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.
Coenzyme M
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Coenzyme M is a coenzyme required for methyl-transfer reactions in the metabolism of methanogens. The coenzyme is an anion with the formula HSCH 2CH 2SO−3 and it is named 2-mercaptoethanesulfonate and abbreviated HS–CoM. The cation is unimportant, but the salt is most available. Mercaptoethanesulfonate contains both a thiol, which is the site of reactivity, and a sulfonate group. The coenzyme is the C1 donor in methanogenesis and it is converted to methyl-coenzyme M thioether, the thioether CH 3SCH 2CH 2SO−3, in the penultimate step to methane formation. Mesna – a cancer chemotherapy adjuvant with the same structure
10.
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
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.
Methyltransferase
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Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossman fold for binding S-Adenosyl methionine, class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions and these types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the methyl donor for methyltrasferases, however, examples of other methyl donors are seen in nature. The general mechanism for methyl transfer is a SN2-like nucleophilic attack where the methionine sulfur serves as the nucleophile that transfers the methyl group to the enzyme substrate, SAM is converted to S-Adenosyl homocysteine during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously and these enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Methylation, as well as other modifications, affects transcription, gene stability. It directly impacts chromatin structure and can modulate gene transcription, or even completely silence or activate genes, though the mechanisms of this genetic control are complex, hypo- and hypermethylation of DNA is implicated in many diseases. Methylation of proteins has a role in protein-protein interactions, protein-DNA interactions. Examples, RCC1, an important mitotic protein, is methylated so that it can interact with centromeres of chromosomes and this is an example of regulation of protein-protein interaction, as methylation regulates the attachment of RCC1 to histone proteins H2A and H2B. The RCC1-chromatin interaction is also an example of a protein-DNA interaction, when RCC1 is not methylated, dividing cells have multiple spindle poles and usually cannot survive. P53 methylated on lysine to regulate its activation and interaction with proteins in the DNA damage response. This is an example of regulation of protein-protein interactions and protein activation, p53 is a known tumor suppressor that activates DNA repair pathways, initiates apoptosis, and pauses the cell cycle. Overall, it responds to mutations in DNA, signaling to the cell to fix them or to cell death so that these mutations cannot contribute to cancer. NF-κB is a known methylation target of the methyltransferase SETD6, which turns off NF-κB signaling by inhibiting of one of its subunits and this reduces the transcriptional activation and inflammatory response, making methylation of NF-κB a regulatory process by which cell signaling through this pathway is reduced. Natural product methyltransferases provide a variety of inputs into metabolic pathways, including the availability of cofactors, signalling molecules and this regulates various cellular pathways by controlling protein activity. Histone methyltransferases are critical for genetic regulation at the epigenetic level and they modify mainly lysine on the ε-nitrogen and the arginine guanidinium group on histone tails. Lysine methyltransferases and Arginine methyltransferases are unique classes of enzymes, Lysine amino acids can be modified with one, two, or three methyl groups, while Arginine amino acids can be modified with one or two methyl groups
13.
Histamine N-methyltransferase
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Histamine N-methyltransferase is an enzyme that in humans is encoded by the HNMT gene. Histamine N-methyltransferase is one of two involved in the metabolism of histamine, the other being diamine oxidase. Histamine N-methyltransferase catalyzes the methylation of histamine in the presence of S-adenosylmethionine forming N-methylhistamine, HMT is present in most body tissues but is not present in serum. Histamine N-methyltransferase is encoded by a gene which has been mapped to chromosome 2. In mammals, histamine is metabolized by two pathways, N-methylation via histamine N-methyltransferase and oxidative deamination via diamine oxidase. This gene encodes the first enzyme which is found in the cytosol, in the mammalian brain, the neurotransmitter activity of histamine is controlled by N-methylation as diamine oxidase is not found in the central nervous system. A common genetic polymorphism affects the activity levels of gene product in red blood cells
14.
Phenylethanolamine N-methyltransferase
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Phenylethanolamine N-methyltransferase is an enzyme found primarily in the adrenal medulla that converts norepinephrine to epinephrine. It is also expressed in small groups of neurons in the human brain, PNMT is a protein whose encoding gene is found on chromosome 17 in humans. It consists of 4 exons and is a 30kDa protein and it shares many properties found among the other methyltransferases. It is closest in sequence to glycine-N-methyl transferase and it also shares many structural properties like the shape of the folding lip with catechol-O-methyl transferase, though it shares less sequence identity. Among all known PNMT variants in nature there are 7 crucial aromatic residues conserved in the active site, the residue Glutamine 185 is necessary in binding the catecholamine substrate. The replacement of this residue another reduces the efficiency of PNMT by tenfold up to three hundredfold. In the absence of an inhibitor or ligand, a group is bound to the active site to stabilize this region. Human PNMT forms dimers in solution, when PNMT crystals are grown in non-reducing solutions, two disulfide bonds form between cysteines 48 and 139 on opposite chains. This dimerization has no effect on the activity of the enzyme. PNMT catalyzes the transfer of a group from SAM to norepinephrine. The methyl group of SAM is very reactive, so the structure, methyltransferases are very common in the catecholamine synthesis and deactivation pathways. PNMT is also involved in the biosynthesis of N-methylated trace amines, it metabolizes phenethylamine into N-methylphenethylamine, p-octopamine into synephrine, elevated PNMT expression is one of the ways that the stress response positively feeds back on itself. An increase in stress hormones or nerve impulses due to stress can cause PNMT to convert more norepinephrine into epinephrine and this increases the potency of the catecholamine response system, increasing the sympathetic output and making the stress response more profound. PNMT is known to be regulated by glucocorticoids made in the adrenal gland, one way that it can regulate PNMT expression is by corticosterones positive influence on the maintenance of PNMT mRNA. Glucocorticoids have also shown to increase the biological half life of the enzyme in vitro. In animals who have had their pituitary gland removed, the addition of glucocorticoids significantly lengthens the life of PNMT enzymes. Elevated PNMT levels can also be triggered by nerve impulses. Nerve impulses increase the synthesis of PNMT mRNA by affecting certain promoter sequences, stress immobilization for a few hours has also been shown to increase PNMT activity in rats
15.
Amine N-methyltransferase
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In enzymology, an amine N-methyltransferase is an enzyme that is ubiquitously present in non-neural tissues and that catalyzes the N-methylation of tryptamine and structurally related compounds. In the case of tryptamine and serotonin these then become the dimethylated indolethylamines dimethyltryptamine and bufotenine and this enzyme belongs to the family of transferases, specifically those transferring one-carbon group methyltransferases. The systematic name of this class is S-adenosyl-L-methionine, amine N-methyltransferase. Other names in use include nicotine N-methyltransferase, tryptamine N-methyltransferase, indolethylamine N-methyltransferase. This enzyme participates in tryptophan metabolism, a wide range of primary, secondary and tertiary amines can act as acceptors, including tryptamine, aniline, nicotine and a variety of drugs and other xenobiotics. As of late 2007, only one structure has been solved for this class of enzymes, crooks PA, Godin CS, Damani LA, Ansher SS, Jakoby WB. Formation of quaternary amines by N-methylation of azaheterocycles with homogeneous amine N-methyltransferases, EC2.1.1.49 Lyon ES, Jakoby WB. Boarder MR, Rodnight R. Tryptamine-N-methyltransferase activity in brain tissue, a re-examination
16.
Phosphatidylethanolamine N-methyltransferase
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Phosphatidylethanolamine N-methyltransferase is a transferase enzyme which converts phosphatidylethanolamine to phosphatidylcholine in the liver. In humans it is encoded by the PEMT gene within the Smith-Magenis syndrome region on chromosome 17, furthermore, PC made via PEMT plays a wide range of physiological roles, utilized in choline synthesis, hepatocyte membrane structure, bile secretion, and very-low-density lipoprotein secretion. The PEMT enzyme converts phosphatidylethanolamine to phosphatidylcholine via three sequential methylations by S-adenosyl methionine, the enzyme is found in endoplasmic reticulum and mitochondria-associated membranes. It accounts for ~30% of PC biosynthesis, with the CDP-choline, or Kennedy, PC, typically the most abundant phospholipid in animals and plants, accounts for more than half of cell membrane phospholipids and approximately 30% of all cellular lipid content. The PEMT pathway is crucial for maintaining membrane integrity. PC made via the PEMT pathway can be degraded by phospholipases C/D, thus, the PEMT pathway contributes to maintaining brain and liver function and larger-scale energy metabolism in the body. A major pathway for hepatic PC utilization is secretion of bile into the intestine, PEMT activity also dictates normal very-low-density lipoprotein secretion by the liver. PEMT is also a significant source and regulator of plasma homocysteine, the exact mechanism by which PEMT catalyzes the sequential methylation of PE by three molecules of SAM to form PC remains unknown. Kinetic analyses as well as acid and gene sequencing have shed some light on how the enzyme works. Studies suggest that a single binding site binds all three phospholipids methylated by PEMT, PE, phosphatidyl-monomethylethanolamine and phosphatidyl-dimethylethanolamine. The first methylation, that of PE to PMME, has shown to be the rate-limiting step in conversion of PE to PC. Purification of PEMT by Neale D. Ridgway and Dennis E. Vance in 1987 produced an 18.3 kDa protein, subsequent cloning, sequencing, and expression of PEMT cDNA resulted in a 22.3 kDa, 199-amino acid protein. Although the enzymatic structure is unknown, PEMT is proposed to contain four hydrophobic membrane-spanning regions, kinetic studies indicate a common binding site for PE, PMME, and PDME substrates. SAM binding motifs have been identified on both the third and fourth transmembrane sequences, site-directed mutagenesis has pinpointed the residues Gly98, Gly100, Glu180, and Glu181 to be essential for SAM binding in the active site. PEMT activity is unrelated to enzyme mass, but rather is regulated by supply of substrates including PE, as well as PMME, PDME, the enzyme is further regulated by S-adenosylhomocysteine produced after each methylation. PEMT gene expression is regulated by factors including activator protein 1. Sp1 is a regulator of PEMT transcription, yet is it is a positive regulator of choline-phosphate cytidylyltransferase transcription. This is one of examples of the reciprocal regulation of PEMT and CT in the PEMT
17.
Catechol-O-methyl transferase
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Catechol-O-methyltransferase is one of several enzymes that degrade catecholamines, catecholestrogens, and various drugs and substances having a catechol structure. In humans, catechol-O-methyltransferase protein is encoded by the COMT gene, two isoforms of COMT are produced, the soluble short form and the membrane bound long form. As the regulation of catecholamines is impaired in a number of conditions, several pharmaceutical drugs target COMT to alter its activity. COMT was first discovered by the biochemist Julius Axelrod in 1957, catechol-O-methyltransferase is involved in the inactivation of the catecholamine neurotransmitters. The enzyme introduces a group to the catecholamine, which is donated by S-adenosyl methionine. Any compound having a structure, like catecholestrogens and catechol-containing flavonoids, are substrates of COMT. Levodopa, a precursor of catecholamines, is an important substrate of COMT, COMT inhibitors, like entacapone, save levodopa from COMT and prolong the action of levodopa. Entacapone is a widely used adjunct drug of levodopa therapy, when given with an inhibitor of dopa decarboxylase, levodopa is optimally saved. This triple therapy is becoming a standard in the treatment of Parkinsons disease, soluble COMT can also be found extracellularly, although extracellular COMT plays a less significant role in the CNS than it does peripherally. Despite its importance in neurons, COMT is actually primarily expressed in the liver, the COMT protein is coded by the gene COMT. The gene is associated with allelic variants, others are rs737865 and rs165599 that have been studied, e. g. for association with personality traits, response to antidepressant medications, and psychosis risk associated with Alzheimers disease. A functional single-nucleotide polymorphism of the gene for catechol-O-methyltransferase results in a valine to methionine mutation at position 158 rs4680, the homozygous Val variant metabolizes dopamine at up to four times the rate of its methionine counterpart. However, the Met variant is overexpressed in the brain, resulting in a 40% decrease in enzyme activity. Given the preferential role of COMT in prefrontal dopamine degradation, the Val158Met polymorphism is thought to exert its effects on cognition by modulating dopamine signaling in the frontal lobes. Comparable effects on cognitive tasks, the frontal lobes. However, a recent study cast doubt on the proposed connection between this gene and the effects of cannabis on schizophrenia development. It is increasingly recognised that allelic variation at the COMT gene are also relevant for emotional processing, the COMT Val158Met polymorphism also has a pleiotropic effect on emotional processing. Furthermore, the polymorphism has shown to affect ratings of subjective well-being
18.
Homocysteine
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Homocysteine /ˌhoʊmoʊˈsɪstiːn/ is a non-protein α-amino acid. It is a homologue of the amino acid cysteine, differing by a methylene bridge. It is biosynthesized from methionine by the removal of its terminal Cε methyl group, homocysteine can be recycled into methionine or converted into cysteine with the aid of certain B-vitamins. Hyperhomocysteinemia is therefore a risk factor for coronary artery disease. Coronary artery disease occurs when an atherosclerotic plaque blocks blood flow to the coronary arteries, hyperhomoscyteinemia has also been associated with early pregnancy loss and with neural tube defects. Homocysteine exists at neutral pH values as a zwitterion, homocysteine is not obtained from the diet. Instead, it is biosynthesized from methionine via a multi-step process, first, methionine receives an adenosine group from ATP, a reaction catalyzed by S-adenosyl-methionine synthetase, to give S-adenosyl methionine. SAM then transfers the methyl group to an acceptor molecule, the adenosine is then hydrolyzed to yield L-homocysteine. L-Homocysteine has two primary fates, conversion via tetrahydrofolate back into L-methionine or conversion to L-cysteine, mammals biosynthesize the amino acid cysteine via homocysteine. Cystathionine β-synthase catalyses the condensation of homocysteine and serine to give cystathionine and this reaction uses pyridoxine as a cofactor. Cystathionine γ-lyase then converts this double amino acid to cysteine, ammonia, bacteria and plants rely on a different pathway to produce cysteine, relying on O-acetylserine. Homocysteine can be recycled into methionine and this process uses N5-methyl tetrahydrofolate as the methyl donor and cobalamin -related enzymes. More detail on these enzymes can be found in the article for methionine synthase, homocysteine can cyclize to give homocysteine thiolactone, a five-membered heterocycle. Because of this reaction, homocysteine-containing peptides tend to cleave themselves by reactions generating oxidative stress. Homocysteine also acts as an allosteric antagonist at Dopamine D2 receptors, homocysteine levels are typically higher in men than women, and increase with age. Common levels in Western populations are 10 to 12 μmol/L, the ranges above are provided as examples only, test results should always be interpreted using the range provided by the laboratory that produced the result. Abnormally high levels of homocysteine in the serum, above 15 µmol/L, are a condition called hyperhomocysteinemia. This has been claimed to be a significant risk factor for the development of a range of diseases, including thrombosis, neuropsychiatric illness
19.
Methionine synthase
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Methionine synthase also known as MS, MeSe, MetH is responsible for the regeneration of methionine from homocysteine. In humans it is encoded by the MTR gene, Methionine synthase forms part of the S-adenosylmethionine biosynthesis and regeneration cycle. In animals this enzyme requires Vitamin B12 as a cofactor, whereas the form found in plants is cobalamin-independent, microorganisms express both cobalamin-dependent and cobalamin-independent forms. Methionine synthase catalyzes the final step in the regeneration of methionine from homocysteine, the overall reaction transforms 5-methyltetrahydrofolate into tetrahydrofolate while transferring a methyl group to Hcy to form Met. Methionine synthase is the mammalian enzyme that metabolizes N5-MeTHF to regenerate the active cofactor THF. In cobalamin-dependent forms of the enzyme, the proceeds by two steps in a ping-pong reaction. Then, a Hcy that has coordinated to an enzyme-bound zinc to form a reactive thiolate reacts with the Me-Cob, the activated methyl group is transferred from Me-Cob to the Hcy thiolate, which regenerates Co in cob, and Met is released from the enzyme. The cob-independent mechanism follows the general pathway but with a direct reaction between the zinc thiolate and N5-MeTHF. The mechanism of the enzyme depends on the constant regeneration of Co in cob, instead, every 1-2000 catalytic turnovers, the Co may be oxidized into Co, which would permanently shut down catalytic activity. A separate protein, Methionine Synthase Reductase, catalyzes the regeneration of Co, the two enzymes form a scavenger network seen on the lower left. Cob-dependent MetH is divided into 4 separate domains, Activation, Cobalamin-binding, Homocysteine binding, the activation domain is the site of interaction with Methionine Synthase Reductase and binds SAM that is used as part of the re-activation cycle of the enzyme. The Cob domain contains Cob sandwiched between several large alpha helices and bound to the enzyme so that the atom of the group is exposed for contact with other domains. The N5-MeTHF binding domain contains a barrel in which N5-MeTHF can hydrogen bond with asparagine, arginine. Methionine synthases main purpose is to regenerate Met in the S-Adenosyl Methionine cycle, in plants and microorganisms, methionine synthase serves a dual purpose of both perpetuating the SAM cycle and catalyzing the final synthetic step in the de novo synthesis of Met. Mutations in the MTR gene have been identified as the cause of methylcobalamin deficiency complementation group G. Most cases of methionine synthase deficiency are symptomatic within 2 years of birth with many patients rapidly developing severe encephalopathy, one consequence of reduced methionine synthase activity that is measurable by routine clinical blood tests is megaloblastic anemia. Several polymorphisms in the MTR gene have been identified.1.1.13 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase at the US National Library of Medicine Medical Subject Headings
20.
DNMT3B
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DNA -methyltransferase 3 beta, also known as DNMT3B, is a protein associated with immunodeficiency, centromere instability and facial anomalies syndrome. CpG methylation is a modification that is important for embryonic development, imprinting. Studies in mice have demonstrated that DNA methylation is required for mammalian development and this gene encodes a DNA methyltransferase which is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes primarily to the nucleus and its expression is developmentally regulated, mutations in this gene cause the immunodeficiency-centromeric instability-facial anomalies syndrome. Eight alternatively spliced variants have been described. The full length sequences of variants 4 and 5 have not been determined, DNMT3B has been shown to interact with, DNMT3b at the US National Library of Medicine Medical Subject Headings EC2.1.1.37
21.
Histone methyltransferase
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Histone methyltransferases are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3, two major types of histone methyltranferases exist, lysine-specific and arginine-specific. In both types of histone methyltransferases, cofactor S-Adenosyl methionine serves as a cofactor and methyl donor group, in eukaryotic cells, the genome is tightly condensed into chromatin, so enzymes, such as histone methyltransferases, must overcome this inaccessibility. Histone methyltransferase does so by modifying histones at certain sites through methylation, the class of lysine-specific histone methyltransferases is subdivided into SET domain-containing and non-SET domain-containing. As indicated by their monikers, these differ in the presence of a SET domain, the pre-SET and post-SET domains flank the SET domain on either side. The pre-SET region contains cysteine residues that form triangular zinc clusters, tightly binding the zinc atoms, the SET domain itself contains a catalytic core rich in β-strands that, in turn, make up several regions of β-sheets. Often, the found in the pre-SET domain will form β-sheets with the β-strands of the SET domain. These small changes alter the target residue site specificity for methylation and this interplay between the pre-SET domain and the catalytic core is critical for enzyme function. In order for the reaction to proceed, S-Adenosyl methionine and the residue of the substrate histone tail must first be bound. Next, a tyrosine residue deprotonates the ε-amino group of the lysine residue. The lysine chain then makes an attack on the methyl group on the sulfur atom of the SAM molecule. Instead of SET, non-SET domain-containing histone methyltransferase utilizes the enzyme Dot1, unlike the SET domain, which targets the lysine tail region of the histone, Dot1 methylates a lysine residue in the globular core of the histone, and is the only enzyme known to do so. A possible homolog of Dot1 was found in archaea which shows the ability to methylate archaeal histone-like protein in recent studies, the N terminal of Dot1 contains the active site. A loop serving as the site for SAM links the N-terminal. Due to structural constraints, Dot1 is only able to methylate histone H3, there are two different types of protein arginine methyltransferases and three types of methylation that can occur at arginine residues on histone tails. The first type of PRMTs produce monomethylarginine and asymmetric dimethylarginine, the second type produces monomethyl or symmetric dimethylarginine. The differences in the two types of PRMTs arise from restrictions in the binding pocket. The catalytic domain of PRMTs consists of a SAM binding domain, each PRMT has a unique N-terminal region and a catalytic core
22.
Thymidylate synthase
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Thymidylate synthetase is an enzyme that catalyzes the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. Thymidine is one of the nucleotides in DNA, with inhibition of TS, an imbalance of deoxynucleotides and increased levels of dUMP arise. This provides the de novo pathway for production of dTMP and is the only enzyme in folate metabolism in which the 5. The enzyme is an important target for certain chemotherapeutic drugs, Thymidylate synthase is an enzyme of about 30 to 35 kDa in most species except in protozoan and plants where it exists as a bifunctional enzyme that includes a dihydrofolate reductase domain. A cysteine residue is involved in the catalytic mechanism, the sequence around the active site of this enzyme is conserved from phages to vertebrates. Thymidylate synthase is induced by a transcription factor LSF/TFCP2 and LSF is an oncogene in hepatocellular carcinoma, LSF and Thymidylate synthase plays significant role in Liver Cancer proliferation and progression and Drug resistance. Thymidylate synthase plays a role in the early stages of DNA biosynthesis. DNA damage or deletion occur on a basis as a result of both endogenous and environmental factors. Such environmental factors include ultraviolet damage and cigarette smoke that contain a variety of carcinogens, therefore, synthesis and insertion of healthy DNA is vital for normal body functions and avoidance of cancerous activity. In addition, inhibition in synthesis of important nucleotides necessary for growth is important. For this reason, TS has become an important target for treatment by means of chemotherapy. The sensitivity of TS to succumb to TS inhibitors is a key part to its success as treatment for colorectal, pancreatic, ovarian, gastric, the use of TS inhibitors has become a main focus of using TS as a drug target. The most widely used inhibitor is 5-fluorouracil, which acts as an antimetabolite that irreversibly inhibits TS by competitive binding. Experimentally, it has shown that low levels of TS expression leads to a better response to 5-FU and higher success rates and survival of colon. TS’s relation to the cycle also contributes to its use in cancer treatment. In an auto-regulatory manner, TS not only controls its own translation, through its translation, TS has a varying expression in cancer cells and tumors, which leads to early cell death. Click on genes, proteins and metabolites below to link to respective articles, in the proposed mechanism, TS forms a covalent bond to the substrate dUMP through a 1, 4-addition involving a cysteine nucleophile. The coenzyme tetrahydrofolate donates a methyl group to the alpha carbon while reducing the new methyl on dUMP to form dTMP, the mutant TS is unable to accomplish the C-terminal conformational change needed to break covalent bonds to form dTMP, thus showing the proposed mechanism to be true
23.
DNA methyltransferase
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In biochemistry, the DNA methyltransferase family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a variety of biological functions. All the known DNA methyltransferases use S-adenosyl methionine as the methyl donor, m5C methyltransfereases are found in some lower eukaryotes, in most higher plants, and in animals beginning with the echinoderms. The m6A methyltransferases are enzymes that methylate the amino group at the C-6 position of adenines in DNA. They are found in the three existing types of bacterial restriction-modification systems and these enzymes are responsible for the methylation of specific DNA sequences in order to prevent the host from digesting its own genome via its restriction enzymes. These methylases have the sequence specificity as their corresponding restriction enzymes. These enzymes contain a conserved motif Asp/Asn-Pro-Pro-Tyr/Phe in their N-terminal section, the structure of N6-MTase TaqI has been resolved to 2.4 A. The N- and C-terminal domains form a cleft that accommodates the DNA substrate, a classification of N-MTases has been proposed, based on conserved motif arrangements. According to this classification, N6-MTases that have a DPPY motif occurring after the FxGxG motif are designated D12 class N6-adenine MTases, the type I restriction and modification system is composed of three polypeptides R, M and S. The M and S subunits together form a methyltransferase that methylates two adenine residues in complementary strands of a bipartite DNA recognition sequence. In the presence of the R subunit, the complex can act as an endonuclease, binding to the same target sequence. Whether the DNA is cut or modified depends on the state of the target sequence. When the target site is unmodified, the DNA is cut, when the target site is hemimethylated, the complex acts as a maintenance methyltransferase, modifying the DNA so that both strands become methylated. HsdM contains a domain at the N-terminus, the HsdM N-terminal domain. M4C methyltransferases are enzymes that methylate the amino group at the C-4 position of cytosines in DNA. Such enzymes are found as components of type II restriction-modification systems in prokaryotes, such enzymes recognise a specific sequence in DNA and methylate a cytosine in that sequence. In mammalian cells, cytosine-specific methyltransferases methylate certain CpG sequences, which are believed to modulate gene expression, in bacteria, these enzymes are a component of restriction-modification systems and serve as valuable tools for the manipulation of DNA. De novo methyltransferases recognize something in the DNA that allows them to newly methylate cytosines and these are expressed mainly in early embryo development and they set up the pattern of methylation
24.
Thiopurine methyltransferase
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Thiopurine methyltransferase or thiopurine S-methyltransferase is an enzyme that in humans is encoded by the TPMT gene. A pseudogene for this locus is located on chromosome 18q, the methyl donor is S-adenosyl-L-methionine, which is converted to S-adenosyl-L-homocysteine. This enzyme metabolizes thiopurine drugs via S-adenosyl-L-methionine as the S-methyl donor, thiopurine drugs such as 6-mercaptopurine are used as chemotherapeutic agents and immunosuppressive drugs. Genetic polymorphisms that affect this enzymatic activity are correlated with variations in sensitivity and toxicity to such drugs within individuals, about 1/300 individual is deficient for the enzyme. TPMT is best known for its role in the metabolism of the thiopurine drugs such as azathioprine, 6-mercaptopurine and 6-thioguanine, TPMT catalyzes the S-methylation of thiopurine drugs. Measurement of TPMT activity is encouraged prior to commencing the treatment of patients with thiopurine drugs such as azathioprine, 6-mercaptopurine and 6-thioguanine, patients with low activity or especially absent activity are at a heightened risk of drug-induced bone marrow toxicity due to accumulation of the unmetabolised drug. Reuther et al. found that about 5% of all thiopurine therapies will fail due to toxicity and this intolerant group could be anticipated by routine measurement of TPMT activity. There appears to be a deal of variation in TPMT mutation. Genetic variants of TPMT have also associated with cisplatin-induced ototoxicity in children. TPMT is now listed as a biomarker for adverse drug reactions to cisplatin by the FDA. City Assays page on the TPMT assay
25.
Hydroxymethyl
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Hydroxymethyl in the field of chemistry, particularly in organic chemistry, is the name for a substituent with the structural formula -CH2-OH. The hydroxymethyl group consists of a methylene bridge bonded to a hydroxy group and this makes the hydroxymethyl group an alcohol. The hydroxymethyl group has the chemical formula with the methoxy group that differs only in the attachment site. However, their properties are different
26.
Aldehyde
–
The group—without R—is the aldehyde group, also known as the formyl group. Aldehydes are common in organic chemistry, Aldehydes feature an sp2-hybridized, planar carbon center that is connected by a double bond to oxygen and a single bond to hydrogen. The C–H bond is not ordinarily acidic, because of resonance stabilization of the conjugate base, an α-hydrogen in an aldehyde is far more acidic, with a pKa near 15, compared to the acidity of a typical alkane. This acidification is attributed to the quality of the formyl center and the fact that the conjugate base. Related to, the group is somewhat polar. Aldehydes can exist in either the keto or the enol tautomer, keto-enol tautomerism is catalyzed by either acid or base. Usually the enol is the minority tautomer, but it is more reactive, the common names for aldehydes do not strictly follow official guidelines, such as those recommended by IUPAC, but these rules are useful. IUPAC prescribes the following nomenclature for aldehydes, Acyclic aliphatic aldehydes are named as derivatives of the longest carbon chain containing the aldehyde group, thus, HCHO is named as a derivative of methane, and CH3CH2CH2CHO is named as a derivative of butane. The name is formed by changing the suffix -e of the parent alkane to -al, so that HCHO is named methanal, in other cases, such as when a -CHO group is attached to a ring, the suffix -carbaldehyde may be used. Thus, C6H11CHO is known as cyclohexanecarbaldehyde, if the presence of another functional group demands the use of a suffix, the aldehyde group is named with the prefix formyl-. This prefix is preferred to methanoyl-, the word aldehyde was coined by Justus von Liebig as a contraction of the Latin alcohol dehydrogenatus. In the past, aldehydes were sometimes named after the corresponding alcohols, for example, the term formyl group is derived from the Latin word formica ant. This word can be recognized in the simplest aldehyde, formaldehyde, Aldehydes have properties that are diverse and that depend on the remainder of the molecule. Smaller aldehydes are more soluble in water, formaldehyde and acetaldehyde completely so, the volatile aldehydes have pungent odors. Aldehydes degrade in air via the process of autoxidation, the two aldehydes of greatest importance in industry, formaldehyde and acetaldehyde, have complicated behavior because of their tendency to oligomerize or polymerize. They also tend to hydrate, forming the geminal diol, the oligomers/polymers and the hydrates exist in equilibrium with the parent aldehyde. Aldehydes are readily identified by spectroscopic methods, using IR spectroscopy, they display a strong νCO band near 1700 cm−1. In their 1H NMR spectra, the formyl hydrogen center absorbs near δH =9 and this signal shows the characteristic coupling to any protons on the alpha carbon
27.
Phosphoribosylglycinamide formyltransferase
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Phosphoribosylglycinamide formyltransferase is an enzyme with systematic name 10-formyltetrahydrofolate, 5-phosphoribosylglycinamide N-formyltransferase. This reaction plays an important role in the formation of purine through the de novo purine biosynthesis pathway and this pathway creates inosine monophosphate, a precursor to adenosine monophosphate and guanosine monophosphate. AMP is a block for important energy carriers such as ATP, NAD+ and FAD. GARTfases role in de novo purine biosynthesis makes it a target for anti-cancer drugs, there are two known types of genes encoding GAR transformylase in E. coli, purN and purT, while only purN is found in humans. Many residues in the site are conserved across bacterial, yeast. In humans, GARTfase is part of trifunctional enzyme which also includes glycinamide ribnucleotide synthase and this protein catalyzes steps 2,3 and 5 of de novo purine biosynthesis. The proximity of these units and flexibility of the protein serves to increase pathway throughput. GARTfase is located on the C-terminal end of the protein, Human GARTfase has been crystallized by vapor-diffusion sitting drop method and imaged at the Stanford Synchrotron Radiation Laboratory by at least two groups. The structure can be described by two subdomains which are connected by a beta sheet. The N- terminal domain consists of a Rossman type mononucleotide fold, the beta sheet continues into the C terminal domain, where on one side it is covered by a long alpha helix and on the other it is partially exposed to solvent. It is the cleft between the two subdomains where the site lies. The cleft consists of the GAR binding site and the binding pocket. This folate binding region has been the subject of research because its inhibition by small molecules has led to the discovery of antineoplastic drugs. The folate binding loop has been shown to change depending on the pH of solution. Lower pH conditions change the conformation of the substrate binding loops as well, Klein et al first suggested a water molecule assisted mechanism. A single water molecule possibly held in place by hydrogen bonding with the group of the persistent Asp144 residue transfers protons from the GAR-N to the THF-N. The nucleophilic nitrogen on the amino group of GAR attacks the carbonyl carbon of the formyl group on THF pushing negative charge onto the oxygen. Calculations by Qiao et al suggest that the water assisted stepwise proton transfer from Gar-N to THF-N is 80-100 kj/mol more favorable than the concerted transfer suggested by Klein, the mechanism shown is suggested by Qiao et al, whom admittedly did not consider surrounding residues in their calculations
28.
Glutamate formimidoyltransferase
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The formiminotransferase domain of formiminotransferase-cyclodeaminase forms a homodimer, with each protomer comprising two subdomains. This, in turn, faces the beta-sheet of the C-terminal subdomain to form a double beta-sheet layer, the two subdomains are separated by a short linker sequence, which is not thought to be any more flexible than the remainder of the molecule. The substrate is predicted to form a number of contacts with residues found in both the N-terminal and C-terminal subdomains, in humans, deficiency of this enzyme results in a disease phenotype
29.
Aminomethyltransferase
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Aminomethyltransferase is an enzyme that catabolizes the creation of methylenetetrahydrofolate. It is part of the glycine decarboxylase complex, the gene is about 6 kb in length and consists of nine exons. The 5′-flanking region of the gene lacks typical TATAA sequence but has a single defined transcription initiation site detected by the primer extension method, two putative glucocorticoid-responsive elements and a putative thyroid hormone-responsive element are present. The AMT gene has been localized to 3p21. 2-p21.1 by fluorescence in situ hybridization, the protein encoded by this gene has its crystal structure resolved at 2 Angstroms. The most recent model contains two monomers related by a non-crystallographic 2-fold axis,1176 water molecules, and 11 molecules sulfate ions in an asymmetric unit. Several dimeric interactions are observed among the residues on the N-terminal loop, on α-helix D, the protein encoded by AMT catalyzes the release of ammonia and the transfer of a methylene carbon unit to a tetrahydrofolate moiety. The aminomethyl intermediate is the product of the decarboxylation of glycine catalyzed by P-protein, the majority of glycine encephalopathy presents in the neonatal period. Of those presenting in infancy, 50% have the infantile attenuated form, overall, 20% of all children presenting as either neonates or infants have a less severe outcome, defined as developmental quotient greater than 20. A minority of patients have mild or atypical forms of glycine encephalopathy, the neonatal form manifests in the first hours to days of life with progressive lethargy, hypotonia, and myoclonic jerks leading to apnea and often death. Surviving infants have profound intellectual disability and intractable seizures, the infantile form is characterized by hypotonia, developmental delay, and seizures. The atypical forms range from disease, with onset from late infancy to adulthood, to rapidly progressing. Glycine encephalopathy is suspected in individuals with elevated glycine concentration in blood, an increase in CSF glycine concentration together with an increased CSF-to-plasma glycine ratio suggests the diagnosis. Enzymatic confirmation of the diagnosis relies on measurement of glycine cleavage system enzyme activity in liver obtained by open biopsy or autopsy, the majority of affected individuals have no detectable enzyme activity. The three genes in which mutations are known to cause glycine encephalopathy are, GLDC, AMT. About 5% of individuals with enzyme-proven glycine encephalopathy do not have a mutation in any of three genes and have a variant form of glycine encephalopathy. Aminomethyltransferase at the US National Library of Medicine Medical Subject Headings Human AMT genome location and AMT gene details page in the UCSC Genome Browser
30.
Carboxylic acid
–
A carboxylic acid /ˌkɑːrbɒkˈsɪlɪk/ is an organic compound that contains a carboxyl group. The general formula of an acid is R–COOH, with R referring to the rest of the molecule. Carboxylic acids occur widely and include the amino acids and acetic acid, salts and esters of carboxylic acids are called carboxylates. When a carboxyl group is deprotonated, its conjugate base forms a carboxylate anion, carboxylate ions are resonance-stabilized, and this increased stability makes carboxylic acids more acidic than alcohols. Carboxylic acids can be seen as reduced or alkylated forms of the Lewis acid carbon dioxide, carboxylic acids are commonly identified using their trivial names, and usually have the suffix -ic acid. IUPAC-recommended names also exist, in system, carboxylic acids have an -oic acid suffix. For example, butyric acid is butanoic acid by IUPAC guidelines, the -oic acid nomenclature detail is based on the name of the previously-known chemical benzoic acid. Alternately, it can be named as a carboxy or carboxylic acid substituent on another parent structure, for example, 2-carboxyfuran. The carboxylate anion of an acid is usually named with the suffix -ate, in keeping with the general pattern of -ic acid and -ate for a conjugate acid and its conjugate base. For example, the base of acetic acid is acetate. The radical •COOH has only a fleeting existence. The acid dissociation constant of •COOH has been measured using electron paramagnetic resonance spectroscopy, the carboxyl group tends to dimerise to form oxalic acid. Because they are both hydrogen-bond acceptors and hydrogen-bond donors, they participate in hydrogen bonding. Together the hydroxyl and carbonyl group forms the functional group carboxyl, carboxylic acids usually exist as dimeric pairs in nonpolar media due to their tendency to self-associate. Smaller carboxylic acids are soluble in water, whereas higher carboxylic acids are less due to the increasing hydrophobic nature of the alkyl chain. These longer chain acids tend to be soluble in less-polar solvents such as ethers. Carboxylic acids tend to have higher boiling points than water, not only because of their surface area. Carboxylic acids tend to evaporate or boil as these dimers, for boiling to occur, either the dimer bonds must be broken or the entire dimer arrangement must be vaporised, both of which increase the enthalpy of vaporization requirements significantly
31.
Aspartate carbamoyltransferase
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Aspartate carbamoyltransferase catalyzes the first step in the pyrimidine biosynthetic pathway. In E. coli, the enzyme is a protein complex composed of 12 subunits. The composition of the subunits is C6R6, forming 2 trimers of catalytic subunits and 3 dimers of regulatory subunits, the particular arrangement of catalytic and regulatory subunits in this enzyme affords the complex with strongly allosteric behaviour with respect to its substrates. The enzyme is an example of allosteric modulation of fine control of metabolic enzyme reactions. ATCase does not follow Michaelis-Menten kinetics, but lies between the low-activity, low-affinity tense or T and the high-activity, high-affinity relaxed or R states, binding of ATP to the regulatory subunits results in an equilibrium shift towards the R state. ATCase controls the rate of pyrimidine biosynthesis by altering its catalytic velocity in response to levels of both pyrimidines and purines. The end-product of the pathway, CTP, decreases catalytic velocity, whereas ATP. Early studies demonstrated that ATCase consists of two different kinds of chains, which have different roles. These residues coordinate a zinc atom that is not involved in any catalytic property, the three-dimensional arrangement of the catalytic and regulatory subunits involves several ionic and hydrophobic stabilizing contacts between amino acid residues. Each catalytic chain is in contact with three other catalytic chains and two regulatory chains, each regulatory monomer is in contact with one other regulatory chain and two catalytic chains. In the unliganded enzyme, the two catalytic trimers are also in contact, the catalytic site of ATCase is located at the interface between two neighboring catalytic chains in the same trimer and incorporates amino acid side-chains from both of these subunits. Insight into the mode of binding of substrates to the center of ATCase was first made possible by the binding of a bisubstrate analogue. This compound is an inhibitor of ATCase and has a structure that is thought to be very close to that of the transition state of the substrates. Additionally, crystal structures of ATCase bound to carbamoylphosphate and succinate have been obtained, the active site is a highly positively charged pocket. Arg105, His134, and Thr55 help to increase the electrophilicity of the carbon by interacting with the carbonyl oxygen. The allosteric site in the domain of the R chains of the ATCase complex binds to the nucleotides ATP, CTP and/or UTP. There is one site with high affinity for ATP and CTP, ATP binds predominantly to the high-affinity sites and subsequently activates the enzyme, while UTP and CTP binding leads to inhibition of activity. UTP can bind to the site, but inhibition of ATCase by UTP is possible only in combination with CTP
32.
Ornithine transcarbamylase
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Ornithine transcarbamylase is an enzyme that catalyzes the reaction between carbamoyl phosphate and ornithine to form citrulline and phosphate. In plants and microbes, OTC is involved in arginine biosynthesis, the monomer unit has a CP-binding domain and an amino acid-binding domain. Each of the two discrete substrate-binding domains have an α/β topology with a central β-pleated sheet embedded in flanking α-helices, the active sites are located at the interface between the protein monomers. The gene is located on the arm of chromosome X. The gene is located in the Watson strand and is 68,968 bases in length, the encoded protein is 354 amino acids long with a predicted molecular weight of 39.935 kiloDaltons. The protein is located in the mitochondrial matrix, if a person is deficient in OTC, ammonia levels will build up, and this will cause neurological problems. Levels of the amino acids glutamate and alanine will be increased, the typical initial symptoms of a child with hyperammonemia are non-specific, failure to feed, loss of thermoregulation with a low core temperature, and somnolence. Symptoms progress from somnolence to lethargy and coma, abnormal posturing and encephalopathy are often related to the degree of central nervous system swelling and pressure upon the brainstem. About 50% of neonates with severe hyperammonemia have seizures, hyperventilation, secondary to cerebral edema, is a common early finding in a hyperammonemic attack, which causes a respiratory alkalosis. Hypoventilation and respiratory arrest follow, as pressure increases on the brainstem, in milder urea cycle enzyme deficiencies, ammonia accumulation may be triggered by illness or stress at almost any time of life, resulting in multiple mild elevations of plasma ammonia concentration. The hyperammonemia is less severe and the more subtle. In patients with partial enzyme deficiencies, the first recognized clinical episode may be delayed for months or years, one in 70000 adults has an ornithine transcarbamylase deficiency. Levels of urea cycle intermediates may be decreased, as carbamoyl phosphate cannot replenish the cycle, the carbamoyl phosphate instead goes into the uridine monophosphate synthetic pathway. Here, orotic acid levels in the blood are increased, a potential treatment for the high ammonia levels is to give sodium benzoate, which combines with glycine to produce hippurate, at the same time removing an ammonium group. Biotin also plays an important role in the functioning of the OTC enzyme and has shown to reduce ammonia intoxication in animal experiments. GeneReviews/NCBI/NIH/UW entry on Urea Cycle Disorders Overview
