1.
BRENDA
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BRENDA is an information system representing one of the most comprehensive enzyme repositories. It is a resource that comprises molecular and biochemical information on enzymes that have been classified by the IUBMB. Every classified enzyme is characterized with respect to its catalyzed biochemical reaction, kinetic properties of the corresponding reactants are described in detail. BRENDA contains enzyme-specific data manually extracted from scientific literature and additional data derived from automatic information retrieval methods such as text mining. It provides a user interface that allows a convenient and sophisticated access to the data. BRENDA was founded in 1987 at the former German National Research Centre for Biotechnology in Braunschweig and was published as a series of books. Its name was originally an acronym for the Braunschweig Enzyme Database, from 1996 to 2007, BRENDA was located at the University of Cologne. There, BRENDA developed into a publicly accessible enzyme information system, in 2007, BRENDA returned to Braunschweig. Currently, BRENDA is maintained and further developed at the Department of Bioinformatics, a major update of the data in BRENDA is performed twice a year. Besides the upgrade of its content, improvements of the interface are also incorporated into the BRENDA database. The latest update was performed in January 2015, Database, The database contains more than 40 data fields with enzyme-specific information on more than 7000 EC numbers that are classified according to the IUBMB. Currently, BRENDA contains manually annotated data from over 140,000 different scientific articles, each enzyme entry is clearly linked to at least one literature reference, to its source organism, and, where available, to the protein sequence of the enzyme. An important part of BRENDA represent the more than 110,000 enzyme ligands, the term ligand is used in this context to all low molecular weight compounds which interact with enzymes. These include not only metabolites of primary metabolism, co-substrates or cofactors, the origin of these molecules ranges from naturally occurring antibiotics to synthetic compounds that have been synthesized for the development of drugs or pesticides. Furthermore, cross-references to external resources such as sequence and 3D-structure databases. Extensions, Since 2006, the data in BRENDA is supplemented with information extracted from the literature by a co-occurrence based text mining approach. For this purpose, four text-mining repositories FRENDA, AMENDA, DRENDA and KENDA were introduced and these text-mining results were derived from the titles and abstracts of all articles in the literature database PubMed. Data access, There are several tools to access to the data in BRENDA
2.
MetaCyc
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The MetaCyc database contains extensive information on metabolic pathways and enzymes from many organisms. MetaCyc is also used in engineering and metabolomics research. MetaCyc contains extensive data on individual enzymes, describing their subunit structure, cofactors, activators and inhibitors, substrate specificity, MetaCyc data on reactions includes predicted atom mappings that describe the correspondence between atoms in the reactant compounds and the product compounds. It also provides enzyme mini-reviews and literature references, MetaCyc data on metabolites includes chemical structures, predicted Gibbs free energies of formation, and links to external databases
3.
Protein Data Bank
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The Protein Data Bank is a crystallographic database for the three-dimensional structural data of large biological molecules, such as proteins and nucleic acids. The PDB is overseen by a called the Worldwide Protein Data Bank. The PDB is a key resource in areas of structural biology, most major scientific journals, and some funding agencies, now require scientists to submit their structure data to the PDB. Many other databases use protein structures deposited in the PDB, for example, SCOP and CATH classify protein structures, while PDBsum provides a graphic overview of PDB entries using information from other sources, such as Gene ontology. By 1971, one of Meyers programs, SEARCH, enabled researchers to access information from the database to study protein structures offline. SEARCH was instrumental in enabling networking, thus marking the beginning of the PDB. Upon Hamiltons death in 1973, Tom Koeztle took over direction of the PDB for the subsequent 20 years, in January 1994, Joel Sussman of Israels Weizmann Institute of Science was appointed head of the PDB. In October 1998, the PDB was transferred to the Research Collaboratory for Structural Bioinformatics, the new director was Helen M. Berman of Rutgers University. In 2003, with the formation of the wwPDB, the PDB became an international organization, the founding members are PDBe, RCSB, and PDBj. Each of the four members of wwPDB can act as deposition, data processing, the data processing refers to the fact that wwPDB staff review and annotate each submitted entry. The data are automatically checked for plausibility. The PDB database is updated weekly, likewise, the PDB holdings list is also updated weekly. As of 14 March 2017, the breakdown of current holdings is as follows,103,514 structures in the PDB have a structure factor file,9,057 structures have an NMR restraint file. 2,826 structures in the PDB have a chemical shifts file, therefore, the final conformation of the protein is obtained, in the latter case, by solving a distance geometry problem. A few proteins are determined by cryo-electron microscopy, the significance of the structure factor files, mentioned above, is that, for PDB structures determined by X-ray diffraction that have a structure file, the electron density map may be viewed. The data of such structures is stored on the electron density server, however, since 2007, the rate of accumulation of new protein structures appears to have plateaued. The file format used by the PDB was called the PDB file format. This original format was restricted by the width of computer punch cards to 80 characters per line, around 1996, the macromolecular Crystallographic Information file format, mmCIF, which is an extension of the CIF format started to be phased in
4.
PubMed
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PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. The United States National Library of Medicine at the National Institutes of Health maintains the database as part of the Entrez system of information retrieval, from 1971 to 1997, MEDLINE online access to the MEDLARS Online computerized database primarily had been through institutional facilities, such as university libraries. PubMed, first released in January 1996, ushered in the era of private, free, home-, the PubMed system was offered free to the public in June 1997, when MEDLINE searches via the Web were demonstrated, in a ceremony, by Vice President Al Gore. Information about the journals indexed in MEDLINE, and available through PubMed, is found in the NLM Catalog. As of 5 January 2017, PubMed has more than 26.8 million records going back to 1966, selectively to the year 1865, and very selectively to 1809, about 500,000 new records are added each year. As of the date,13.1 million of PubMeds records are listed with their abstracts. In 2016, NLM changed the system so that publishers will be able to directly correct typos. Simple searches on PubMed can be carried out by entering key aspects of a subject into PubMeds search window, when a journal article is indexed, numerous article parameters are extracted and stored as structured information. Such parameters are, Article Type, Secondary identifiers, Language, publication type parameter enables many special features. As these clinical girish can generate small sets of robust studies with considerable precision, since July 2005, the MEDLINE article indexing process extracts important identifiers from the article abstract and puts those in a field called Secondary Identifier. The secondary identifier field is to store numbers to various databases of molecular sequence data, gene expression or chemical compounds. For clinical trials, PubMed extracts trial IDs for the two largest trial registries, ClinicalTrials. gov and the International Standard Randomized Controlled Trial Number Register, a reference which is judged particularly relevant can be marked and related articles can be identified. If relevant, several studies can be selected and related articles to all of them can be generated using the Find related data option, the related articles are then listed in order of relatedness. To create these lists of related articles, PubMed compares words from the title and abstract of each citation, as well as the MeSH headings assigned, using a powerful word-weighted algorithm. The related articles function has been judged to be so precise that some researchers suggest it can be used instead of a full search, a strong feature of PubMed is its ability to automatically link to MeSH terms and subheadings. Examples would be, bad breath links to halitosis, heart attack to myocardial infarction, where appropriate, these MeSH terms are automatically expanded, that is, include more specific terms. Terms like nursing are automatically linked to Nursing or Nursing and this important feature makes PubMed searches automatically more sensitive and avoids false-negative hits by compensating for the diversity of medical terminology. The My NCBI area can be accessed from any computer with web-access, an earlier version of My NCBI was called PubMed Cubby
5.
National Center for Biotechnology Information
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The National Center for Biotechnology Information is part of the United States National Library of Medicine, a branch of the National Institutes of Health. The NCBI is located in Bethesda, Maryland and was founded in 1988 through legislation sponsored by Senator Claude Pepper, the NCBI houses a series of databases relevant to biotechnology and biomedicine and is an important resource for bioinformatics tools and services. Major databases include GenBank for DNA sequences and PubMed, a database for the biomedical literature. Other databases include the NCBI Epigenomics database, all these databases are available online through the Entrez search engine. NCBI is directed by David Lipman, one of the authors of the BLAST sequence alignment program. He also leads a research program, including groups led by Stephen Altschul, David Landsman, Eugene Koonin, John Wilbur, Teresa Przytycka. NCBI is listed in the Registry of Research Data Repositories re3data. org, NCBI has had responsibility for making available the GenBank DNA sequence database since 1992. GenBank coordinates with individual laboratories and other databases such as those of the European Molecular Biology Laboratory. Since 1992, NCBI has grown to other databases in addition to GenBank. The NCBI assigns a unique identifier to each species of organism, the NCBI has software tools that are available by WWW browsing or by FTP. For example, BLAST is a sequence similarity searching program, BLAST can do sequence comparisons against the GenBank DNA database in less than 15 seconds. RAG2/IL2RG The NCBI Bookshelf is a collection of freely accessible, downloadable, some of the books are online versions of previously published books, while others, such as Coffee Break, are written and edited by NCBI staff. BLAST is a used for calculating sequence similarity between biological sequences such as nucleotide sequences of DNA and amino acid sequences of proteins. BLAST is a tool for finding sequences similar to the query sequence within the same organism or in different organisms. It searches the query sequence on NCBI databases and servers and post the results back to the browser in chosen format. Input sequences to the BLAST are mostly in FASTA or Genbank format while output could be delivered in variety of such as HTML, XML formatting. HTML is the output format for NCBIs web-page. Entrez is both indexing and retrieval system having data from sources for biomedical research
6.
Enzyme
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Enzymes /ˈɛnzaɪmz/ are macromolecular biological catalysts. Enzymes accelerate, or catalyze, chemical reactions, the molecules at the beginning of the process upon which enzymes may act are called substrates and the enzyme converts these into different molecules, called products. Almost all metabolic processes in the cell need enzymes in order to occur at rates fast enough to sustain life, the set of enzymes made in a cell determines which metabolic pathways occur in that cell. The study of enzymes is called enzymology, enzymes are known to catalyze more than 5,000 biochemical reaction types. Most enzymes are proteins, although a few are catalytic RNA molecules, enzymes specificity comes from their unique three-dimensional structures. Like all catalysts, enzymes increase the rate of a reaction by lowering its activation energy, some enzymes can make their conversion of substrate to product occur many millions of times faster. An extreme example is orotidine 5-phosphate decarboxylase, which allows a reaction that would take millions of years to occur in milliseconds. Chemically, enzymes are like any catalyst and are not consumed in chemical reactions, enzymes differ from most other catalysts by being much more specific. Enzyme activity can be affected by other molecules, inhibitors are molecules that decrease enzyme activity, many drugs and poisons are enzyme inhibitors. An enzymes activity decreases markedly outside its optimal temperature and pH, some enzymes are used commercially, for example, in the synthesis of antibiotics. French chemist Anselme Payen was the first to discover an enzyme, diastase and he wrote that alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells. In 1877, German physiologist Wilhelm Kühne first used the term enzyme, the word enzyme was used later to refer to nonliving substances such as pepsin, and the word ferment was used to refer to chemical activity produced by living organisms. Eduard Buchner submitted his first paper on the study of yeast extracts in 1897, in a series of experiments at the University of Berlin, he found that sugar was fermented by yeast extracts even when there were no living yeast cells in the mixture. He named the enzyme that brought about the fermentation of sucrose zymase, in 1907, he received the Nobel Prize in Chemistry for his discovery of cell-free fermentation. Following Buchners example, enzymes are usually named according to the reaction they carry out, the biochemical identity of enzymes was still unknown in the early 1900s. Sumner showed that the enzyme urease was a protein and crystallized it. These three scientists were awarded the 1946 Nobel Prize in Chemistry, the discovery that enzymes could be crystallized eventually allowed their structures to be solved by x-ray crystallography. This high-resolution structure of lysozyme marked the beginning of the field of structural biology, an enzymes name is often derived from its substrate or the chemical reaction it catalyzes, with the word ending in -ase
7.
Catalysis
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Catalysis is the increase in the rate of a chemical reaction due to the participation of an additional substance called a catalyst. In most cases, reactions occur faster with a catalyst because they require less activation energy, furthermore, since they are not consumed in the catalyzed reaction, catalysts can continue to act repeatedly. Often only tiny amounts are required in principle, in the presence of a catalyst, less free energy is required to reach the transition state, but the total free energy from reactants to products does not change. A catalyst may participate in multiple chemical transformations, the effect of a catalyst may vary due to the presence of other substances known as inhibitors or poisons or promoters. Catalyzed reactions have an activation energy than the corresponding uncatalyzed reaction, resulting in a higher reaction rate at the same temperature. However, the mechanics of catalysis is complex. Usually, the catalyst participates in this slowest step, and rates are limited by amount of catalyst, in heterogeneous catalysis, the diffusion of reagents to the surface and diffusion of products from the surface can be rate determining. A nanomaterial-based catalyst is an example of a heterogeneous catalyst, analogous events associated with substrate binding and product dissociation apply to homogeneous catalysts. Although catalysts are not consumed by the reaction itself, they may be inhibited, deactivated, in heterogeneous catalysis, typical secondary processes include coking where the catalyst becomes covered by polymeric side products. Additionally, heterogeneous catalysts can dissolve into the solution in a system or sublimate in a solid–gas system. The production of most industrially important chemicals involves catalysis, similarly, most biochemically significant processes are catalysed. Research into catalysis is a field in applied science and involves many areas of chemistry, notably organometallic chemistry. Catalysis is relevant to aspects of environmental science, e. g. the catalytic converter in automobiles. Many transition metals and transition metal complexes are used in catalysis as well, Catalysts called enzymes are important in biology. A catalyst works by providing a reaction pathway to the reaction product. The rate of the reaction is increased as this route has a lower activation energy than the reaction route not mediated by the catalyst. The disproportionation of hydrogen peroxide creates water and oxygen, as shown below,2 H2O2 →2 H2O + O2 This reaction is preferable in the sense that the reaction products are more stable than the starting material, though the uncatalysed reaction is slow. In fact, the decomposition of hydrogen peroxide is so slow that hydrogen peroxide solutions are commercially available and this reaction is strongly affected by catalysts such as manganese dioxide, or the enzyme peroxidase in organisms
8.
Chemical reaction
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A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Nuclear chemistry is a sub-discipline of chemistry that involves the reactions of unstable. The substance initially involved in a reaction are called reactants or reagents. Chemical reactions are characterized by a chemical change, and they yield one or more products. Reactions often consist of a sequence of individual sub-steps, the elementary reactions. Chemical reactions are described with chemical equations, which present the starting materials, end products. Chemical reactions happen at a characteristic reaction rate at a given temperature, typically, reaction rates increase with increasing temperature because there is more thermal energy available to reach the activation energy necessary for breaking bonds between atoms. Reactions may proceed in the forward or reverse direction until they go to completion or reach equilibrium, Reactions that proceed in the forward direction to approach equilibrium are often described as spontaneous, requiring no input of free energy to go forward. Non-spontaneous reactions require input of energy to go forward. Different chemical reactions are used in combinations during chemical synthesis in order to obtain a desired product, in biochemistry, a consecutive series of chemical reactions form metabolic pathways. These reactions are catalyzed by protein enzymes. Chemical reactions such as combustion in fire, fermentation and the reduction of ores to metals were known since antiquity, in the Middle Ages, chemical transformations were studied by Alchemists. They attempted, in particular, to lead into gold, for which purpose they used reactions of lead. The process involved heating of sulfate and nitrate minerals such as sulfate, alum. In the 17th century, Johann Rudolph Glauber produced hydrochloric acid and sodium sulfate by reacting sulfuric acid, further optimization of sulfuric acid technology resulted in the contact process in the 1880s, and the Haber process was developed in 1909–1910 for ammonia synthesis. From the 16th century, researchers including Jan Baptist van Helmont, Robert Boyle, the phlogiston theory was proposed in 1667 by Johann Joachim Becher. It postulated the existence of an element called phlogiston, which was contained within combustible bodies. This proved to be false in 1785 by Antoine Lavoisier who found the explanation of the combustion as reaction with oxygen from the air
9.
Nicotinamide adenine dinucleotide
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Nicotinamide adenine dinucleotide is a coenzyme found in all living cells. The compound is a dinucleotide, because it consists of two nucleotides joined through their phosphate groups, one nucleotide contains an adenine base and the other nicotinamide. Nicotinamide adenine dinucleotide exists in two forms, an oxidized and reduced form abbreviated as NAD+ and NADH respectively, in metabolism, nicotinamide adenine dinucleotide is involved in redox reactions, carrying electrons from one reaction to another. The coenzyme is, therefore, found in two forms in cells, NAD+ is an oxidizing agent – it accepts electrons from other molecules and becomes reduced and this reaction forms NADH, which can then be used as a reducing agent to donate electrons. These electron transfer reactions are the function of NAD. However, it is used in other cellular processes, the most notable one being a substrate of enzymes that add or remove chemical groups from proteins. Because of the importance of these functions, the involved in NAD metabolism are targets for drug discovery. In organisms, NAD can be synthesized from simple building-blocks from the amino acids tryptophan or aspartic acid, in an alternative fashion, more complex components of the coenzymes are taken up from food as the vitamin called niacin. Similar compounds are released by reactions that break down the structure of NAD and these preformed components then pass through a salvage pathway that recycles them back into the active form. Some NAD is also converted into nicotinamide adenine dinucleotide phosphate, the chemistry of this related coenzyme is similar to that of NAD, nicotinamide adenine dinucleotide, like all dinucleotides, consists of two nucleosides joined by a pair of bridging phosphate groups. The nucleosides each contain a ring, one with adenine attached to the first carbon atom. The nicotinamide moiety can be attached in two orientations to this carbon atom. Because of these two structures, the compound exists as two diastereomers. It is the diastereomer of NAD+ that is found in organisms. These nucleotides are joined together by a bridge of two groups through the 5 carbons. In metabolism, the compound accepts or donates electrons in redox reactions, such reactions involve the removal of two hydrogen atoms from the reactant, in the form of a hydride ion, and a proton. The proton is released into solution, while the reductant RH2 is oxidized, the midpoint potential of the NAD+/NADH redox pair is −0.32 volts, which makes NADH a strong reducing agent. The reaction is reversible, when NADH reduces another molecule and is re-oxidized to NAD+
10.
Product (chemistry)
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Products are the species formed from chemical reactions. During a chemical reaction reactants are transformed into products after passing through an energy transition state. This process results in the consumption of the reactants, when represented in chemical equations products are by convention drawn on the right-hand side, even in the case of reversible reactions. The properties of such as their energies help determine several characteristics of a chemical reaction such as whether the reaction is exergonic or endergonic. Additionally the properties of a product can make it easier to extract and purify following a chemical reaction, reactants are molecular materials used to create chemical reactions. The atoms arent created or destroyed, the materials are reactive and reactants are rearranging during a chemical reaction. Here is an example of reactants, CH4 + O2, a non-example is CO2 + H2O or energy. Much of chemistry research is focused on the synthesis and characterization of beneficial products, as well as the detection, other fields include natural product chemists who isolate products created by living organisms and then characterize and study these products. The products of a chemical reaction influence several aspects of the reaction, if the products are lower in energy than the reactants, then the reaction will give off excess energy making it an exergonic reaction. Such reactions are thermodynamically favorable and tend to happen on their own, if the kinetics of the reaction are high enough, however, then the reaction may occur too slowly to be observed, or not even occur at all. If the products are higher in energy than the reactants then the reaction will require energy to be performed and is therefore an endergonic reaction. Additionally if the product is less stable than a reactant, then Lefflers assumption holds that the state will more closely resemble the product than the reactant. Ever since the mid nineteenth century chemists have been preoccupied with synthesizing chemical products. Much of synthetic chemistry is concerned with the synthesis of new chemicals as occurs in the design and creation of new drugs, in biochemistry, enzymes act as biological catalysts to convert substrate to product. For example, the products of the enzyme lactase are galactose and glucose, S + E → P + E Where S is substrate, P is product and E is enzyme. Some enzymes display a form of promiscuity where they convert a single substrate into multiple different products and it occurs when the reaction occurs via a high energy transition state that can be resolved into a variety of different chemical products. Some enzymes are inhibited by the product of their reaction binds to the enzyme and this can be important in the regulation of metabolism as a form of negative feedback controlling metabolic pathways. Product inhibition is also an important topic in biotechnology, as overcoming this effect can increase the yield of a product, Chemical reaction Substrate Reagent Precursor Catalyst Enzyme Product Derivative Chemical equilibrium Second law of thermodynamics
11.
Hydrogen ion
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A hydrogen ion is created when a hydrogen atom loses or gains an electron. A lone positively charged ion can readily combine with other particles. Due to its high charge density of approximately 2×1010 times that of a sodium ion. The hydrogen ion is recommended by IUPAC as a term for all ions of hydrogen. Depending on the charge of the ion, two different classes can be distinguished, positively charged ions and negatively charged ions, a hydrogen atom is made up of a nucleus with charge +1, and a single electron. Therefore, the positively charged ion possible has charge +1. In connection with acids, hydrogen ions typically refers to hydrons, Hydrogen atom contains a single proton and a single electron. Removal of the electron gives a cation, whereas addition of a gives a anion. The hydrogen anion, with its loosely held two-electron cloud, has a larger radius than the neutral atom, which in turn is much larger than the bare proton of the cation. Hydrogen forms the cation that has no electrons, but even cations that still retain one or more electrons are still smaller than the neutral atoms or molecules from which they are derived. This happens when hydrogen ions get pushed across the membrane creating a high concentration inside the thylakoid membrane, however, because of osmosis the H+ will force itself out of the membrane through ATP synthase. Utilizing their kinetic energy to escape, the protons will spin the ATP synthase which in turn will create ATP and this happens in cellular respiration as well though the concentrated membrane will instead be the inner membrane of the mitochondria. Hydrogen ions are also important in pH as they are responsible for if a compound is acidic or basic, water detaches to form H+ and hydroxides. This process is referred to as the self-ionization of water Acid Protonation Dihydrogen cation Trihydrogen cation Britannica Molecular Hydrogen Foundation
12.
PubMed Identifier
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PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. The United States National Library of Medicine at the National Institutes of Health maintains the database as part of the Entrez system of information retrieval, from 1971 to 1997, MEDLINE online access to the MEDLARS Online computerized database primarily had been through institutional facilities, such as university libraries. PubMed, first released in January 1996, ushered in the era of private, free, home-, the PubMed system was offered free to the public in June 1997, when MEDLINE searches via the Web were demonstrated, in a ceremony, by Vice President Al Gore. Information about the journals indexed in MEDLINE, and available through PubMed, is found in the NLM Catalog. As of 5 January 2017, PubMed has more than 26.8 million records going back to 1966, selectively to the year 1865, and very selectively to 1809, about 500,000 new records are added each year. As of the date,13.1 million of PubMeds records are listed with their abstracts. In 2016, NLM changed the system so that publishers will be able to directly correct typos. Simple searches on PubMed can be carried out by entering key aspects of a subject into PubMeds search window, when a journal article is indexed, numerous article parameters are extracted and stored as structured information. Such parameters are, Article Type, Secondary identifiers, Language, publication type parameter enables many special features. As these clinical girish can generate small sets of robust studies with considerable precision, since July 2005, the MEDLINE article indexing process extracts important identifiers from the article abstract and puts those in a field called Secondary Identifier. The secondary identifier field is to store numbers to various databases of molecular sequence data, gene expression or chemical compounds. For clinical trials, PubMed extracts trial IDs for the two largest trial registries, ClinicalTrials. gov and the International Standard Randomized Controlled Trial Number Register, a reference which is judged particularly relevant can be marked and related articles can be identified. If relevant, several studies can be selected and related articles to all of them can be generated using the Find related data option, the related articles are then listed in order of relatedness. To create these lists of related articles, PubMed compares words from the title and abstract of each citation, as well as the MeSH headings assigned, using a powerful word-weighted algorithm. The related articles function has been judged to be so precise that some researchers suggest it can be used instead of a full search, a strong feature of PubMed is its ability to automatically link to MeSH terms and subheadings. Examples would be, bad breath links to halitosis, heart attack to myocardial infarction, where appropriate, these MeSH terms are automatically expanded, that is, include more specific terms. Terms like nursing are automatically linked to Nursing or Nursing and this important feature makes PubMed searches automatically more sensitive and avoids false-negative hits by compensating for the diversity of medical terminology. The My NCBI area can be accessed from any computer with web-access, an earlier version of My NCBI was called PubMed Cubby
13.
Enoyl-acyl carrier protein reductase
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Enoyl-acyl carrier protein reductase, is a key enzyme of the type II fatty acid synthesis system. ENR is a target for narrow-spectrum antibacterial drug discovery because of its essential role in metabolism. In addition, the bacterial ENR sequence and structural organization are distinctly different from those of mammalian fatty acid biosynthesis enzymes, at lower concentrations, Triclosan and Triclocarban provide a bacteriostatic effect by binding to ENR. Atromentin and leucomelone possess antibacterial activity, inhibiting the enzyme in the bacteria Streptococcus pneumoniae, Enoyl- reductase Enoyl- reductase Cis-2-enoyl-CoA reductase NADH-Enoyl ACP Reductase at the US National Library of Medicine Medical Subject Headings EC1.3.1.9
14.
Biliverdin reductase
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Biliverdin reductase is an enzyme found in all tissues under normal conditions, but especially in reticulo-macrophages of the liver and spleen. BVR facilitates the conversion of biliverdin to bilirubin via the reduction of a double-bond between the second and third pyrrole ring into a single-bond, there are two isozymes, in humans, each encoded by its own gene, biliverdin reductase A and biliverdin reductase B. BVR acts on biliverdin by reducing its double-bond between the rings into a single-bond. It accomplishes this using NADPH + H+ as a donor, forming bilirubin. BVR catalyzes this reaction through a binding site including Lys18, Lys22, Lys179, Arg183. This binding site attaches to biliverdin, and causes its dissociation from heme oxygenase, BVR is composed of two closely packed domains, between 247-415 amino acids long and containing a Rossmann fold. BVR has also determined to be a zinc-binding protein with each enzyme protein having one strong-binding zinc atom. The C-terminal half of BVR contains the domain, which adopts a structure containing a six-stranded beta-sheet that is flanked on one face by several alpha-helices. BVR works with the biliverdin/bilirubin redox cycle and it converts biliverdin to bilirubin, which is then converted back into biliverdin through the actions of reactive oxygen species. This cycle allows for the neutralization of ROS, and the reuse of biliverdin products, biliverdin also is replenished in the cycle with its formation from heme units through heme oxygenase localized from the endoplasmic reticulum. Bilirubin, being one of the last products of degradation in the liver, is further processed and excreted in bile after conjugation with glucuronic acid. BVR has also recently been recognized as a regulator of glucose metabolism and in cell growth and apoptosis control. BVR acts as a means to regenerate bilirubin in a redox cycle without significantly modifying the concentration of available bilirubin. With these levels maintained, it appears that BVR represents a new strategy for the treatment of multiple sclerosis, the mechanism is due to the amplification of the potent antioxidant actions of bilirubin, as this can ameliorate free radical-mediated diseases. Studies have shown that the BVR redox cycle is essential in providing physiological cytoprotection, genetic knock-outs and reduced BVR levels have demonstrated increased formation of ROS, and results in augmented cell death. Cells that experienced a 90% reduction in BVR experienced three times normal ROS levels
15.
2,4 Dienoyl-CoA reductase
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2,4 Dienoyl-CoA reductase also known as DECR1 is a protein which in humans is encoded by the DECR1 gene which resides on chromosome 8. This gene encodes an enzyme that participates in the beta oxidation. Specifically, it catalyzes the reduction of 2,4 Dienoyl-CoA thioesters of varying length by NADPH cofactor to 3-trans-enoyl-CoA of equivalent length, DECR is the second such enzyme and is the rate limiting step in this auxiliary flow. DECR is capable of reducing both 2-trans, 4-cis-dienoyl-CoA and 2-trans, 4-trans-dienoyl-CoA thioesters, as well as double bonds at odd carbon positions, at this time, there is no clear explanation for this of lack of stereo-specificity. The human DECR1 gene has 11 exons and resides on chromosome 8 at q21.3, sequence alignment indicates that there are five highly conserved acidic residues, one of which might act as a proton donor. Eukaryotic DECR exists in both the mitochondria and the peroxisome, the enzymes from each organelle are homologous and part of the short-chain dehydrogenase/reductase SDR super-family. MDECR is 124kD consisting of 335 amino acids before posttranslational modification, the secondary structure shares many of the motifs of SDR, including a Rossman fold for strong NADPH binding. The protein exists as a homotetramer in physiological environment, but has shown to also form monomers and dimers in solution. The enolate intermediate discussed earlier is stabilized by residues additional hydrogen bonds to Tyr199, lys214 and Ser210 are thought to increase the pKa of Tyr199 and stabilize the transition state. Additionally, at one end of the site there is a flexible loop that provides sufficient room for long carbon chains. This likely gives the flexibility to process fatty acid chains of various lengths. Substrate length for mDECR catalysis is thought to be limited at 20 carbons,2,4 Dienoyl-CoA thioester reduction by NADPH to 3-Enoyl CoA occurs by a two-step sequential mechanism via an enolate intermediate. DECR binds NADPH and the fatty acid thioester and positions them for specific hydride transfer to the Cδ on the hydrocarbon chain, the electrons from the Cγ-Cδ double bond move over to the Cβ-Cγ position, and those from the Cα-Cβ form an enolate. In the final step, a proton is abstracted from the water to the Cα, since the final proton comes from water, the pH has a significant effect on the catalytic rate with the enzyme demonstrating maximal activity at ~6.0. A decrease in activity at pH <6.0 can be explained by de-protonation of titratable residues that affect protein folding or substrate binding, mutant proteins with modifications at key acidic amino acids show order of magnitude increases in Km and/or decreases in Vmax. 2,4 Dienoyl-CoA Reductase from Escherichia Coli shares very similar properties to that of eukaryotes. In addition to NADPH, E. Coli DECR requires a set of FAD, FMN, a further distinction is E. Coli DECR produces the final 2-trans-enoyl-CoA without the need for Enoyl CoA Isomerase. The active site contains accurately positioned Tyr199 that donates a proton to the Cγ after hydride attack at the Cδ, surprisingly, mutation of the Tyr199 does not eliminate enzyme activity but instead changes the product to 3-trans-enoyl-CoA
16.
Oxygen
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Oxygen is a chemical element with symbol O and atomic number 8. It is a member of the group on the periodic table and is a highly reactive nonmetal. By mass, oxygen is the third-most abundant element in the universe, after hydrogen, at standard temperature and pressure, two atoms of the element bind to form dioxygen, a colorless and odorless diatomic gas with the formula O2. This is an important part of the atmosphere and diatomic oxygen gas constitutes 20. 8% of the Earths atmosphere, additionally, as oxides the element makes up almost half of the Earths crust. Most of the mass of living organisms is oxygen as a component of water, conversely, oxygen is continuously replenished by photosynthesis, which uses the energy of sunlight to produce oxygen from water and carbon dioxide. Oxygen is too reactive to remain a free element in air without being continuously replenished by the photosynthetic action of living organisms. Another form of oxygen, ozone, strongly absorbs ultraviolet UVB radiation, but ozone is a pollutant near the surface where it is a by-product of smog. At low earth orbit altitudes, sufficient atomic oxygen is present to cause corrosion of spacecraft, the name oxygen was coined in 1777 by Antoine Lavoisier, whose experiments with oxygen helped to discredit the then-popular phlogiston theory of combustion and corrosion. One of the first known experiments on the relationship between combustion and air was conducted by the 2nd century BCE Greek writer on mechanics, Philo of Byzantium. In his work Pneumatica, Philo observed that inverting a vessel over a burning candle, Philo incorrectly surmised that parts of the air in the vessel were converted into the classical element fire and thus were able to escape through pores in the glass. Many centuries later Leonardo da Vinci built on Philos work by observing that a portion of air is consumed during combustion and respiration, Oxygen was discovered by the Polish alchemist Sendivogius, who considered it the philosophers stone. In the late 17th century, Robert Boyle proved that air is necessary for combustion, English chemist John Mayow refined this work by showing that fire requires only a part of air that he called spiritus nitroaereus. From this he surmised that nitroaereus is consumed in both respiration and combustion, Mayow observed that antimony increased in weight when heated, and inferred that the nitroaereus must have combined with it. Accounts of these and other experiments and ideas were published in 1668 in his work Tractatus duo in the tract De respiratione. Robert Hooke, Ole Borch, Mikhail Lomonosov, and Pierre Bayen all produced oxygen in experiments in the 17th and the 18th century but none of them recognized it as a chemical element. This may have been in part due to the prevalence of the philosophy of combustion and corrosion called the phlogiston theory, which was then the favored explanation of those processes. Established in 1667 by the German alchemist J. J. Becher, one part, called phlogiston, was given off when the substance containing it was burned, while the dephlogisticated part was thought to be its true form, or calx. The fact that a substance like wood gains overall weight in burning was hidden by the buoyancy of the combustion products
17.
Dihydroorotate dehydrogenase
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Dihydroorotate dehydrogenase is an enzyme that in humans is encoded by the DHODH gene on chromosome 16. The protein encoded by this gene catalyzes the fourth enzymatic step and this protein is a mitochondrial protein located on the outer surface of the inner mitochondrial membrane. Inhibitors of this enzyme are used to treat diseases such as rheumatoid arthritis. DHODH can vary in content, oligomeric state, subcellular localization. An overall sequence alignment of these DHODH variants presents two classes of DHODHs, the cytosolic Class 1 and the membrane-bound Class 2, in Class 1 DHODH, a basic cysteine residue catalyzes the oxidation reaction, whereas in Class 2, the serine serves this catalytic function. This second subclass contains an addition subunit containing an iron-sulfur cluster, meanwhile, Class 2 DHODHs use coenzyme Q/ubiquinones for their oxidant. This sequence is adjacent to a pair of α-helices, α1 and α2, together, this pair forms a hydrophobic funnel that is suggested to serve as the insertion site for ubiquinone, in conjunction with the FMN binding cavity at the C-terminal. The two terminal domains are connected by an extended loop. The C-terminal domain is the larger of the two and folds into a conserved α/β-barrel structure with a core of eight parallel β-strands surrounded by eight α helices, human DHODH is a ubiquitous FMN flavoprotein. In bacteria, it is located on the side of the cytosolic membrane. In some yeasts, such as in Saccharomyces cerevisiae, it is a protein, whereas, in other eukaryotes. It is also the only enzyme in the biosynthesis pathway located in the mitochondria rather than the cytosol. Class 1 DHODHs follow a concerted mechanism, in which the two C–H bonds of dihydroorotic acid break in concert, Class 2 DHODHs follow a stepwise mechanism, in which the breaking of the C–H bonds precedes the equilibration of iminium into orotic acid. As an enzyme associated with the transport chain, DHODH could link mitochondrial bioenergetics, cell proliferation, ROS production. DHODH depletion also resulted in increased ROS production, decreased membrane potential, also, due to its role in DNA synthesis, inhibition of DHODH may provide a means to regulate transcriptional elongation. The immunomodulatory drugs teriflunomide and leflunomide have been shown to inhibit DHODH, human DHODH has two domains, an alpha/beta-barrel domain containing the active site and an alpha-helical domain that forms the opening of a tunnel leading to the active site. Leflunomide has been shown to bind in this tunnel, leflunomide is being used for treatment of rheumatoid and psoriatic arthritis, as well as multiple sclerosis. Additionally, DHODH may play a role in retinoid N-retinamide -mediated cancer suppression, inhibition of DHODH activity with teriflunomide or expression with RNA interference resulted in reduced ROS generation in, and thus apoptosis of, transformed skin and prostate epithelial cells
18.
Coproporphyrinogen III oxidase
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Coproporphyrinogen-III oxidase, mitochondrial is an enzyme that in humans is encoded by the CPOX gene. A genetic defect in the results in a reduced production of heme in animals. The medical condition associated with this defect is called hereditary coproporphyria. CPOX, the enzyme of the haem biosynthetic pathway, converts coproporphyrinogen III to protoporphyrinogen IX through two sequential steps of oxidative decarboxylation. The activity of the CPOX enzyme, located in the membrane, is measured in lymphocytes. The protein is a homodimer containing two internally bound iron atoms per molecule of native protein, the enzyme is active in the presence of molecular oxygen that acts as an electron acceptor. The enzyme is widely distributed having been found in a variety of eukaryotic and prokaryotic sources, human CPOX is a mitochondrial enzyme encoded by a 14 kb CPOX gene containing seven exons located on chromosome 3 at q11.2. CPOX is expressed as a 40 kDa precursor and contains an amino terminal mitochondrial targeting signal, after proteolytic processing, the protein is present as a mature form of a homodimer with a molecular mass of 37 kDa. Hereditary coproporphyria and harderoporphyria are two separate disorders that concern partial deficiency of CPOX. Additionally, it may be associated with abdominal pain and/or skin photosensitivity, hyper-excretion of coproporphyrin III in urine and faeces has been recorded in biochemical tests. HCP is a dominant inherited disorder, whereas harderoporphyria is a rare erythropoietic variant form of HCP and is inherited in an autosomal recessive fashion. Clinically, it is characterized by neonatal haemolytic anaemia, sometimes, the presence of skin lesions with marked faecal excretion of harderoporphyrin is also described in harderoporphyric patients. To date, over 50 CPOX mutations causing HCP have been described, most of these mutations result in substitution of amino acid residues within the structural framework of CPOX. CPOX has been shown to interact with the atypical keto-isocoproporphyrin in human subjects with mercury exposure, coproporphyrinogen III Oxidases at the US National Library of Medicine Medical Subject Headings This article incorporates text from the public domain Pfam and InterPro IPR001260
19.
Protoporphyrinogen oxidase
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Protoporphyrinogen oxidase is an enzyme that in humans is encoded by the PPOX gene. Protoporphyrinogen oxidase is responsible for the step in biosynthesis of protoporphyrin IX. This porphyrin is the precursor to hemoglobin, the carrier in animals, and chlorophyll. The enzyme catalyzes the dehydrogenation of protoporphyrinogen IX to form protoporphyrin IX, one additional enzyme must modify protoporphyrin IX before it becomes heme. Inhibition of this enzyme is a used in certain herbicides. The PPOX gene is located on the arm of chromosome 1 at position 22. This gene encodes the enzyme of heme biosynthesis, which catalyzes the 6-electron oxidation of protoporphyrinogen IX to form protoporphyrin IX. This protein is a associated with the outer surface of the inner mitochondrial membrane. More than 100 mutations that can cause variegate porphyria have been identified in the PPOX gene, one mutation, a substitution of the amino acid tryptophan for arginine at position 59, is found in about 95 percent of South African families with variegate porphyria. Mutations in the PPOX gene reduce the activity of the enzyme made by the gene and this buildup, in combination with nongenetic factors, causes this type of porphyria
20.
Bilirubin oxidase
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This enzyme belongs to the family of oxidoreductases, to be specific those acting on the CH-CH group of donor with oxygen as acceptor. The systematic name of this class is bilirubin, oxygen oxidoreductase. This enzyme is called bilirubin oxidase M-1. This enzyme participates in porphyrin and chlorophyll metabolism, two structures of bilirubin oxidase from the ascomycete Myrothecium verrucaria have been deposited in the Protein Data Bank
21.
Quinone
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The class includes some heterocyclic compounds. The prototypical member of the class is 1, 4-benzoquinone or cyclohexadienedione, other important examples are 1, 2-benzoquinone,1, 4-naphthoquinone and 9, 10-anthraquinone. Quinones are electrophilic Michael acceptors stabilised by conjugation, depending on the quinone and the site of reduction, reduction can either rearomatise the compound or break the conjugation. Conjugate addition nearly always breaks the conjugation, the term quinone is also used more generally for a large class of compounds formally derived from aromatic quinones through replacement of some hydrogen atoms by other atoms or radicals. A large scale application of quinones is for the production of hydrogen peroxide. Derivatives of quinones are common in biologically active molecules, some serve as electron acceptors in electron transport chains such as those in photosynthesis, and aerobic respiration. Phylloquinone is also known as Vitamin K1 as it is used by animals to help form certain proteins, which are involved in coagulation, bone formation. Natural or synthetic quinones show a biological or pharmacological activity, and they embody some claims in herbal medicine. These applications include purgative, antimicrobial and antiparasitic, anti-tumor, inhibition of PGE2 biosynthesis, many natural and artificial coloring substances are quinone derivatives. They are second only to azo dyes in importance as dyestuffs, alizarin, extracted from the madder plant, was the first natural dye to be synthesized from coal tar. Benzoquinone is used in chemistry as an oxidizing agent. Strongly oxidizing quinones include chloranil and 2, 3-dichloro-5, 6-dicyano-1,9, 10-Anthraquinone-2, 7-disulphonic acid a quinone similar to one found naturally in rhubarb has been used as a charge carrier in metal-free flow batteries. Quinones are commonly named with a prefix indicates the parent aromatic hydrocarbon. Infix multipliers -di-, -tri-, -tetra- are used there are 4,6,8 carbonyls. The position of the groups can be indicated before the prefix or after it. Anthraquinone Benzoquinone Naphthoquinone Plastoquinone Pyrroloquinoline quinone Quinones at the US National Library of Medicine Medical Subject Headings
22.
Succinate dehydrogenase
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Succinate dehydrogenase or succinate-coenzyme Q reductase or respiratory Complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the enzyme that participates in both the citric acid cycle and the electron transport chain. In step 6 of the citric cycle, SQR catalyzes the oxidation of succinate to fumarate with the reduction of ubiquinone to ubiquinol. This occurs in the mitochondrial membrane by coupling the two reactions together. Mitochondrial and many bacterial monomer SQRs are composed of four subunits, the first two subunits, a flavoprotein and an iron-sulfur protein, are hydrophilic. SdhA contains a covalently attached flavin adenine dinucleotide cofactor and the binding site. The second two subunits are hydrophobic membrane anchor subunits, SdhC and SdhD, human mitochondria contain two distinct isoforms of SdhA, these isoforms are also found in Ascaris suum and Caenorhabditis elegans. The subunits form a membrane-bound cytochrome b complex with six transmembrane helices containing one heme b group and a ubiquinone-binding site, two phospholipid molecules, one cardiolipin and one phosphatidylethanolamine, are also found in the SdhC and SdhD subunits. They serve to occupy the space below the heme b. These subunits are displayed in image 3, SdhA is green, SdhB is teal, SdhC is fuchsia, and SdhD is yellow. Around SdhC and SdhD is a membrane with the intermembrane space at the top of the image. Ubiquinone’s binding site, image 4, is located in a gap composed of SdhB, SdhC, ubiquinone is stabilized by the side chains of His207 of subunit B, Ser27 and Arg31 of subunit C, and Tyr83 of subunit D. The quinone ring is surrounded by Ile28 of subunit C and Pro160 of subunit B and these residues, along with Il209, Trp163, and Trp164 of subunit B, and Ser27 of subunit C, form the hydrophobic environment of the quinone-binding pocket. SdhA provides the site for the oxidation of succinate. The side chains Thr254, His354, and Arg399 of subunit A stabilize the molecule while FAD oxidizes and carries the electrons to the first of the iron-sulfur clusters and this can be seen in image 5. The succinate-binding site and ubiquinone-binding site are connected by a chain of redox centers including FAD and this chain extends over 40 Å through the enzyme monomer. All edge-to-edge distances between the centers are less than the suggested 14 Å limit for electron transfer. This electron transfer is demonstrated in image 8, little is known about the exact succinate oxidation mechanism
23.
SDHA
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Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the SDHA gene. This gene encodes a catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the inner membrane. SDHA contains the FAD binding site where succinate is deprotonated and converted to fumarate, mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29, alternatively spliced transcript variants encoding different isoforms have been found for this gene. The SDHA gene is located on the p arm of chromosome 5 at locus 15 and is composed of 16 exons, the SDHA protein encoded by this gene is 664 amino acids long and weighs 72.7 kDA. The SDH complex is located on the membrane of the mitochondria. The succinate dehydrogenase protein complex catalyzes the oxidation of succinate, initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, forming FADH2 and leaving fumarate, loosely bound to the active site, free to exit the protein. The electrons derived from succinate tunnel along the relay in the SDHB subunit until they reach the iron sulfur cluster, the electrons are then transferred to an awaiting ubiquinone molecule at the Q pool active site in the SDHC/SDHD dimer. The O1 carbonyl oxygen of ubiquinone is oriented at the site by hydrogen bond interactions with Tyr83 of SDHD. The presence of electrons in the iron sulphur cluster induces the movement of ubiquinone into a second orientation and this facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of SDHC. Following the first single electron reduction step, a radical species is formed. The second electron arrives from the cluster to provide full reduction of the ubiquinone to ubiquinol, SDHA acts as an intermediate in the basic SDH enzyme action, SDHA converts succinate to fumarate as part of the Citric Acid Cycle. This reaction also converts FAD to FADH2, electrons from the FADH2 are transferred to the SDHB subunit iron clusters. This function is part of the Respiratory chain Finally the electrons are transferred to the Ubiquinone pool via the SDHC/SDHD subunits, bi-allelic mutations have been described in Leigh syndrome, a progressive brain disorder that typically appears in infancy or early childhood. Affected children may experience vomiting, seizures, delayed development, muscle weakness, heart disease, kidney problems, and difficulty breathing can also occur in people with this disorder. The SDHA gene mutations responsible for Leigh syndrome change single amino acids in the SDHA protein or result in a short protein. These genetic changes disrupt the activity of the SDH enzyme, impairing the ability of mitochondria to produce energy and it is not known, however, how mutations in the SDHA gene are related to the specific features of Leigh syndrome
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SDHB
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Succinate dehydrogenase iron-sulfur subunit, mitochondrial also known as iron-sulfur subunit of complex II is a protein that in humans is encoded by the SDHB gene. The succinate dehydrogenase protein complex catalyzes the oxidation of succinate, SDHB is one of four protein subunits forming succinate dehydrogenase, the other three being SDHA, SDHC and SDHD. The SDHB subunit is connected to the SDHA subunit on the hydrophilic, catalytic end of the SDH complex and it is also connected to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. The subunit is a protein with three iron-sulfur clusters. The gene that codes for the SDHB protein is nuclear, not mitchondrial DNA, however, the expressed protein is located in the inner membrane of the mitochondria. The location of the gene in humans is on the first chromosome at locus p36. 1-p35, the gene is coded in 1,162 base pairs, partitioned in 8 exons. The expressed protein weighs 18.6 kDa and is composed of 180 amino acids, SDHB contains the iron-sulphur clusters necessary for tunneling electrons through the complex. It is located between SDHA and the two transmembrane subunits SDHC and SDHD, the SDH complex is located on the inner membrane of the mitochondria and participates in both the Citric Acid Cycle and Respiratory chain. SDHB acts as an intermediate in the basic SDH enzyme action shown in Figure 1 and this reaction also converts FAD to FADH2. Electrons from the FADH2 are transferred to the SDHB subunit iron clusters, finally the electrons are transferred to the Ubiquinone pool via the SDHC/SDHD subunits. This function is part of the Respiratory chain, initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, forming FADH2 and leaving fumarate, loosely bound to the active site, free to exit the protein. Electrons from FADH2 are transferred to the SDHB subunit iron clusters, the electrons are then transferred to an awaiting ubiquinone molecule at the Q pool active site in the SDHC/SDHD dimer. The O1 carbonyl oxygen of ubiquinone is oriented at the site by hydrogen bond interactions with Tyr83 of SDHD. The presence of electrons in the iron sulphur cluster induces the movement of ubiquinone into a second orientation and this facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of SDHC. Following the first single electron reduction step, a radical species is formed. The second electron arrives from the cluster to provide full reduction of the ubiquinone to ubiquinol, germline mutations in the gene can cause familial paraganglioma. The same condition is often called familial pheochromocytoma, less frequently, renal cell carcinoma can be caused by this mutation. Paragangliomas related to SDHB mutations have a rate of malignancy
25.
Succinate dehydrogenase complex subunit C
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Succinate dehydrogenase complex subunit C, also known as succinate dehydrogenase cytochrome b560 subunit, mitochondrial, is a protein that in humans is encoded by the SDHC gene. The encoded protein is one of two integral membrane proteins that anchor other subunits of the complex, which form the catalytic core, there are several related pseudogenes for this gene on different chromosomes. Mutations in this gene have been associated with paragangliomas, alternatively spliced transcript variants have been described. The gene that codes for the SDHC protein is nuclear, even though the protein is located in the membrane of the mitochondria. The location of the gene in humans is on the first chromosome at q21, the gene is partitioned in 6 exons. The SDHC gene produces an 18.6 kDa protein composed of 169 amino acids, the SDHC protein is one of the two transmembrane subunits of the four-subunit succinate dehydrogenase protein complex that resides in the inner mitochondrial membrane. The other transmembrane subunit is SDHD, the SDHC/SDHD dimer is connected to the SDHB electron transport subunit which, in turn, is connected to the SDHA subunit. The encoded protein is one of two integral membrane proteins that anchor other subunits of the complex, which form the catalytic core, SDHC forms part of the transmembrane protein dimer with SDHD that anchors Complex II to the inner mitochondrial membrane. The SDHC/SDHD dimer provides binding sites for ubiquinone and water during electron transport at Complex II, initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, forming FADH2 and leaving fumarate, loosely bound to the active site, free to exit the protein. The electrons derived from succinate tunnel along the relay in the SDHB subunit until they reach the iron sulfur cluster, the electrons are then transferred to an awaiting ubiquinone molecule at the Q pool active site in the SDHC/SDHD dimer. The O1 carbonyl oxygen of ubiquinone is oriented at the site by hydrogen bond interactions with Tyr83 of SDHD. The presence of electrons in the iron sulphur cluster induces the movement of ubiquinone into a second orientation and this facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of SDHC. Following the first single electron reduction step, a radical species is formed. The second electron arrives from the cluster to provide full reduction of the ubiquinone to ubiquinol, mutations in this gene have been associated with paragangliomas. More than 30 mutations in the SDHC gene have been found to increase the risk of hereditary paraganglioma-pheochromocytoma type 3, people with this condition have paragangliomas, pheochromocytomas, or both. Most of the inherited SDHC gene mutations change single amino acids in the SDHC protein sequence or result in a shortened protein, as a result, there is little or no SDH enzyme activity. Because the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell, the excess succinate abnormally stabilizes hypoxia-inducible factors, which also builds up in cells. Excess HIF stimulates cells to divide and triggers the production of blood vessels when they are not needed, rapid and uncontrolled cell division, along with the formation of new blood vessels, can lead to the development of tumors in people with hereditary paraganglioma-pheochromocytoma
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SDHD
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Succinate dehydrogenase cytochrome b small subunit, mitochondrial, also known as succinate dehydrogenase complex subunit D, is a protein that in humans is encoded by the SDHD gene. Names previously used for SDHD were PGL and PGL1, succinate dehydrogenase is an important enzyme in both the citric acid cycle and the electron transport chain. The SDHD gene is located on chromosome 11 at locus 11q23, the SDHD gene produces a 17 kDa protein composed of 159 amino acids. The SDHD protein is one of the two subunits of the four-subunit succinate dehydrogenase protein complex that resides in the inner mitochondrial membrane. The other transmembrane subunit is SDHC, the SDHC/SDHD dimer is connected to the SDHB electron transport subunit which, in turn, is connected to the SDHA subunit. SDHD forms part of the protein dimer with SDHC that anchors Complex II to the inner mitochondrial membrane. The SDHC/SDHD dimer provides binding sites for ubiquinone and water during electron transport at Complex II, initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, leaving fumarate, loosely bound to the active site, free to exit the protein. The electrons derived from succinate tunnel along the relay in the SDHB subunit until they reach the iron sulfur cluster, the electrons are then transferred to an awaiting ubiquinone molecule at the active site in the SDHC/SDHD dimer. The O1 carbonyl oxygen of ubiquinone is oriented at the site by hydrogen bond interactions with Tyr83 of SDHD. The presence of electrons in the iron sulphur cluster induces the movement of ubiquinone into a second orientation and this facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of subunit C. Following the first single electron reduction step, a radical species is formed. The second electron arrives from the cluster to provide full reduction of the ubiquinone to ubiquinol, mutations in the SDHD gene can cause familial paraganglioma. Germline mutations in SDHD were first linked to hereditary paraganglioma in 2000, since then, it has been shown that mutations in SDHB and to a lesser degree SDHC can cause paranglioma as well familial pheochromocytoma. Notably, the spectrum is different for the different mutations. SDHB mutations often lead to disease that is extra-adrenal, while SDHD mutation related tumors are more typically benign, originating in the head. The exact mechanism for tumorigenesis is not determined, but it is suspected that malfunction of the SDH complex can cause a response in the cell that leads to tumor formation. Mutations in the SDHB, SDHC, SDHD, and SDHAF2 genes lead to the loss or reduction of SDH enzyme activity, because the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell. As a result, the pathways are triggered in normal oxygen conditions
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Fumarate reductase
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Fumarate reductase is the enzyme that converts fumarate to succinate, and is important in microbial metabolism as a part of anaerobic respiration. Fumarate reductase complex includes four subunits, subunit A contains the site of fumarate reduction and a covalently bound flavin adenine dinucleotide prosthetic group. Subunit B contains three iron-sulphur centres, the menaquinol-oxidizing subunit C consists of five membrane-spanning, primarily helical segments and binds two haem b molecules. The D subunit may be required to anchor the catalytic components of the fumarate reductase complex to the cytoplasmic membrane, succinate dehydrogenase Fumarate reductase / succinate dehydrogenase FAD-binding site in PROSITE Fumarate Reductase at the US National Library of Medicine Medical Subject Headings EC1.3.99
