matrix, pex5 dissociation from pex14 occurs via ubiquitinylation by a membrane complex comprising pex2, pex12, and pex10 followed by an ATP dependent removal involving the cytosolic protein complex pex1 and pex6. The cycle for pex5 mediated import into the peroxisomal matrix is restored after the ATP dependent removal of ubiquitin and is free to bind with another protein containing a PTS1 sequence. Proteins containing a PTS2 targeting sequence are mediated by a different cytosolic protein but are believed to follow a similar mechanism to that of those containing the PTS1 sequence.
== Diseases ==
Protein transport is defective in the following genetic diseases:
Mohr–Tranebjaerg syndrome
Zellweger syndrome
Adrenoleukodystrophy (ALD).
Refsum disease
Parkinson's disease
Hypercholesterolemia, atherosclerosis, obesity, and diabetes
== In bacteria and archaea ==
As discussed above (see protein translocation), most prokaryotic membrane-bound and secretory proteins are targeted to the plasma membrane by either a co-translation pathway that uses bacterial SRP or a post-translation pathway that requires SecA and SecB. At the plasma membrane, these two pathways deliver proteins to the SecYEG translocon for translocation. Bacteria may have a single plasma membrane (Gram-positive bacteria), or an inner membrane plus an outer membrane separated by the periplasm (Gram-negative bacteria). Besides the plasma membrane the majority of prokaryotes lack membrane-bound organelles as found in eukaryotes, but they may assemble proteins onto various types of inclusions such as gas vesicles and storage granules.
=== Gram-negative bacteria ===
In gram-negative bacteria proteins may be incorporated into the plasma membrane, the outer membrane, the periplasm or secreted into the environment. Systems for secreting proteins across the bacterial outer membrane may be quite complex and play key roles in pathogenesis. These systems may be described as type I secretion, type II secretion, etc.
=== Gram-positive bacteria ===
In most gram-positive bacteria, certain proteins are targeted for export across the plasma membrane and subsequent covalent attachment to the bacterial cell wall. A specialized enzyme, sortase, cleaves the target protein at a characteristic recognition site near the protein C-terminus, such as an LPXTG motif (where X can be any amino acid), then transfers the protein onto the cell wall. Several analogous systems are found that likewise feature a signature motif on the extra-cytoplasmic face, a C-terminal transmembrane domain, and cluster of basic residues on the cytosolic face at the protein's extreme C-terminus. The PEP-CTERM/exosortase system, found in many Gram-negative bacteria, seems to be related to extracellular polymeric substance production. The PGF-CTERM/archaeosortase A system in archaea is related to S-layer production. The GlyGly-CTERM/rhombosortase system, found in the Shewanella, Vibrio, and a few other genera, seems involved in the release of proteases, nucleases, and other enzymes.
== Bioinformatic tools ==
Minimotif Miner is a bioinformatics tool that searches protein sequence queries for a known protein targeting sequence motifs.
Phobius predicts signal peptides based on a supplied primary sequence.
SignalP predicts signal peptide cleavage sites.
LOCtree Archived 2021-12-21 at the Wayback Machine predicts the subcellular localization of proteins.
== Notes ==
== See also ==
Bulk flow
COPI
COPII
Clathrin
LocDB
PSORTdb
Signal peptide
== References ==
== External links ==
Protein+Transport at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Protein_targeting |
Kelch proteins (and Kelch-like proteins) are a widespread group of proteins that contain multiple Kelch motifs. The kelch domain generally occurs as a set of five to seven kelch tandem repeats that form a β-propeller tertiary structure. Kelch-repeat β-propellers are generally involved in protein–protein interactions, though the large diversity of domain architectures and limited sequence identity between kelch motifs make characterisation of the kelch superfamily difficult.
== Structure ==
The N-terminus of several Kelch proteins contain other protein domains, including Discoidin, F-box, and Broad-complex, Tramtrack, Bric-a-Brac/Poxvirus Zinc finger (BTB/POZ) domains. Kelch proteins may also only have a β-propeller architecture. The BTB domain of kelch proteins (if present) allows the formation of homo- or heterodimers that mediate protein–protein interactions.
The C-terminus of Kelch proteins contains kelch repeats. Each kelch repeat is a sequence of 44–55 amino acids in length, usually occurring in clusters of 4 – 7 repeats.
Each kelch repeat forms a "blade" of the β-propeller fold, consisting of a four-stranded antiparallel β-sheet secondary structure, arranged radially around a central axis, packed onto its adjoining repeats via hydrophobic contacts.
Kelch-repeat β-propellers undergo a variety of binding interactions with other proteins, notably the actin filaments of a cell.
== Function ==
Kelch-like proteins are known to act as substrate adaptors for Cullin 3 ubiquitin ligases.
== Organisms ==
The first Kelch protein (from which this family derives its name) was isolated from Drosophila, in which Kelch-mutant females lay sterile, cup-shaped eggs; The word Kelch is German for 'chalice, cup'. Kelch proteins have also been isolated in many other animals, plants, bacteria, fungi, and even virus (restricted to Poxviridae).
== Human proteins containing Kelch motifs ==
ATRN; ATRNL1; CCIN; ENC1; FBXO42;
GAN; HCFC1; HCFC2; IPP; IVNS1ABP; KBTBD10; KBTBD11; KBTBD2;
KBTBD3; KBTBD4; KBTBD5; KBTBD6; KBTBD7; KBTBD8; KEAP1;
KIAA1900; KLHDC1; KLHDC2; KLHDC3; KLHDC4; KLHDC5; KLHDC6; KLHDC7A; KLHDC7B;
KLHDC8A; KLHDC8B; KLHDC9; KLHDC10; KLHL1; KLHL10; KLHL11; KLHL12; KLHL13;
KLHL14; KLHL15; KLHL17; KLHL18; KLHL2; KLHL20; KLHL21; KLHL22;
KLHL23; KLHL24; KLHL25; KLHL26; KLHL28; KLHL29; KLHL3; KLHL30;
KLHL31; KLHL32; KLHL34; KLHL4; KLHL40; KLHL5; KLHL6; KLHL7; KLHL8;
KLHL9; LZTR1; MEGF8; MKLN1; RABEPK; SARCOSIN;
== References == | Wikipedia/Kelch_protein |
In biology, cell signaling (cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both prokaryotes and eukaryotes.
Typically, the signaling process involves three components: the signal, the receptor, and the effector.
In biology, signals are mostly chemical in nature, but can also be physical cues such as pressure, voltage, temperature, or light. Chemical signals are molecules with the ability to bind and activate a specific receptor. These molecules, also referred to as ligands, are chemically diverse, including ions (e.g. Na+, K+, Ca2+, etc.), lipids (e.g. steroid, prostaglandin), peptides (e.g. insulin, ACTH), carbohydrates, glycosylated proteins (proteoglycans), nucleic acids, etc. Peptide and lipid ligands are particularly important, as most hormones belong to these classes of chemicals. Peptides are usually polar, hydrophilic molecules. As such they are unable to diffuse freely across the bi-lipid layer of the plasma membrane, so their action is mediated by a cell membrane bound receptor. On the other hand, liposoluble chemicals such as steroid hormones, can diffuse passively across the plasma membrane and interact with intracellular receptors.
Cell signaling can occur over short or long distances, and can be further classified as autocrine, intracrine, juxtacrine, paracrine, or endocrine. Autocrine signaling occurs when the chemical signal acts on the same cell that produced the signaling chemical. Intracrine signaling occurs when the chemical signal produced by a cell acts on receptors located in the cytoplasm or nucleus of the same cell. Juxtacrine signaling occurs between physically adjacent cells. Paracrine signaling occurs between nearby cells. Endocrine interaction occurs between distant cells, with the chemical signal usually carried by the blood.
Receptors are complex proteins or tightly bound multimer of proteins, located in the plasma membrane or within the interior of the cell such as in the cytoplasm, organelles, and nucleus. Receptors have the ability to detect a signal either by binding to a specific chemical or by undergoing a conformational change when interacting with physical agents. It is the specificity of the chemical interaction between a given ligand and its receptor that confers the ability to trigger a specific cellular response. Receptors can be broadly classified into cell membrane receptors and intracellular receptors.
Cell membrane receptors can be further classified into ion channel linked receptors, G-Protein coupled receptors and enzyme linked receptors.
Ion channels receptors are large transmembrane proteins with a ligand activated gate function. When these receptors are activated, they may allow or block passage of specific ions across the cell membrane. Most receptors activated by physical stimuli such as pressure or temperature belongs to this category.
G-protein receptors are multimeric proteins embedded within the plasma membrane. These receptors have extracellular, trans-membrane and intracellular domains. The extracellular domain is responsible for the interaction with a specific ligand. The intracellular domain is responsible for the initiation of a cascade of chemical reactions which ultimately triggers the specific cellular function controlled by the receptor.
Enzyme-linked receptors are transmembrane proteins with an extracellular domain responsible for binding a specific ligand and an intracellular domain with enzymatic or catalytic activity. Upon activation the enzymatic portion is responsible for promoting specific intracellular chemical reactions.
Intracellular receptors have a different mechanism of action. They usually bind to lipid soluble ligands that diffuse passively through the plasma membrane such as steroid hormones. These ligands bind to specific cytoplasmic transporters that shuttle the hormone-transporter complex inside the nucleus where specific genes are activated and the synthesis of specific proteins is promoted.
The effector component of the signaling pathway begins with signal transduction. In this process, the signal, by interacting with the receptor, starts a series of molecular events within the cell leading to the final effect of the signaling process. Typically the final effect consists in the activation of an ion channel (ligand-gated ion channel) or the initiation of a second messenger system cascade that propagates the signal through the cell. Second messenger systems can amplify or modulate a signal, in which activation of a few receptors results in multiple secondary messengers being activated, thereby amplifying the initial signal (the first messenger). The downstream effects of these signaling pathways may include additional enzymatic activities such as proteolytic cleavage, phosphorylation, methylation, and ubiquitinylation.
Signaling molecules can be synthesized from various biosynthetic pathways and released through passive or active transports, or even from cell damage.
Each cell is programmed to respond to specific extracellular signal molecules, and is the basis of development, tissue repair, immunity, and homeostasis. Errors in signaling interactions may cause diseases such as cancer, autoimmunity, and diabetes.
== Taxonomic range ==
In many small organisms such as bacteria, quorum sensing enables individuals to begin an activity only when the population is sufficiently large. This signaling between cells was first observed in the marine bacterium Aliivibrio fischeri, which produces light when the population is dense enough. The mechanism involves the production and detection of a signaling molecule, and the regulation of gene transcription in response. Quorum sensing operates in both gram-positive and gram-negative bacteria, and both within and between species.
In slime molds, individual cells aggregate together to form fruiting bodies and eventually spores, under the influence of a chemical signal, known as an acrasin. The individuals move by chemotaxis, i.e. they are attracted by the chemical gradient. Some species use cyclic AMP as the signal; others such as Polysphondylium violaceum use a dipeptide known as glorin.
In plants and animals, signaling between cells occurs either through release into the extracellular space, divided in paracrine signaling (over short distances) and endocrine signaling (over long distances), or by direct contact, known as juxtacrine signaling such as notch signaling. Autocrine signaling is a special case of paracrine signaling where the secreting cell has the ability to respond to the secreted signaling molecule. Synaptic signaling is a special case of paracrine signaling (for chemical synapses) or juxtacrine signaling (for electrical synapses) between neurons and target cells.
== Extracellular signal ==
=== Synthesis and release ===
Many cell signals are carried by molecules that are released by one cell and move to make contact with another cell. Signaling molecules can belong to several chemical classes: lipids, phospholipids, amino acids, monoamines, proteins, glycoproteins, or gases. Signaling molecules binding surface receptors are generally large and hydrophilic (e.g. TRH, Vasopressin, Acetylcholine), while those entering the cell are generally small and hydrophobic (e.g. glucocorticoids, thyroid hormones, cholecalciferol, retinoic acid), but important exceptions to both are numerous, and the same molecule can act both via surface receptors or in an intracrine manner to different effects. In animal cells, specialized cells release these hormones and send them through the circulatory system to other parts of the body. They then reach target cells, which can recognize and respond to the hormones and produce a result. This is also known as endocrine signaling. Plant growth regulators, or plant hormones, move through cells or by diffusing through the air as a gas to reach their targets. Hydrogen sulfide is produced in small amounts by some cells of the human body and has a number of biological signaling functions. Only two other such gases are currently known to act as signaling molecules in the human body: nitric oxide and carbon monoxide.
==== Exocytosis ====
Exocytosis is the process by which a cell transports molecules such as neurotransmitters and proteins out of the cell. As an active transport mechanism, exocytosis requires the use of energy to transport material. Exocytosis and its counterpart, endocytosis, the process that brings substances into the cell, are used by all cells because most chemical substances important to them are large polar molecules that cannot pass through the hydrophobic portion of the cell membrane by passive transport. Exocytosis is the process by which a large amount of molecules are released; thus it is a form of bulk transport. Exocytosis occurs via secretory portals at the cell plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structures at the cell plasma membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.
In the context of neurotransmission, neurotransmitters are typically released from synaptic vesicles into the synaptic cleft via exocytosis; however, neurotransmitters can also be released via reverse transport through membrane transport proteins.
=== Forms of Cell Signaling ===
==== Autocrine ====
Autocrine signaling involves a cell secreting a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell itself. This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.
==== Intracrine ====
In intracrine signaling, the signaling chemicals are produced inside the cell and bind to cytosolic or nuclear receptors without being secreted from the cell. The intracrine signals not being secreted outside of the cell is what sets apart intracrine signaling from the other cell signaling mechanisms such as autocrine signaling. In both autocrine and intracrine signaling, the signal has an effect on the cell that produced it.
==== Juxtacrine ====
Juxtacrine signaling is a type of cell–cell or cell–extracellular matrix signaling in multicellular organisms that requires close contact. There are three types:
A membrane ligand (protein, oligosaccharide, lipid) and a membrane protein of two adjacent cells interact.
A communicating junction links the intracellular compartments of two adjacent cells, allowing transit of relatively small molecules.
An extracellular matrix glycoprotein and a membrane protein interact.
Additionally, in unicellular organisms such as bacteria, juxtacrine signaling means interactions by membrane contact. Juxtacrine signaling has been observed for some growth factors, cytokine and chemokine cellular signals, playing an important role in the immune response. Juxtacrine signalling via direct membrane contacts is also present between neuronal cell bodies and motile processes of microglia both during development, and in the adult brain.
==== Paracrine ====
In paracrine signaling, a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance (local action), as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.
Paracrine signals such as retinoic acid target only cells in the vicinity of the emitting cell. Neurotransmitters represent another example of a paracrine signal.
Some signaling molecules can function as both a hormone and a neurotransmitter. For example, epinephrine and norepinephrine can function as hormones when released from the adrenal gland and are transported to the heart by way of the blood stream. Norepinephrine can also be produced by neurons to function as a neurotransmitter within the brain. Estrogen can be released by the ovary and function as a hormone or act locally via paracrine or autocrine signaling.
Although paracrine signaling elicits a diverse array of responses in the induced cells, most paracrine factors utilize a relatively streamlined set of receptors and pathways. In fact, different organs in the body - even between different species - are known to utilize a similar sets of paracrine factors in differential development. The highly conserved receptors and pathways can be organized into four major families based on similar structures: fibroblast growth factor (FGF) family, Hedgehog family, Wnt family, and TGF-β superfamily. Binding of a paracrine factor to its respective receptor initiates signal transduction cascades, eliciting different responses.
==== Endocrine ====
Endocrine signals are called hormones. Hormones are produced by endocrine cells and they travel through the blood to reach all parts of the body. Specificity of signaling can be controlled if only some cells can respond to a particular hormone. Endocrine signaling involves the release of hormones by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neural control center for all endocrine systems. In humans, the major endocrine glands are the thyroid gland and the adrenal glands. The study of the endocrine system and its disorders is known as endocrinology.
== Receptors ==
Cells receive information from their neighbors through a class of proteins known as receptors. Receptors may bind with some molecules (ligands) or may interact with physical agents like light, mechanical temperature, pressure, etc. Reception occurs when the target cell (any cell with a receptor protein specific to the signal molecule) detects a signal, usually in the form of a small, water-soluble molecule, via binding to a receptor protein on the cell surface, or once inside the cell, the signaling molecule can bind to intracellular receptors, other elements, or stimulate enzyme activity (e.g. gasses), as in intracrine signaling.
Signaling molecules interact with a target cell as a ligand to cell surface receptors, and/or by entering into the cell through its membrane or endocytosis for intracrine signaling. This generally results in the activation of second messengers, leading to various physiological effects. In many mammals, early embryo cells exchange signals with cells of the uterus. In the human gastrointestinal tract, bacteria exchange signals with each other and with human epithelial and immune system cells. For the yeast Saccharomyces cerevisiae during mating, some cells send a peptide signal (mating factor pheromones) into their environment. The mating factor peptide may bind to a cell surface receptor on other yeast cells and induce them to prepare for mating.
=== Cell surface receptors ===
Cell surface receptors play an essential role in the biological systems of single- and multi-cellular organisms and malfunction or damage to these proteins is associated with cancer, heart disease, and asthma. These trans-membrane receptors are able to transmit information from outside the cell to the inside because they change conformation when a specific ligand binds to it. There are three major types: Ion channel linked receptors, G protein–coupled receptors, and enzyme-linked receptors.
==== Ion channel linked receptors ====
Ion channel linked receptors are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.
When a presynaptic neuron is excited, it releases a neurotransmitter from vesicles into the synaptic cleft. The neurotransmitter then binds to receptors located on the postsynaptic neuron. If these receptors are ligand-gated ion channels (LICs), a resulting conformational change opens the ion channels, which leads to a flow of ions across the cell membrane. This, in turn, results in either a depolarization, for an excitatory receptor response, or a hyperpolarization, for an inhibitory response.
These receptor proteins are typically composed of at least two different domains: a transmembrane domain which includes the ion pore, and an extracellular domain which includes the ligand binding location (an allosteric binding site). This modularity has enabled a 'divide and conquer' approach to finding the structure of the proteins (crystallising each domain separately). The function of such receptors located at synapses is to convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal. Many LICs are additionally modulated by allosteric ligands, by channel blockers, ions, or the membrane potential. LICs are classified into three superfamilies which lack evolutionary relationship: cys-loop receptors, ionotropic glutamate receptors and ATP-gated channels.
==== G protein–coupled receptors ====
G protein-coupled receptors are a large group of evolutionarily-related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times. The G-protein acts as a "middle man" transferring the signal from its activated receptor to its target and therefore indirectly regulates that target protein. Ligands can bind either to extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (Rhodopsin-like family). They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed.
G protein-coupled receptors are found only in eukaryotes, including yeast, choanoflagellates, and animals. The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins. G protein-coupled receptors are involved in many diseases.
There are two principal signal transduction pathways involving the G protein-coupled receptors: cAMP signal pathway and phosphatidylinositol signal pathway. When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor (GEF). The GPCR can then activate an associated G protein by exchanging the GDP bound to the G protein for a GTP. The G protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type (Gαs, Gαi/o, Gαq/11, Gα12/13).: 1160
G protein-coupled receptors are an important drug target and approximately 34% of all Food and Drug Administration (FDA) approved drugs target 108 members of this family. The global sales volume for these drugs is estimated to be 180 billion US dollars as of 2018. It is estimated that GPCRs are targets for about 50% of drugs currently on the market, mainly due to their involvement in signaling pathways related to many diseases i.e. mental, metabolic including endocrinological disorders, immunological including viral infections, cardiovascular, inflammatory, senses disorders, and cancer. The long ago discovered association between GPCRs and many endogenous and exogenous substances, resulting in e.g. analgesia, is another dynamically developing field of pharmaceutical research.
==== Enzyme-linked receptors ====
Enzyme-linked receptors (or catalytic receptors) are transmembrane receptors that, upon activation by an extracellular ligand, causes enzymatic activity on the intracellular side. Hence a catalytic receptor is an integral membrane protein possessing both enzymatic, catalytic, and receptor functions.
They have two important domains, an extra-cellular ligand binding domain and an intracellular domain, which has a catalytic function; and a single transmembrane helix. The signaling molecule binds to the receptor on the outside of the cell and causes a conformational change on the catalytic function located on the receptor inside the cell. Examples of the enzymatic activity include:
Receptor tyrosine kinase, as in fibroblast growth factor receptor. Most enzyme-linked receptors are of this type.
Receptor protein serine/threonine kinase, as in bone morphogenetic protein
Guanylate cyclase, as in atrial natriuretic factor receptor
=== Intracellular receptors ===
Intracellular receptors exist freely in the cytoplasm, nucleus, or can be bound to organelles or membranes. For example, the presence of nuclear and mitochondrial receptors is well documented. The binding of a ligand to the intracellular receptor typically induces a response in the cell. Intracellular receptors often have a level of specificity, this allows the receptors to initiate certain responses when bound to a corresponding ligand. Intracellular receptors typically act on lipid soluble molecules. The receptors bind to a group of DNA binding proteins. Upon binding, the receptor-ligand complex translocates to the nucleus where they can alter patterns of gene expression.
Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen (group NR3A) and 3-ketosteroids (group NR3C). In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.
== Mechanisms of Receptor Down-Regulation ==
Receptor mediated endocytosis is common way of turning receptors "off". Endocytic down regulation is regarded as a means for reducing receptor signaling. The process involves the binding of a ligand to the receptor, which then triggers the formation of coated pits, the coated pits transform to coated vesicles and are transported to the endosome.
Receptor Phosphorylation is another type of receptor down-regulation. Biochemical changes can reduce receptor affinity for a ligand.
Reducing the sensitivity of the receptor is a result of receptors being occupied for a long time. This results in a receptor adaptation in which the receptor no longer responds to the signaling molecule. Many receptors have the ability to change in response to ligand concentration.
== Signal transduction pathways ==
When binding to the signaling molecule, the receptor protein changes in some way and starts the process of transduction, which can occur in a single step or as a series of changes in a sequence of different molecules (called a signal transduction pathway). The molecules that compose these pathways are known as relay molecules. The multistep process of the transduction stage is often composed of the activation of proteins by addition or removal of phosphate groups or even the release of other small molecules or ions that can act as messengers. The amplifying of a signal is one of the benefits to this multiple step sequence. Other benefits include more opportunities for regulation than simpler systems do and the fine-tuning of the response, in both unicellular and multicellular organism.
In some cases, receptor activation caused by ligand binding to a receptor is directly coupled to the cell's response to the ligand. For example, the neurotransmitter GABA can activate a cell surface receptor that is part of an ion channel. GABA binding to a GABAA receptor on a neuron opens a chloride-selective ion channel that is part of the receptor. GABAA receptor activation allows negatively charged chloride ions to move into the neuron, which inhibits the ability of the neuron to produce action potentials. However, for many cell surface receptors, ligand-receptor interactions are not directly linked to the cell's response. The activated receptor must first interact with other proteins inside the cell before the ultimate physiological effect of the ligand on the cell's behavior is produced. Often, the behavior of a chain of several interacting cell proteins is altered following receptor activation. The entire set of cell changes induced by receptor activation is called a signal transduction mechanism or pathway.
A more complex signal transduction pathway is the MAPK/ERK pathway, which involves changes of protein–protein interactions inside the cell, induced by an external signal. Many growth factors bind to receptors at the cell surface and stimulate cells to progress through the cell cycle and divide. Several of these receptors are kinases that start to phosphorylate themselves and other proteins when binding to a ligand. This phosphorylation can generate a binding site for a different protein and thus induce protein–protein interaction. In this case, the ligand (called epidermal growth factor, or EGF) binds to the receptor (called EGFR). This activates the receptor to phosphorylate itself. The phosphorylated receptor binds to an adaptor protein (GRB2), which couples the signal to further downstream signaling processes. For example, one of the signal transduction pathways that are activated is called the mitogen-activated protein kinase (MAPK) pathway. The signal transduction component labeled as "MAPK" in the pathway was originally called "ERK," so the pathway is called the MAPK/ERK pathway. The MAPK protein is an enzyme, a protein kinase that can attach phosphate to target proteins such as the transcription factor MYC and, thus, alter gene transcription and, ultimately, cell cycle progression. Many cellular proteins are activated downstream of the growth factor receptors (such as EGFR) that initiate this signal transduction pathway.
Some signaling transduction pathways respond differently, depending on the amount of signaling received by the cell. For instance, the hedgehog protein activates different genes, depending on the amount of hedgehog protein present.
Complex multi-component signal transduction pathways provide opportunities for feedback, signal amplification, and interactions inside one cell between multiple signals and signaling pathways.
A specific cellular response is the result of the transduced signal in the final stage of cell signaling. This response can essentially be any cellular activity that is present in a body. It can spur the rearrangement of the cytoskeleton, or even as catalysis by an enzyme. These three steps of cell signaling all ensure that the right cells are behaving as told, at the right time, and in synchronization with other cells and their own functions within the organism. At the end, the end of a signal pathway leads to the regulation of a cellular activity. This response can take place in the nucleus or in the cytoplasm of the cell. A majority of signaling pathways control protein synthesis by turning certain genes on and off in the nucleus.
In unicellular organisms such as bacteria, signaling can be used to 'activate' peers from a dormant state, enhance virulence, defend against bacteriophages, etc. In quorum sensing, which is also found in social insects, the multiplicity of individual signals has the potentiality to create a positive feedback loop, generating coordinated response. In this context, the signaling molecules are called autoinducers. This signaling mechanism may have been involved in evolution from unicellular to multicellular organisms. Bacteria also use contact-dependent signaling, notably to limit their growth.
Signaling molecules used by multicellular organisms are often called pheromones. They can have such purposes as alerting against danger, indicating food supply, or assisting in reproduction.
=== Short-term cellular responses ===
=== Regulating gene activity ===
==== Notch signaling pathway ====
Notch is a cell surface protein that functions as a receptor. Animals have a small set of genes that code for signaling proteins that interact specifically with Notch receptors and stimulate a response in cells that express Notch on their surface. Molecules that activate (or, in some cases, inhibit) receptors can be classified as hormones, neurotransmitters, cytokines, and growth factors, in general called receptor ligands. Ligand receptor interactions such as that of the Notch receptor interaction, are known to be the main interactions responsible for cell signaling mechanisms and communication. Notch acts as a receptor for ligands that are expressed on adjacent cells. While some receptors are cell-surface proteins, others are found inside cells. For example, estrogen is a hydrophobic molecule that can pass through the lipid bilayer of the membranes. As part of the endocrine system, intracellular estrogen receptors from a variety of cell types can be activated by estrogen produced in the ovaries.
In the case of Notch-mediated signaling, the signal transduction mechanism can be relatively simple. As shown in Figure 2, the activation of Notch can cause the Notch protein to be altered by a protease. Part of the Notch protein is released from the cell surface membrane and takes part in gene regulation. Cell signaling research involves studying the spatial and temporal dynamics of both receptors and the components of signaling pathways that are activated by receptors in various cell types. Emerging methods for single-cell mass-spectrometry analysis promise to enable studying signal transduction with single-cell resolution.
In notch signaling, direct contact between cells allows for precise control of cell differentiation during embryonic development. In the worm Caenorhabditis elegans, two cells of the developing gonad each have an equal chance of terminally differentiating or becoming a uterine precursor cell that continues to divide. The choice of which cell continues to divide is controlled by competition of cell surface signals. One cell will happen to produce more of a cell surface protein that activates the Notch receptor on the adjacent cell. This activates a feedback loop or system that reduces Notch expression in the cell that will differentiate and that increases Notch on the surface of the cell that continues as a stem cell.
== See also ==
== References ==
== Further reading ==
== External links ==
NCI-Nature Pathway Interaction Database: authoritative information about signaling pathways in human cells.
Intercellular+Signaling+Peptides+and+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Cell+Communication at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Signaling Pathways Project: cell signaling hypothesis generation knowledgebase constructed using biocurated archived transcriptomic and ChIP-Seq datasets | Wikipedia/Signaling_protein |
In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word dimer has roots meaning "two parts", di- + -mer. A protein dimer is a type of protein quaternary structure.
A protein homodimer is formed by two identical proteins while a protein heterodimer is formed by two different proteins.
Most protein dimers in biochemistry are not connected by covalent bonds. An example of a non-covalent heterodimer is the enzyme reverse transcriptase, which is composed of two different amino acid chains. An exception is dimers that are linked by disulfide bridges such as the homodimeric protein NEMO.
Some proteins contain specialized domains to ensure dimerization (dimerization domains) and specificity.
The G protein-coupled cannabinoid receptors have the ability to form both homo- and heterodimers with several types of receptors such as mu-opioid, dopamine and adenosine A2 receptors.
== Examples ==
Transcription factors
Leucine zipper motif proteins
14-3-3 proteins
Variable surface glycoproteins of the Trypanosoma parasite
Tubulin
Some clotting factors
Factor XI
Factor XIII
Fibrinogen
Some receptors
Nuclear receptors
G protein βγ-subunit dimer
Toll-like receptor
Receptor tyrosine kinases
Some enzymes
Type II restriction enzymes
Triosephosphateisomerase (TIM)
Alcohol dehydrogenase
Some viral proteins
Mammarenaviruses Z matrix protein
== Alkaline phosphatase ==
E. coli alkaline phosphatase, a dimer enzyme, exhibits intragenic complementation. That is, when particular mutant versions of alkaline phosphatase were combined, the heterodimeric enzymes formed as a result exhibited a higher level of activity than would be expected based on the relative activities of the parental enzymes. These findings indicated that the dimer structure of the E. coli alkaline phosphatase allows cooperative interactions between the constituent mutant monomers that can generate a more functional form of the holoenzyme. The dimer has two active sites, each containing two zinc ions and a magnesium ion.
== See also ==
Dimerization
Protein trimer
Oligomer
ProtCID
== References ==
Conn. (2013). G protein coupled receptors modeling, activation, interactions and virtual screening (1st ed.). Academic Press.
Matthews, Jacqueline M. Protein Dimerization and Oligomerization in Biology. Springer New York, 2012. | Wikipedia/Protein_dimer |
A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred (see homology). Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if no sequence similarity is evident. Sequence homology can then be deduced even if not apparent (due to low sequence similarity). Superfamilies typically contain several protein families which show sequence similarity within each family. The term protein clan is commonly used for protease and glycosyl hydrolases superfamilies based on the MEROPS and CAZy classification systems.
== Identification ==
Superfamilies of proteins are identified using a number of methods. Closely related members can be identified by different methods to those needed to group the most evolutionarily divergent members.
=== Sequence similarity ===
Historically, the similarity of different amino acid sequences has been the most common method of inferring homology. Sequence similarity is considered a good predictor of relatedness, since similar sequences are more likely the result of gene duplication and divergent evolution, rather than the result of convergent evolution. Amino acid sequence is typically more conserved than DNA sequence (due to the degenerate genetic code), so it is a more sensitive detection method. Since some of the amino acids have similar properties (e.g., charge, hydrophobicity, size), conservative mutations that interchange them are often neutral to function. The most conserved sequence regions of a protein often correspond to functionally important regions like catalytic sites and binding sites, since these regions are less tolerant to sequence changes.
Using sequence similarity to infer homology has several limitations. There is no minimum level of sequence similarity guaranteed to produce identical structures. Over long periods of evolution, related proteins may show no detectable sequence similarity to one another. Sequences with many insertions and deletions can also sometimes be difficult to align and so identify the homologous sequence regions. In the PA clan of proteases, for example, not a single residue is conserved through the superfamily, not even those in the catalytic triad. Conversely, the individual families that make up a superfamily are defined on the basis of their sequence alignment, for example the C04 protease family within the PA clan.
Nevertheless, sequence similarity is the most commonly used form of evidence to infer relatedness, since the number of known sequences vastly outnumbers the number of known tertiary structures. In the absence of structural information, sequence similarity constrains the limits of which proteins can be assigned to a superfamily.
=== Structural similarity ===
Structure is much more evolutionarily conserved than sequence, such that proteins with highly similar structures can have entirely different sequences. Over very long evolutionary timescales, very few residues show detectable amino acid sequence conservation, however secondary structural elements and tertiary structural motifs are highly conserved. Some protein dynamics and conformational changes of the protein structure may also be conserved, as is seen in the serpin superfamily. Consequently, protein tertiary structure can be used to detect homology between proteins even when no evidence of relatedness remains in their sequences. Structural alignment programs, such as DALI, use the 3D structure of a protein of interest to find proteins with similar folds. However, on rare occasions, related proteins may evolve to be structurally dissimilar and relatedness can only be inferred by other methods.
=== Mechanistic similarity ===
The catalytic mechanism of enzymes within a superfamily is commonly conserved, although substrate specificity may be significantly different. Catalytic residues also tend to occur in the same order in the protein sequence. For the families within the PA clan of proteases, although there has been divergent evolution of the catalytic triad residues used to perform catalysis, all members use a similar mechanism to perform covalent, nucleophilic catalysis on proteins, peptides or amino acids. However, mechanism alone is not sufficient to infer relatedness. Some catalytic mechanisms have been convergently evolved multiple times independently, and so form separate superfamilies, and in some superfamilies display a range of different (though often chemically similar) mechanisms.
== Evolutionary significance ==
Protein superfamilies represent the current limits of our ability to identify common ancestry. They are the largest evolutionary grouping based on direct evidence that is currently possible. They are therefore amongst the most ancient evolutionary events currently studied. Some superfamilies have members present in all kingdoms of life, indicating that the last common ancestor of that superfamily was in the last universal common ancestor of all life (LUCA).
Superfamily members may be in different species, with the ancestral protein being the form of the protein that existed in the ancestral species (orthology). Conversely, the proteins may be in the same species, but evolved from a single protein whose gene was duplicated in the genome (paralogy).
=== Diversification ===
A majority of proteins contain multiple domains. Between 66-80% of eukaryotic proteins have multiple domains while about 40-60% of prokaryotic proteins have multiple domains. Over time, many of the superfamilies of domains have mixed together. In fact, it is very rare to find “consistently isolated superfamilies”. When domains do combine, the N- to C-terminal domain order (the "domain architecture") is typically well conserved. Additionally, the number of domain combinations seen in nature is small compared to the number of possibilities, suggesting that selection acts on all combinations.
== Examples ==
α/β hydrolase superfamily
Members share an α/β sheet, containing 8 strands connected by helices, with catalytic triad residues in the same order, activities include proteases, lipases, peroxidases, esterases, epoxide hydrolases and dehalogenases.
Alkaline phosphatase superfamily
Members share an αβα sandwich structure as well as performing common promiscuous reactions by a common mechanism.
Globin superfamily
Members share an 8-alpha helix globular globin fold.
Immunoglobulin superfamily
Members share a sandwich-like structure of two sheets of antiparallel β strands (Ig-fold), and are involved in recognition, binding, and adhesion.
PA clan
Members share a chymotrypsin-like double β-barrel fold and similar proteolysis mechanisms but sequence identity of <10%. The clan contains both cysteine and serine proteases (different nucleophiles).
Ras superfamily
Members share a common catalytic G domain of a 6-strand β sheet surrounded by 5 α-helices.
RSH superfamily
Members share capability to hydrolyze and/or synthesize ppGpp alarmones in the stringent response.
Serpin superfamily
Members share a high-energy, stressed fold which can undergo a large conformational change, which is typically used to inhibit serine and cysteine proteases by disrupting their structure.
TIM barrel superfamily
Members share a large α8β8 barrel structure. It is one of the most common protein folds and the monophylicity of this superfamily is still contested.
== Protein superfamily resources ==
Several biological databases document protein superfamilies and protein folds, for example:
Pfam - Protein families database of alignments and HMMs
PROSITE - Database of protein domains, families and functional sites
PIRSF - SuperFamily Classification System
PASS2 - Protein Alignment as Structural Superfamilies v2
SUPERFAMILY - Library of HMMs representing superfamilies and database of (superfamily and family) annotations for all completely sequenced organisms
SCOP and CATH - Classifications of protein structures into superfamilies, families and domains
Similarly there are algorithms that search the PDB for proteins with structural homology to a target structure, for example:
DALI - Structural alignment based on a distance alignment matrix method
== See also ==
== References ==
== External links ==
Media related to Protein superfamilies at Wikimedia Commons | Wikipedia/Protein_superfamily |
Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this fusion gene results in a single or multiple polypeptides with functional properties derived from each of the original proteins. Recombinant fusion proteins are created artificially by recombinant DNA technology for use in biological research or therapeutics. Chimeric or chimera usually designate hybrid proteins made of polypeptides having different functions or physico-chemical patterns. Chimeric mutant proteins occur naturally when a complex mutation, such as a chromosomal translocation, tandem duplication, or retrotransposition creates a novel coding sequence containing parts of the coding sequences from two different genes. Naturally occurring fusion proteins are commonly found in cancer cells, where they may function as oncoproteins. The bcr-abl fusion protein is a well-known example of an oncogenic fusion protein, and is considered to be the primary oncogenic driver of chronic myelogenous leukemia.
== Functions ==
Some fusion proteins combine whole peptides and therefore contain all functional domains of the original proteins. However, other fusion proteins, especially those that occur naturally, combine only portions of coding sequences and therefore do not maintain the original functions of the parental genes that formed them.
Many whole gene fusions are fully functional and can still act to replace the original peptides. Some, however, experience interactions between the two proteins that can modify their functions. Beyond these effects, some gene fusions may cause regulatory changes that alter when and where these genes act. For partial gene fusions, the shuffling of different active sites and binding domains have the potential to result in new proteins with novel functions.
=== Fluorescent protein tags ===
The fusion of fluorescent tags to proteins in a host cell is a widely popular technique used in experimental cell and biology research in order to track protein interactions in real time. The first fluorescent tag, green fluorescent protein (GFP), was isolated from Aequorea victoria and is still used frequently in modern research. More recent derivations include photoconvertible fluorescent proteins (PCFPs), which were first isolated from Anthozoa. The most commonly used PCFP is the Kaede fluorescent tag, but the development of Kikume green-red (KikGR) in 2005 offers a brighter signal and more efficient photoconversion. The advantage of using PCFP fluorescent tags is the ability to track the interaction of overlapping biochemical pathways in real time. The tag will change color from green to red once the protein reaches a point of interest in the pathway, and the alternate colored protein can be monitored through the duration of pathway. This technique is especially useful when studying G-protein coupled receptor (GPCR) recycling pathways. The fates of recycled G-protein receptors may either be sent to the plasma membrane to be recycled, marked by a green fluorescent tag, or may be sent to a lysosome for degradation, marked by a red fluorescent tag.
=== Chimeric protein drugs ===
The purpose of creating fusion proteins in drug development is to impart properties from each of the "parent" proteins to the resulting chimeric protein. Several chimeric protein drugs are currently available for medical use.
Many chimeric protein drugs are monoclonal antibodies whose specificity for a target molecule was developed using mice and hence were initially "mouse" antibodies. As non-human proteins, mouse antibodies tend to evoke an immune reaction if administered to humans. The chimerization process involves engineering the replacement of segments of the antibody molecule that distinguish it from a human antibody. For example, human constant domains can be introduced, thereby eliminating most of the potentially immunogenic portions of the drug without altering its specificity for the intended therapeutic target. Antibody nomenclature indicates this type of modification by inserting -xi- into the non-proprietary name (e.g., abci-xi-mab). If parts of the variable domains are also replaced by human portions, humanized antibodies are obtained. Although not conceptually distinct from chimeras, this type is indicated using -zu- such as in dacli-zu-mab. See the list of monoclonal antibodies for more examples.
In addition to chimeric and humanized antibodies, there are other pharmaceutical purposes for the creation of chimeric constructs. Etanercept, for example, is a TNFα blocker created through the combination of a tumor necrosis factor receptor (TNFR) with the immunoglobulin G1 Fc segment. TNFR provides specificity for the drug target and the antibody Fc segment is believed to add stability and deliverability of the drug. Additional chimeric proteins used for therapeutic applications include:
Aflibercept: A human recombinant protein that aids in the treatment of oxaliplatin-resistant metastatic colorectal cancer, neo-vascular macular degeneration, and macular edema.
Rilonacept: Reduces inflammation by preventing activation of IL-1 receptors to treat cryopyrin-associated periodic syndromes (CAPS).
Alefacept: Regulated T-cell responses by selectively targeting effector memory T-cells to treat psoriasis vulgaris.
Romiplostim: A peptibody that treats immune thrombocytopenia.
Abatacept/Belatacept: Interferes with T-cell co-stimulation to treat autoimmune disorders like rheumatoid arthritis, psoriatic arthritis, and psoriasis.
Denileukin-diftitox: Treats cutaneous lymphoma.
== Recombinant technology ==
A recombinant fusion protein is a protein created through genetic engineering of a fusion gene. This typically involves removing the stop codon from a cDNA sequence coding for the first protein, then appending the cDNA sequence of the second protein in frame through ligation or overlap extension PCR. That DNA sequence will then be expressed by a cell as a single protein. The protein can be engineered to include the full sequence of both original proteins, or only a portion of either.
If the two entities are proteins, often linker (or "spacer") peptides are also added, which make it more likely that the proteins fold independently and behave as expected. Especially in the case where the linkers enable protein purification, linkers in protein or peptide fusions are sometimes engineered with cleavage sites for proteases or chemical agents that enable the liberation of the two separate proteins. This technique is often used for identification and purification of proteins, by fusing a GST protein, FLAG peptide, or a hexa-his peptide (6xHis-tag), which can be isolated using affinity chromatography with nickel or cobalt resins. Di- or multimeric chimeric proteins can be manufactured through genetic engineering by fusion to the original proteins of peptide domains that induce artificial protein di- or multimerization (e.g., streptavidin or leucine zippers). Fusion proteins can also be manufactured with toxins or antibodies attached to them in order to study disease development. Hydrogenase promoter, PSH, was studied constructing a PSH promoter-gfp fusion by using green fluorescent protein (gfp) reporter gene.
=== Recombinant functionality ===
Novel recombinant technologies have made it possible to improve fusion protein design for use in fields as diverse as biodetection, paper and food industries, and biopharmaceuticals. Recent improvements have involved the fusion of single peptides or protein fragments to regions of existing proteins, such as N and C termini, and are known to increase the following properties:
Catalytic efficiency: Fusion of certain peptides allow for greater catalytic efficiency by altering the tertiary and quaternary structure of the target protein.
Solubility: A common challenge in fusion protein design is the issue of insolubility of newly synthesized fusion proteins in the recombinant host, leading to an over-aggregation of the target protein in the cell. Molecular chaperones that are able to aid in protein folding may be added, thereby better segregating hydrophobic and hydrophilic interactions in the solute to increase protein solubility.
Thermostability: Singular peptides or protein fragments are typically added to reduce flexibility of either the N or C terminus of the target protein, which reinforces thermostability and stabilizes pH range.
Enzyme activity: Fusion that involves the introduction of hydrogen bonds may be used to expand overall enzyme activity.
Expression levels: Addition of numerous fusion fragments, such as maltose binding protein (MBP) or small ubiquitin-like molecule (SUMO), serve to enhance enzyme expression and secretion of the target protein.
Immobilization: PHA synthase, an enzyme that allows for the immobilization of proteins of interest, is an important fusion tag in industrial research.
Crystal quality: Crystal quality can be improved by adding covalent links between proteins, aiding in structure determination techniques.
== Recombinant protein design ==
The earliest applications of recombinant protein design can be documented in the use of single peptide tags for purification of proteins in affinity chromatography. Since then, a variety of fusion protein design techniques have been developed for applications as diverse as fluorescent protein tags to recombinant fusion protein drugs. Three commonly used design techniques include tandem fusion, domain insertion, and post-translational conjugation.
=== Tandem fusion ===
The proteins of interest are simply connected end-to-end via fusion of N or C termini between the proteins. This provides a flexible bridge structure allowing enough space between fusion partners to ensure proper folding. However, the N or C termini of the peptide are often crucial components in obtaining the desired folding pattern for the recombinant protein, making simple end-to-end conjoining of domains ineffective in this case. For this reason, a protein linker is often needed to maintain the functionality of the protein domains of interest.
=== Domain insertion ===
This technique involves the fusion of consecutive protein domains by encoding desired structures into a single polypeptide chain, but sometimes may require insertion of a domain within another domain. This technique is typically regarding as more difficult to carry out than tandem fusion, due to difficulty finding an appropriate ligation site in the gene of interest.
=== Post-translational conjugation ===
This technique fuses protein domains following ribosomal translation of the proteins of interest, in contrast to genetic fusion prior to translation used in other recombinant technologies.
=== Protein linkers ===
Protein linkers aid fusion protein design by providing appropriate spacing between domains, supporting correct protein folding in the case that N or C termini interactions are crucial to folding. Commonly, protein linkers permit important domain interactions, reinforce stability, and reduce steric hindrance, making them preferred for use in fusion protein design even when N and C termini can be fused. Three major types of linkers are flexible, rigid, and in vivo cleavable.
Flexible linkers may consist of many small glycine residues, giving them the ability curl into a dynamic, adaptable shape.
Rigid linkers may be formed of large, cyclic proline residues, which can be helpful when highly specific spacing between domains must be maintained.
In vivo cleavable linkers are unique in that they are designed to allow the release of one or more fused domains under certain reaction conditions, such as a specific pH gradient, or when coming in contact with another biomolecule in the cell.
== Natural occurrence ==
Naturally occurring fusion genes are most commonly created when a chromosomal translocation replaces the terminal exons of one gene with intact exons from a second gene. This creates a single gene that can be transcribed, spliced, and translated to produce a functional fusion protein. Many important cancer-promoting oncogenes are fusion genes produced in this way.
Examples include:
Gag-onc fusion protein
Bcr-abl fusion protein
Tpr-met fusion protein
Antibodies are fusion proteins produced by V(D)J recombination.
There are also rare examples of naturally occurring polypeptides that appear to be a fusion of two clearly defined modules, in which each module displays its characteristic activity or function, independent of the other. Two major examples are: double PP2C chimera in Plasmodium falciparum (the malaria parasite), in which each PP2C module exhibits protein phosphatase 2C enzymatic activity, and the dual-family immunophilins that occur in a number of unicellular organisms (such as protozoan parasites and Flavobacteria) and contain full-length cyclophilin and FKBP chaperone modules. The evolutionary origin of such chimera remains unclear.
== See also ==
Genetic engineering
Protein engineering
Cell–cell fusogens
== References ==
== External links ==
Mutant+Chimeric+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
ChiPPI Archived 2021-11-10 at the Wayback Machine: The Server Protein–Protein Interaction of Chimeric Proteins. | Wikipedia/Chimera_(protein) |
This list of protein structure prediction software summarizes notable used software tools in protein structure prediction, including homology modeling, protein threading, ab initio methods, secondary structure prediction, and transmembrane helix and signal peptide prediction.
== Software list ==
Below is a list which separates programs according to the method used for structure prediction.
=== Homology modeling ===
=== Threading and fold recognition ===
=== Ab initio structure prediction ===
=== Secondary structure prediction ===
Detailed list of programs can be found at List of protein secondary structure prediction programs
== See also ==
List of protein secondary structure prediction programs
Comparison of nucleic acid simulation software
List of software for molecular mechanics modeling
Molecular design software
Protein design
AlphaFold
== External links ==
bio.tools, finding more tools
== References == | Wikipedia/Protein_structure_prediction_software |
An array of protein tandem repeats is defined as several (at least two) adjacent copies having the same or similar sequence motifs. These periodic sequences are generated by internal duplications in both coding and non-coding genomic sequences. Repetitive units of protein tandem repeats are considerably diverse, ranging from the repetition of a single amino acid to domains of 100 or more residues.
== "Repeats" in proteins ==
In proteins, a "repeat" is any sequence block that returns more than one time in the sequence, either in an identical or a highly similar form. The degree of similarity can be highly variable, with some repeats maintaining only a few conserved amino acid positions and a characteristic length. Highly degenerate repeats can be very difficult to detect from sequence alone. Structural similarity can help to identify repetitive patterns in sequence.
== Structure ==
Repetitiveness does not in itself indicate anything about the structure of the protein. As a "rule of thumb", short repetitive sequences (e.g. those below the length of 10 amino acids) may be intrinsically disordered, and not part of any folded protein domains. Repeats that are at least 30 to 40 amino acids long are far more likely to be folded as part of a domain. Such long repeats are frequently indicative of the presence of a solenoid domain in the protein.
Approximately half of the tandem repeat regions have intrinsically disordered conformation being naturally unfolded. Examples of disordered repetitive sequences include the 7-mer peptide repeats found in the RPB1 subunit of RNA polymerase II, or the tandem beta-catenin or axin binding linear motifs in APC (adenomatous polyposis coli). The other half of the regions with the stable 3D structure has a plethora of shapes and functions. Examples of short repeats exhibiting ordered structures include the three-residue collagen repeat or the five-residue pentapeptide repeat that forms a beta helix structure.
== Classification ==
Depending on the length of the repetitive units, their protein structures can be subdivided into five classes:
crystalline aggregates formed by regions with 1 or 2 residue long repeats, archetypical low complexity regions
fibrous structures stabilized by inter-chain interactions with 3-7 residue repeats
elongated structures with repeats of 5–40 residues dominated by solenoid proteins
closed (not elongated) structures with repeats of 30-60 residues as toroid repeats
beads on a string structures with typical size of repeats over 50 residues, which are already large enough to fold independently into stable domains.
== Function ==
Some well-known examples of proteins with tandem repeats are collagen, which plays a key role in the arrangement of the extracellular matrix; alpha-helical coiled coils having structural and oligomerization functions; leucine-rich repeat proteins, which specifically bind some globular proteins by their concave surfaces; and zinc-finger proteins, which regulate the expression of genes by binding DNA.
Tandem repeat proteins frequently function as protein-protein interaction modules. The WD40 repeat is a prime example of this function.
== Distribution in proteomes ==
Tandem repeats are ubiquitous in proteomes and occur in at least 14% of all proteins. For example, they are present in almost every third human protein and even in every second protein from Plasmodium falciparum or Dictyostelium discoideum. Tandem repeats with short repetitive units (especially homorepeats) are more frequent than others.
== Annotation methods ==
Protein tandem repeats can be either detected from sequence or annotated from structure. Specialized methods were built for the identification of repeat proteins.
Sequence-based strategies, based on homology search or domain assignment, mostly underestimate TRs due to the presence of highly degenerate repeat units. A recent study to understand and improve Pfam coverage of the human proteome showed that five of the ten largest sequence clusters not annotated with Pfam are repeat regions. Alternatively, methods requiring no prior knowledge for the detection of repeated substrings can be based on self-comparison, clustering or hidden Markov models. Some others rely on complexity measurements or take advantage of meta searches to combine outputs from different sources.
Structure-based methods instead take advantage of the modularity of available PDB structures to recognize repetitive elements.
== References ==
== External links ==
RepeatsDB: a database of annotated tandem repeat protein structures | Wikipedia/Protein_tandem_repeats |
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