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.
Acyl-CoA
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Acyl-CoA is a group of coenzymes involved in the metabolism of fatty acids. It is a compound formed when coenzyme A attaches to the end of a long-chain fatty acid inside living cells. The compound undergoes beta oxidation, forming one or more molecules of acetyl-CoA and this, in turn, enters the citric acid cycle, eventually forming several molecules of ATP. To be oxidatively degraded, a fatty acid must first be activated in a reaction catalyzed by acyl-CoA synthetase. First, the fatty acid displaces the group of ATP. The acyladenylate product of the first step has a free energy of hydrolysis. The second step, transfer of the group to CoA. Fatty acids are activated in the cytosol, but oxidation occurs in the mitochondria, because there is no transport protein for CoA adducts, acyl groups must enter the mitochondria via a shuttle system involving the small molecule carnitine. Acetyl-CoA Beta oxidation Coenzyme A Acyl CoA dehydrogenase Fatty acid metabolism Acyl Coenzyme A at the US National Library of Medicine Medical Subject Headings
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.
Transferase
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A transferase is any one of a class of enzymes that enact the transfer of specific functional groups from one molecule to another. They are involved in hundreds of different biochemical pathways throughout biology, transferases are involved in myriad reactions in the cell. Transferases are also utilized during translation, in this case, an amino acid chain is the functional group transferred by a peptidyl transferase. Group would be the group transferred as a result of transferase activity. The donor is often a coenzyme, some of the most important discoveries relating to transferases occurred as early as the 1930s. Earliest discoveries of transferase activity occurred in other classifications of enzymes, including Beta-galactosidase, protease, prior to the realization that individual enzymes were capable of such a task, it was believed that two or more enzymes enacted functional group transfers. This observance was later verified by the discovery of its reaction mechanism by Braunstein and their analysis showed that this reversible reaction could be applied to other tissues. This assertion was validated by Rudolf Schoenheimers work with radioisotopes as tracers in 1937 and this in turn would pave the way for the possibility that similar transfers were a primary means of producing most amino acids via amino transfer. Another such example of early research and later reclassification involved the discovery of uridyl transferase. In 1953, the enzyme UDP-glucose pyrophosphorylase was shown to be a transferase, when it was found that it could reversibly produce UTP and G1P from UDP-glucose, another example of historical significance relating to transferase is the discovery of the mechanism of catecholamine breakdown by catechol-O-methyltransferase. This discovery was a part of the reason for Julius Axelrod’s 1970 Nobel Prize in Physiology or Medicine. Classification of transferases continues to this day, with new ones being discovered frequently, an example of this is Pipe, a sulfotransferase involved in the dorsal-ventral patterning of Drosophilia. Initially, the mechanism of Pipe was unknown, due to a lack of information on its substrate. Research into Pipes catalytic activity eliminated the likelihood of it being a heparan sulfate glycosaminoglycan, further research has shown that Pipe targets the ovarian structures for sulfation. Pipe is currently classified as a Drosophilia heparan sulfate 2-O-sulfotransferase, systematic names of transferases are constructed in the form of donor, acceptor grouptransferase. For example, a DNA methyltransferase is a transferase that catalyzes the transfer of a group to a DNA acceptor. In practice, many molecules are not referred to using this terminology due to more prevalent common names, in the EC system of classification, the accepted name for RNA Polymerase is DNA-directed RNA polymerase. Described primarily based on the type of biochemical group transferred, transferases can be divided into ten categories and these categories comprise over 450 different unique enzymes
12.
Metabolism
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Metabolism is the set of life-sustaining chemical transformations within the cells of living organisms. These enzyme-catalyzed reactions allow organisms to grow and reproduce, maintain their structures, usually, breaking down releases energy and building up consumes energy. The chemical reactions of metabolism are organized into metabolic pathways, in one chemical is transformed through a series of steps into another chemical. Enzymes act as catalysts that allow the reactions to proceed more rapidly, enzymes also allow the regulation of metabolic pathways in response to changes in the cells environment or to signals from other cells. The metabolic system of a particular organism determines which substances it will find nutritious, for example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals. The speed of metabolism, the rate, influences how much food an organism will require. A striking feature of metabolism is the similarity of the metabolic pathways. These striking similarities in metabolic pathways are likely due to their appearance in evolutionary history. Most of the structures that make up animals, plants and microbes are made from three classes of molecule, amino acids, carbohydrates and lipids. These biochemicals can be joined together to make such as DNA and proteins. Proteins are made of amino acids arranged in a linear chain joined together by peptide bonds, many proteins are enzymes that catalyze the chemical reactions in metabolism. Other proteins have structural or mechanical functions, such as those that form the cytoskeleton, Proteins are also important in cell signaling, immune responses, cell adhesion, active transport across membranes, and the cell cycle. Lipids are the most diverse group of biochemicals and their main structural uses are as part of biological membranes both internal and external, such as the cell membrane, or as a source of energy. Lipids are usually defined as hydrophobic or amphipathic biological molecules but will dissolve in organic solvents such as benzene or chloroform, the fats are a large group of compounds that contain fatty acids and glycerol, a glycerol molecule attached to three fatty acid esters is called a triacylglyceride. Several variations on this structure exist, including alternate backbones such as sphingosine in the sphingolipids. Steroids such as cholesterol are another class of lipids. Carbohydrates are aldehydes or ketones, with hydroxyl groups attached. Carbohydrates are the most abundant biological molecules, and fill numerous roles, such as the storage and transport of energy, the basic carbohydrate units are called monosaccharides and include galactose, fructose, and most importantly glucose
13.
Glycerophospholipid
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Glycerophospholipids or phosphoglycerides are glycerol-based phospholipids. They are the component of biological membranes. The term glycerophospholipid signifies any derivative of glycerophosphoric acid that contains at least one O-acyl, or O-alkyl, the alcohol here is glycerol, to which two fatty acids and a phosphoric acid are attached as esters. This basic structure is a phosphatidate, phosphatidate is an important intermediate in the synthesis of many phosphoglycerides. The presence of a group attached to the phosphate allows for many different phosphoglycerides. By convention, structures of these show the 3 glycerol carbon atoms vertically with the phosphate attached to carbon atom number three. In general, glycerophospholipids use a sn notation, which stands for stereospecific numbering, when the letters sn appear in the nomenclature, by convention the hydroxyl group of the second carbon of glycerol is on the left on a Fischer projection. The numbering follows the one of Fischers projections, being sn-1 the carbon at the top, the advantage of this particular notation is that the spatial conformation of the glycero-molecule is determined intuitively by the residues on the positions sn-1 and sn-3. For example sn-glycero-3-phosphoric acid and sn-glycero-1-phosphoric acid are enantiomers, Plasmalogens Plasmalogens are a type of phosphoglyceride. The first carbon of glycerol has a chain attached via an ether, not ester. The linkages are more resistant to attack than ester linkages are. The second carbon atom has a fatty acid linked by an ester, the third carbon links to an ethanolamine or choline by means of a phosphate ester. These compounds are key components of the membranes of muscles and nerves, Phosphatidates Phosphatidates are lipids in which the first two carbon atoms of the glycerol are fatty acid esters, and the 3 is a phosphate ester. The phosphate serves as a link to another alcohol-usually ethanolamine, choline, serine, the identity of the alcohol determines the subcategory of the phosphatidate. There is a charge on the phosphate and, in the case of choline or serine. The presence of charges give a head with an overall charge, the phosphate ester portion is hydrophilic, whereas the remainder of the molecule, the fatty acid tail, is hydrophobic. These are important components for the formation of lipid bilayers, phosphatidylethanoamines, phosphatidylcholines, and other phospholipids are examples of phosphatidates. Choline is the alcohol, with a charged quaternary ammonium, bound to the phosphate
14.
Ether lipid
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Ether lipids are lipids in which one or more of the carbon atoms on glycerol is bonded to an alkyl chain via an ether linkage, as opposed to the usual ester linkage. Ether lipids are called plasmalogens if these are glycerol-containing phospholipids with an unsaturated O- group at the first position on the glycerol chain, platelet-activating factor is an ether lipid which has an acetyl group instead of an acyl chain at the second position. The formation of the bond in mammals requires two enzymes, dihydroxyacetonephosphate acyltransferase and alkyldihydroxyacetonephosphate synthase, that reside in the peroxisome. Accordingly, peroxisomal defects often lead to impairment of ether-lipid production, monoalkylglycerol ethers are also generated from 2-acetyl MAGEs by KIAA1363. Plasmalogens as well as some 1-O-alkyl lipids are ubiquitous and sometimes parts of the cell membranes in mammals. In archaea, ether lipids are the polar lipids in the cell envelope. In these cells, diphytanylglycerolipids or bipolar macrocyclic tetraethers can form covalently linked bilayers, Ether lipids can also act directly in cell signaling, as the platelet-activating factor is an ether lipid signaling molecule that is involved in leukocyte function in the mammalian immune system. This antioxidant activity comes from the enol ether double bond being targeted by a variety of reactive oxygen species, archaeol Ether phospholipids at the US National Library of Medicine Medical Subject Headings
15.
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
16.
Thiolase
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Thiolases, also known as acetyl-coenzyme A acetyltransferases, are enzymes which convert two units of acetyl-CoA to acetoacetyl CoA in the mevalonate pathway. Thiolases are ubiquitous enzymes that have key roles in many biochemical pathways, including the beta oxidation pathway of fatty acid degradation. Members of the family can be divided into two broad categories, degradative thiolases and biosynthetic thiolases. These two different types of thiolase are found both in eukaryotes and in prokaryotes, acetoacetyl-CoA thiolase and 3-ketoacyl-CoA thiolase, 3-ketoacyl-CoA thiolase has a broad chain-length specificity for its substrates and is involved in degradative pathways such as fatty acid beta-oxidation. Acetoacetyl-CoA thiolase is specific for the thiolysis of acetoacetyl-CoA and involved in pathways such as poly beta-hydroxybutyric acid synthesis or steroid biogenesis. The formation of a bond is a key step in the biosynthetic pathways by which fatty acids. The thiolase superfamily enzymes catalyse the formation via a thioester-dependent Claisen condensation reaction mechanism. Thiolases are a family of evolutionarily related enzymes, two different types of thiolase are found both in eukaryotes and in prokaryotes, acetoacetyl-CoA thiolase and 3-ketoacyl-CoA thiolase. 3-ketoacyl-CoA thiolase has a broad specificity for its substrates and is involved in degradative pathways such as fatty acid beta-oxidation. Acetoacetyl-CoA thiolase is specific for the thiolysis of acetoacetyl-CoA and involved in pathways such as poly beta-hydroxybutyrate synthesis or steroid biogenesis. In eukaryotes, there are two forms of 3-ketoacyl-CoA thiolase, one located in the mitochondrion and the other in peroxisomes, there are two conserved cysteine residues important for thiolase activity. Mammalian nonspecific lipid-transfer protein is a protein which seems to exist in two different forms, a 14 Kd protein and a larger 58 Kd protein, the former is found in the cytoplasm or the mitochondria and is involved in lipid transport, the latter is found in peroxisomes. The C-terminal part of SCP-x is identical to SCP-2 while the N-terminal portion is evolutionary related to thiolases, thioesters are more reactive than oxygen esters and are common intermediates in fatty-acid metabolism. These thioesters are made by conjugating the fatty acid with the free SH group of the moiety of either coenzyme A or acyl carrier protein. It is well established from studies on the biosynthetic thiolase from Z. ramigera that the reaction occurs in two steps and follows ping-pong kinetics. In the first step of both the degradative and biosynthetic reactions, the nucleophilic Cys89 attacks the substrate, leading to the formation of a covalent acyl-CoA intermediate. In the second step, the addition of CoA or acetyl-CoA to the acyl–enzyme intermediate triggers the release of the product from the enzyme, most enzyme of the thiolase super family are dimers. However, monomers have not been observed, tetrameters are observed only in the thiolase subfamily and, in these cases, the dimers have dimerized to become tetramers
17.
N-Acetylglutamate synthase
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N-acetylglutamate synthase is an enzyme that catalyses the production of N-Acetylglutamate from glutamate and acetyl-CoA. NAG can be used in the production of ornithine and arginine, in mammals, NAGS is expressed primarily in the liver and small intestine, and is localized to the mitochondrial matrix. Most prokaryotes and lower eukaryotes produce NAG through orinithine acetyltransferase, which is part of a ‘cyclic’ ornithine production pathway, NAGS is therefore used in a supportive role, replenishing NAG reserves as required. In some plants and bacteria, however, NAGS catalyzes the first step in a ‘linear’ arginine production pathway, the protein sequences of NAGS between prokaryotes, lower eukaryotes and higher eukaryotes have shown a remarkable lack of similarity. Sequence identity between prokaryotic and eukaryotic NAGS is largely <30%, while sequence identity between lower and higher eukaryotes is ~20%, enzyme activity of NAGS is modulated by L-arginine, which acts as an inhibitor in plant and bacterial NAGS, but an effector in vertebrates. While the role of arginine as an inhibitor of NAG in ornithine and arginine synthesis is well understood, the currently accepted role of NAG in vertebrates is as an essential allosteric cofactor for CPS1, and therefore it acts as the primary controller of flux through the urea cycle. In this role, feedback regulation from arginine would act to signal NAGS that ammonia is plentiful within the cell, as it stands, the evolutionary journey of NAGS from essential synthetic enzyme to primary urea cycle controller is yet to be fully understood. Studies conducted using NAGS derived from Neisseria gonorrhoeae suggest that NAGS proceeds through the previously described one-step mechanism, in this proposal, the carbonyl group of acetyl-CoA is attacked directly by the α-amino nitrogen of glutamate. Inactivity of NAGS results in N-acetylglutamate synthase deficiency, a form of hyperammonemia, in many vertebrates, N-acetylglutamate is an essential allosteric cofactor of CPS1, the enzyme that catalyzes the first step of the urea cycle. Without NAG stimulation, CPS1 cannot convert ammonia to carbamoyl phosphate, carbamoyl glutamate has shown promise as a possible treatment for NAGS deficiency. This is suspected to be a result of the similarities between NAG and carabamoyl glutamate, which allows carbamoyl glutamate to act as an effective agonist for CPS1
18.
Choline acetyltransferase
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Choline acetyltransferase is a transferase enzyme responsible for the synthesis of the neurotransmitter acetylcholine. ChAT catalyzes the transfer of a group from the coenzyme, acetyl-CoA. ChAT is found in concentration in cholinergic neurons, both in the central nervous system and peripheral nervous system. As with most of nerve terminal proteins, ChAT is produced in the body of the neuron and is transported to the nerve terminal, presence of ChAT in a nerve cell classifies this cell as a cholinergic neuron. In humans, the choline acetyltransferase enzyme is encoded by the CHAT gene, Choline acetyltransferase was first described by David Nachmansohn and A. L. Machado in 1943. Based on prior research showing that acetylcholines actions on structural proteins were responsible for nerve impulses, Nachmansohn, an enzyme has been extracted from brain and nervous tissue which forms acetylcholine. The formation occurs only in presence of adenosinetriphosphate, the enzyme is called choline acetylase. It was not until 1945 that Coenzyme A was discovered simultaneously and independently by three laboratories, Nachmansohns being one of these, subsequently acetyl-CoA, at the time called “active acetate, ” was discovered in 1951. The 3D structure of rat-derived ChAT was not solved until nearly 60 years later, the 3D structure of ChAT has been solved by X-ray crystallography PDB, 2FY2. The choline substrate fits into a pocket in the interior of ChAT, the 3D crystal structure shows the acetyl group of acetyl-CoA abuts the choline binding pocket – minimizing the distance between acetyl-group donor and receiver. ChAT is very conserved across the animal genome, among mammals, in particular, there is very high sequence similarity. Human and cat ChAT, for example, have 89% sequence identity, sequence identity with Drosophila is about 30%. There are two forms of ChAT, Soluble form and membrane-bound form, the soluble form accounts for 80-90% of the total enzyme activity while the membrane-bound form is responsible for the rest of 10-20% activity. However, there has long been a debate on how the form of ChAT is bound to the membrane. The membrane-bound form of ChAT is associated with synaptic vesicles, there exist two isoforms of ChAT, both encoded by the same sequence. The common type ChAT is present in both the CNS and PNS, peripheral type ChAT is preferentially expressed in the PNS in humans, and arises from exon skipping during post-transcriptional modification. Therefore, the amino acid sequence is similar, however pChAT is missing parts of the sequence present in cChAT. The pChAT isoform was discovered in 2000 based on observations that brain-derived ChAT antibodies failed to stain peripheral cholinergic neurons as they do for those found in the brain, cholinergic systems are implicated in numerous neurologic functions
19.
Dihydrolipoyl transacetylase
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Dihydrolipoyl transacetylase is an enzyme component of the multienzyme pyruvate dehydrogenase complex. The pyruvate dehydrogenase complex is responsible for the decarboxylation step that links glycolysis to the citric acid cycle. This involves the transformation of pyruvate from glycolysis into acetyl-CoA which is used in the citric acid cycle to carry out cellular respiration. There are three different enzyme components in the pyruvate dehydrogenase complex, pyruvate dehydrogenase is responsible for the oxidation of pyruvate, dihydrolipoyl transacetylase transfers the acetyl group to coenzyme A, and dihydrolipoyl dehydrogenase regenerates the lipoamide. In humans, dihydrolipoyl transacetylase enzymatic activity resides in the pyruvate dehydrogenase complex component E2 that is encoded by the DLAT gene, the systematic name of this enzyme class is acetyl-CoA, enzyme N6-lysine S-acetyltransferase. Other names in use include, All dihydrolipoyl transacetylases have a unique multidomain structure consisting of,3 lipoyl domains, an interaction domain. Interestingly all the domains are connected by disordered, low complexity linker regions, depending on the species, multiple subunits of dihydrolipoyl transacetylase enzymes can arrange together into either a cubic or dodecahedral shape. The cubic core structure, found in such as Azotobacter vinelandii, is made up of 24 subunits total. The catalytic domains are assembled into trimers with the site located at the subunit interface. The topology of this active site is identical to that of chloramphenicol acetyltransferase. Eight of these trimers are then arranged into a truncated cube. The two main substrates, CoA and the lipoamide, are found at two opposite entrances of a 30 Å long channel which runs between the subunits and forms the catalytic center, CoA enters from the inside of the cube, and the lipoamide enters from the outside. The subunits are arranged in sets of three, similar to the trimers in the cubic shape, with each set making up one of the 20 dodecahedral vertices. Dihydrolipoyl transacetylase participates in the decarboxylation reaction that links glycolysis to the citric acid cycle. The various parts of cellular respiration take place in different parts of the cell, thus pyruvate dehydrogenase complexes are found in the mitochondria of eukaryotes. Pyruvate decarboxylation requires a few cofactors in addition to the enzymes that make up the complex, the first is thiamine pyrophosphate, which is used by pyruvate dehydrogenase to oxidize pyruvate and to form a hydroxyethyl-TPP intermediate. This intermediate is taken up by dihydrolipoyl transacetylase and reacted with a second lipoamide cofactor to generate an acetyl-dihydrolipoyl intermediate and this second intermediate can then be attacked by the nucleophilic sulfur attached to Coenzyme A, and the dihydrolipoamide is released. This results in the production of acetyl CoA, which is the end goal of pyruvate decarboxylation, the dihydrolipoamide is taken up by dihydrolipoyl dehydrogenase, and with the additional cofactors FAD and NAD+, regenerates the original lipoamide
20.
HADHB
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Trifunctional enzyme subunit beta, mitochondrial also known as 3-ketoacyl-CoA thiolase, acetyl-CoA acyltransferase, or beta-ketothiolase is an enzyme that in humans is encoded by the HADHB gene. HADHB is a subunit of the trifunctional protein and has thiolase activity. The HADHB gene is located on chromosome 2, with its location being 2p23. HADHB encodes a 51.2 kDa protein that is composed of 474 amino acids,124 peptides have been observed through mass spectrometry data and this gene encodes the beta subunit of the mitochondrial trifunctional protein, a catalyst of mitochondrial beta-oxidation of long chain fatty acids. The HADHB protein catalyzes the final step of beta-oxidation, in which 3-ketoacyl CoA is cleaved by the group of another molecule of Coenzyme A. The thiol is inserted between C-2 and C-3, which yields an acetyl CoA molecule and an acyl CoA molecule, the encoded protein can also bind RNA and decreases the stability of some mRNAs. The genes of the alpha and beta subunits of the trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation. Mutations in this gene, along with mutations in HADHA, result in trifunctional protein deficiency, mutations in either gene have similar clinical presentations. Trifunctional protein deficiency is characterized by decreased activity of long-chain 3-hydroxyacyl-CoA dehydrogenase, long-chain enoyl-CoA hydratase, additionally, some presents showed symptoms associated with myopathy, recurrent and episodic rhabdomyolysis, and sensorimotor axonal neuropathy. In some cases, symptoms of the deficiency can present as dilated cardiomyopathy, congestive heart failure, the deficiency has presented as hydrops fetalis and HELLP syndrome in fetuses. HADHB is a molecular target of ERα in the mitochondria. Additionally, HADHB has been shown to bind to the distal 3’ untranslated region of renin mRNA, HADHB protein, human at the US National Library of Medicine Medical Subject Headings This article incorporates text from the United States National Library of Medicine, which is in the public domain
21.
Chloramphenicol acetyltransferase
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Chloramphenicol acetyltransferase is a bacterial enzyme that detoxifies the antibiotic chloramphenicol and is responsible for chloramphenicol resistance in bacteria. This enzyme covalently attaches an acetyl group from acetyl-CoA to chloramphenicol, a histidine residue, located in the C-terminal section of the enzyme, plays a central role in its catalytic mechanism. The crystal structure of the type III enzyme from Escherichia coli with chloramphenicol bound has been determined. CAT is a trimer of subunits and the trimeric structure is stabilised by a number of hydrogen bonds. CAT is used as a system to measure the level of a promoter or its tissue-specific expression. This article incorporates text from the public domain Pfam and InterPro IPR001707
22.
Aralkylamine N-acetyltransferase
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It is in humans encoded by the ~2.5 kb AANAT gene containing four exons, located on chromosome 17q25. The gene is translated into a 23 kDa large enzyme and it is well conserved through evolution and the human form of the protein is 80% identical to sheep and rat AANAT. It is an acetyl-CoA-dependent enzyme of the GCN5-related family of N-acetyltransferases and it may contribute to multifactorial genetic diseases such as altered behavior in sleep/wake cycle and research is on-going with the aim of developing drugs that regulate AANAT function. The systematic name of this class is acetyl-CoA, 2-arylethylamine N-acetyltransferase. The AANAT mRNA transcript is expressed in the central nervous system. It is detectable at low levels in brain regions including the pituitary gland as well as in the retina. It is most highly abundant in the gland which is the site of melatonin synthesis. Brain and pituitary AANAT may be involved in the modulation of serotonin-dependent aspects of human behavior, in the pinealocyte cells of the pineal gland, aralkylamine N-acetyltransferase is involved in the conversion of serotonin to melatonin. It is the enzyme in the melatonin synthesis controlling the night/day rhythm in melatonin production in the vertebrate pineal gland. Melatonin is essential for reproduction, modulates the function of the circadian clock in the suprachiasmatic nucleus. Due to its important role in rhythm, AANAT is subjected to extensive regulation that is responsive to light exposure. It may contribute to genetic diseases such as altered behavior in sleep/wake cycle. The primary chemical reaction that is catalyzed by aralkylamine N-acetyltransferase uses two substrates, acetyl-CoA and serotonin, AANAT catalyzes the transfer of the acetyl group of Acetyl-CoA to the primary amine of serotonin, thereby producing CoA and N-acetylserotonin. In the biosynthesis of melatonin, N-acetylserotonin is further methylated by another enzyme, the N-acetyltransferase reaction has been suggested to be the rate-determining step, and thus Serotonin N-acetyltransferase has emerged as a target for inhibitor design. AANAT obeys an ordered ternary-complex mechanism, the substrates bind sequentially with acetyl-CoA binding to the free enzyme followed by the binding of serotonin to form the ternary complex. After the transfer of the group has occurred, the products are orderly released with N-acetyl-serotonin first. Arylkylamine N-acetyltransferase is a polypeptide with a length of 207 amino acid residues. The secondary structure consists of helices and beta sheets
23.
ARD1A
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N-alpha-acetyltransferase 10 also known as NatA catalytic subunit Naa10 and arrest-defective protein 1 homolog A is an enzyme that in humans is encoded NAA10 gene. In higher eukaryotes,5 other N-acetyltransferase complexes, NatB-NatF, have described that differ both in substrate specificity and subunit composition. The human NAA10 is located on chromosome Xq28 and is encoded by 8 exons 2 encoding three different isoforms derived from alternate splicing, naa11 has also been found in mouse, where it is mainly expressed in the testis. NAA11 is located on chromosome 4q21.21 in human and 5 E3 in mouse, in mouse, NAA10 is located on chromosome X A7.3 and contains 9 exons. Homologues for Naa10 have been identified in almost all kingdoms of life analyzed, including plants, fungi, amoebozoa, archaeabacteria, to date, no X-ray crystal structure of the human Naa10 has been reported. Furthermore, the recent X-ray crystal structure of the 100 kD holo-NatA complex from S, the X-ray crystal structure of archaeal T. volcanium Naa10 has also been reported, revealing multiple distinct modes of acetyl-Co binding involving the loops between β4 and α3, including the P-loop. A functional nuclear localization signal in the C-terminus of hNaa10 between residues 78 and 83 has been described, furthermore, post-translational acetylation by non-ribosome-associated Naa10 might occur. About 40-50 % of all proteins are potential NatA substrates, additionally, in a monomeric state, structural rearrangements of the substrate binding pocket Naa10 allow acetylation of N-termini with acidic side chains. Furthermore, Nε-acetyltransferase activity and N-terminal propionyltransferase activity have been reported, despite the fact that Nα-terminal acetylation of proteins has been known for many years, the functional consequences of this modification are not well understood. Naa10 is essential in D. melanogaster, C. elegans, in S. Naa10-knockout mice have very recently been reported to be viable, displaying a defect in bone development. The girl was reported as having delayed closure of the fontanels, delayed bone age, broad great toes, mild pectus carinatum, pulmonary stenosis, atrial septal defect. The boy was reported as having small hands/feet, high arched palate, patient fibroblasts displayed cell proliferation defects, dysregulation of genes involved in retinoic acid signaling pathway, such as STRA6, and deficiencies in retinol uptake
24.
Histone acetyltransferase
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Histone acetyltransferases are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on, in general, histone acetylation increases gene expression. In general, histone acetylation is linked to activation and associated with euchromatin. Histone acetyltransferases can also acetylate non-histone proteins, such as nuclear receptors, HATs are traditionally divided into two different classes based on their subcellular localization. Type A HATs are located in the nucleus and are involved in the regulation of expression through acetylation of nucleosomal histones in the context of chromatin. They contain a bromodomain, which helps them recognize and bind to acetylated lysine residues on histone substrates, Gcn5, p300/CBP, and TAFII250 are some examples of type A HATs that cooperate with activators to enhance transcription. Type B HATs are located in the cytoplasm and are responsible for acetylating newly synthesized histones prior to their assembly into nucleosomes and these HATs lack a bromodomain, as their targets are unacetylated. The acetyl groups added by type B HATs to the histones are removed by HDACs once they enter the nucleus and are incorporated into chromatin, Hat1 is one of the few known examples of a type B HAT. Despite this historical classification of HATs, some HAT proteins function in multiple complexes or locations, HATs can be grouped into several different families based on sequence homology as well as shared structural features and functional roles. The Gcn5-related N-acetyltransferase family includes Gcn5, PCAF, Hat1, Elp3, Hpa2, Hpa3, ATF-2 and these HATs are generally characterized by the presence of a bromodomain, and they are found to acetylate lysine residues on histones H2B, H3, and H4. All members of the GNAT family are characterized by up to four conserved motifs found within the catalytic HAT domain and this includes the most highly conserved motif A, which contains an Arg/Gln-X-X-Gly-X-Gly/Ala sequence that is important for acetyl-CoA recognition and binding. The C motif is found in most GNATs, but it is not present in the majority of other known HATs, the yeast Gcn5 HAT is one of the best-characterized members of this family. It has four domains, including an N-terminal domain, a highly conserved catalytic domain, an Ada2 interaction domain. PCAF and GCN5 are mammalian GNATs that share a degree of homology throughout their sequences. These proteins have a 400-residue N-terminal region that is absent in yeast Gcn5, Hat1 was the first HAT protein to be identified. It is responsible for most of the cytoplasmic HAT activity in yeast, Elp3 is an example of a type A HAT found in yeast. It is part of the RNA polymerase II holoenzyme and plays a role in transcriptional elongation, the MYST family of HATs is named after its four founding members MOZ, Ybf2, Sas2, and Tip60. Other important members include Esa1, MOF, MORF, and HBO1 and these HATs are typically characterized by the presence of zinc fingers and chromodomains, and they are found to acetylate lysine residues on histones H2A, H3, and H4
25.
P300-CBP coactivator family
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P300 and CBP have similar structures. Both contain five protein interaction domains, the nuclear receptor interaction domain, the CREB and MYB interaction domain, the cysteine/histidine regions and the interferon response binding domain. The last four domains, KIX, TAZ1, TAZ2 and IBiD of p300, in addition p300 and CBP each contain a protein or histone acetyltransferase domain and a bromodomain that binds acetylated lysines and a PHD finger motif with unknown function. The conserved domains are connected by stretches of unstructured linkers. P300 and CBP are thought to increase gene expression in three ways, by relaxing the chromatin structure at the gene promoter through their intrinsic histone acetyltransferase activity, recruiting the basal transcriptional machinery including RNA polymerase II to the promoter. P300 regulates transcription by binding to transcription factors. The last four domains, KIX, TAZ1, TAZ2 and IBiD of p300, enhancer regions, which regulate gene transcription, are known to be bound by p300 and CBP, and ChIP-seq for these proteins has been used to predict enhancers. Work done by Heintzman and colleagues showed that 70% of the p300 binding occurs in open chromatin regions as seen by the association with DNase I hypersensitive sites. Furthermore, they have described that most p300 binding occurs far away from transcription start sites and they have also found some correlation between p300 and RNAPII binding at enhancers, which can be explained by the physical interaction with promoters or by enhancer RNAs. An example of a process involving p300 and CBP is G protein signaling, some G proteins stimulate adenylate cyclase that results in elevation of cAMP. CAMP stimulates PKA, which consists of four subunits, two regulatory and two catalytic, binding of cAMP to the regulatory subunits causes release of the catalytic subunits. These subunits can then enter the nucleus to interact with transcriptional factors, the transcription factor CREB, which interacts with a DNA sequence called a cAMP response element, is phosphorylated on a serine in the KID domain. This pathway can be initiated by adrenaline activating β-adrenergic receptors on the cell surface, mutations in CBP, and to a lesser extent p300, are the cause of Rubinstein-Taybi Syndrome, which is characterized by severe mental retardation. These mutations result in the loss of one copy of the gene in each cell, some mutations lead to the production of a very short, nonfunctional version of the CBP or p300 protein, while others prevent one copy of the gene from making any protein at all. Defects in CBP HAT activity appears to cause problems in long-term memory formation, CBP and p300 have also been found to be involved in multiple rare chromosomal translocations that are associated with acute myeloid leukemia. For example, researchers have found a translocation between chromosomes 8 and 22 in several people with a cancer of blood cells called acute myeloid leukemia, another translocation, involving chromosomes 11 and 22, has been found in a small number of people who have undergone cancer treatment. This chromosomal change is associated with the development of AML following chemotherapy for other forms of cancer, mutations in the p300 gene have been identified in several other types of cancer. These mutations are somatic, which means they are acquired during a lifetime and are present only in certain cells
26.
NAT2
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N-acetyltransferase 2, also known as NAT2, is an enzyme which in humans is encoded by the NAT2 gene. This gene encodes a type of N-acetyltransferase, the NAT2 isozyme functions to both activate and deactivate arylamine and hydrazine drugs and carcinogens. Polymorphisms in this gene are responsible for the N-acetylation polymorphism in human populations segregate into rapid, intermediate. Polymorphisms in NAT2 are also associated with higher incidences of cancer, a second arylamine N-acetyltransferase gene is located near NAT2. The NAT2 acetylator phenotype can be inferred from NAT2 genotype, NAT2 human gene location in the UCSC Genome Browser. NAT2 human gene details in the UCSC Genome Browser, template, The Arylamine N-acetyltransferase Gene Nomenclature Committee homepage, http, //nat. mbg. duth. gr/
27.
Carnitine palmitoyltransferase I
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The product is often Palmitoylcarnitine, but other fatty acids may also be substrates. It is part of a family of enzymes called carnitine acyltransferases and this preparation allows for subsequent movement of the acyl carnitine from the cytosol into the intermembrane space of mitochondria. Three isoforms of CPT1 are currently known, CPT1A, CPT1B, CPT1 is associated with the outer mitochondrial membrane. This enzyme can be inhibited by malonyl CoA, the first committed intermediate produced during fatty acid synthesis and its role in fatty acid metabolism makes CPT1 important in many metabolic disorders such as diabetes. Since its crystal structure is not known, its mechanism of action remains to be determined. CPT1 is a membrane protein that associates with the mitochondrial outer membrane through transmembrane regions in the peptide chain. Both the N- and C-terminal domains are exposed to the side of the membrane. Three isoforms of CPT1 exist in mammalian tissues, the liver isoform is found throughout the body on the mitochondria of all cells except for skeletal muscle cells and brown adipose cells. The muscle isoform is expressed in heart and skeletal muscle cells. A third isoform, the isoform, was isolated in 2002. It is expressed predominantly in the brain and testes, an important structural difference between CPT1 and CPT2, CRAT and carnitine octanoyltransferase is that CPT1 contains an additional domain at its N-terminal consisting of about 160 amino acids. It has been determined that this additional N-terminal domain is important for the key molecule of CPT1. Two distinct binding sites have been proposed to exist in CPT1A and it has been suggested that malonyl-CoA may behave as a competitive inhibitor of CPT1A at this site. A second “O site” has been proposed to bind more tightly than the A site. Unlike the A site, the O site binds to malonyl-CoA via the group of the malonate moiety of malonyl-CoA. The binding of malonyl-CoA to either the A and O sites inhibits the action of CPT1A by excluding the binding of carnitine to CPT1A, since a crystal structure of CPT1A has yet to be isolated and imaged, its exact structure remains to be elucidated. Because crystal structure data is unavailable, the exact mechanism of CPT1 is not currently known. A couple different possible mechanisms for CPT1 have been postulated, both of which include the histidine residue 473 as the key catalytic residue
28.
Carnitine palmitoyltransferase II
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Carnitine O-palmitoyltransferase 2, mitochondrial is an enzyme that in humans is encoded by the CPT2 gene. Carnitine palmitoyltransferase II precursor is a membrane protein which is transported to the mitochondrial inner membrane. CPT2 together with carnitine palmitoyltransferase I oxidizes long-chain fatty acids in the mitochondria, defects in this gene are associated with mitochondrial long-chain fatty-acid oxidation disorders and carnitine palmitoyltransferase II deficiency. Model organisms have been used in the study of CPT2 function, a conditional knockout mouse line called Cpt2tm1bWtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion, additional screens performed, - In-depth immunological phenotyping Carnitine palmitoyltransferase I
29.
Serine C-palmitoyltransferase
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This reaction is a key step in the biosynthesis of sphingosine which is a precursor of many other sphingolipids. This enzyme participates in sphingolipid metabolism and it employs one cofactor, pyridoxal phosphate. This enzyme belongs to the family of transferases, specifically those acyltransferases transferring groups other than aminoacyl groups, the systematic name of this enzyme class is palmitoyl-CoA, L-serine C-palmitoyltransferase. Other names in use include, serine palmitoyltransferase, SPT, 3-oxosphinganine synthetase. Serine C-palmitoyltransferase is a member of the AOS family of PLP-dependent enzymes, the human enzyme is a heterodimer consisting of two monomeric subunits known as long chain base 1 and 2 encoded by separate genes. As of late 2007, two structures have been solved for this class of enzymes, with PDB accession codes 2JG2, the PLP -dependent serine C-palmitoyltransferase carries out the first enzymatic step of de novo sphingolipid biosynthesis. The enzyme catalyses a Claisen-like condensation between L-serine and an acyl-CoA thioester substrate or an acyl-ACP thioester substrate, to form 3-ketodihydrosphingosine, initially PLP cofactor is bound to the active-site lysine via a Schiff base to form the holo-form or internal aldimine of the enzyme. The amine group of L-serine then attacks and displaces the lysine bound to PLP, subsequently, deprotonation occurs at the Cα of serine, forming the quinonoid intermediate that attacks the incoming thioester substrate. Following decarboxylation and lysine attack, the product 3-ketodihydrosphingosine is released and this condensation reaction forms the sphingoid base or long-chain base found in all subsequent intermediate sphingolipids and complex sphingolipids in the organism. A variety of different serine C-palmitoyltransferase isoforms exist across different species, unlike in eukaryotes, where the enzyme is heterodimeric and membrane bound, bacterial enzymes are homodimers and cytoplasmic. Specifically, the S. paucimobilis isoform features an active-site arginine residue that plays a key role in stabilizing the carboxy moiety of the PLP-L-serine external aldimine intermediate, similar arginine residues in enzyme homologues play analogous roles. Other homologues, such as in Sphingobacterium multivorum, feature the carboxy moiety bound to serine and methionine residues via water in place of arginine. Certain enzyme homologues, such as in S. multivorum as well as B. stolpii, are found to be associated with the cell membrane. The B. stolpii homologue also features substrate inhibition by palmitoyl-CoA and this is consistent with elevated levels of deoxysphingoid bases formed by the condensation of alanine with palmitoyl-CoA observed in HSAN1 patients. Serine C-palmitoyltransferase is expressed in a number of species from bacteria to humans. The bacterial enzyme is a water-soluble homodimer whereas in eukaryotes the enzyme is a heterodimer which is anchored to the endoplasmic reticulum, humans and other mammals express three paralogous subunits SPTLC1, SPTLC2, and SPTLC3. It was originally proposed that the human enzyme is a heterodimer between a SPTLC1 subunit and a second subunit which is either SPTLC2 or SPTLC3. However more recent data suggest that the enzyme may exist as a complex, possibly an octamer
30.
SPTLC2
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Serine palmitoyltransferase, long chain base subunit 2, also known as SPTLC2, is a protein which in humans is encoded by the SPTLC2 gene. This gene encodes a long chain base subunit of serine palmitoyltransferase, serine palmitoyltransferase, which consists of two different subunits, is the initial enzyme in sphingolipid biosynthesis. It catalyzes the pyridoxal 5-phosphate dependent condensation of L-serine and palmitoyl CoA to 3-oxosphinganine, mutations in this gene were identified in patients with hereditary sensory neuropathy type I. Alternatively spliced variants encoding different isoforms have been identified
