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.
Lactic acid
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Lactic acid is an organic compound with the formula CH3CHCO2H. In its solid state, it is white and water-soluble, in its liquid state, it is clear. It is produced naturally and synthetically. With a hydroxyl group adjacent to the group, lactic acid is classified as an alpha-hydroxy acid. In the form of its base called lactate, it plays a role in several biochemical processes. In solution, it can ionize a proton from the carboxyl group, compared to acetic acid, its pKa is 1 unit less, meaning lactic acid deprotonates ten times more easily than acetic acid does. This higher acidity is the consequence of the hydrogen bonding between the α-hydroxyl and the carboxylate group. Lactic acid is chiral, consisting of two optical isomers, one is known as L--lactic acid or -lactic acid and the other, its mirror image, is D--lactic acid or -lactic acid. A mixture of the two in equal amounts is called DL-lactic acid, or racemic lactic acid, DL-lactic acid is miscible with water and with ethanol above its melting point which is around 17 or 18 °C. D-lactic acid and L-lactic acid have a melting point. In animals, L-lactate is constantly produced from pyruvate via the enzyme lactate dehydrogenase in a process of fermentation during normal metabolism and exercise. The concentration of lactate is usually 1–2 mmol/L at rest. In industry, lactic acid fermentation is performed by lactic acid bacteria and these bacteria can also grow in the mouth, the acid they produce is responsible for the tooth decay known as caries. In medicine, lactate is one of the components of lactated Ringers solution. These intravenous fluids consist of sodium and potassium cations along with lactate and chloride anions in solution with distilled water and it is most commonly used for fluid resuscitation after blood loss due to trauma, surgery, or burns. Lactic acid was isolated for the first time by the Swedish chemist Carl Wilhelm Scheele in 1780 from sour milk, the name reflects the lact- combining form derived from the Latin word for milk. In 1808, Jöns Jacob Berzelius discovered that lactic acid also is produced in muscles during exertion and its structure was established by Johannes Wislicenus in 1873. In 1856, Louis Pasteur discovered Lactobacillus and its role in the making of lactic acid, lactic acid started to be produced commercially by the German pharmacy Boehringer Ingelheim in 1895
10.
Oxaloacetic acid
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Oxaloacetic acid is a crystalline organic compound with the chemical formula HO2CCCH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is an intermediate in many processes that occur in animals. It takes part in the gluconeogenesis, urea cycle, glyoxylate cycle, amino acid synthesis, fatty acid synthesis, oxaloacetate forms in several ways in nature. A principal route is upon oxidation of L-malate, catalysed by malate dehydrogenase, malate is also oxidized by succinate dehydrogenase in a slow reaction with the initial product being enol-oxaloacetate. Oxaloacetate can also arise from trans- or de- amination of aspartic acid, oxaloacetate is an intermediate of the citric acid cycle, where it reacts with Acetyl-CoA to form citrate, catalysed by citrate synthase. It is also involved in gluconeogenesis, urea cycle, glyoxylate cycle, amino acid synthesis, oxaloacetate is also a potent inhibitor of Complex II. Gluconeogenesis is a pathway consisting of a series of eleven enzyme-catalyzed reactions. The beginning of this takes place in the mitochondrial matrix. A pyruvate molecule is carboxylated by a pyruvate carboxylase enzyme, activated by a molecule each of ATP and this reaction results in the formation of oxaloacetate. This transformation is needed to transport the molecule out of the mitochondria, once in the cytosol, malate is oxidized to oxaloacetate again using NAD+. Then oxaloacetate remains in the cytosol, where the rest of reactions take place. Oxaloacetate is later decarboxylated and phosphorylated by phosphoenolpyruvate carboxykinase and becomes 2-phosphoenolpyruvate using guanosine triphosphate as phosphate source, glucose is obtained after further downstream processing. The urea cycle is a pathway that results in the formation of urea using two ammonium molecules and one bicarbonate molecule. This route commonly occurs in hepatocytes, the reactions related to the urea cycle produce NADH), and NADH can be produced in two different ways. In the cytosol there are fumarate molecules, fumarate can be transformed into malate by the actions of the enzyme fumarase. Malate is acted on by malate dehydrogenase to become oxaloacetate, producing a molecule of NADH, after that, oxaloacetate will be recycled to aspartate, as transaminases prefer these keto acids over the others. This recycling maintains the flow of nitrogen into the cell, the glyoxylate cycle is a variant of the citric acid cycle. It is a pathway occurring in plants and bacteria utilizing the enzymes isocitrate lyase
11.
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
12.
Pyruvate
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Pyruvic acid is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the base, CH3COCOO−, is a key intermediate in several metabolic pathways. Pyruvic acid can be made from glucose through glycolysis, converted back to carbohydrates via gluconeogenesis and it can also be used to construct the amino acid alanine and can be converted into ethanol or lactic acid via fermentation. Pyruvic acid supplies energy to cells through the citric acid cycle when oxygen is present, pyruvic acid is a colorless liquid with a smell similar to that of acetic acid and is miscible with water. It is the output of the metabolism of known as glycolysis. One molecule of glucose breaks down into two molecules of pyruvate, which are used to provide further energy, in one of two ways. Pyruvate is converted into acetyl-coenzyme A, which is the input for a series of reactions known as the Krebs cycle. Pyruvate is also converted to oxaloacetate by an reaction, which replenishes Krebs cycle intermediates, also. These reactions are named after Hans Adolf Krebs, the biochemist awarded the 1953 Nobel Prize for physiology, jointly with Fritz Lipmann, for research into metabolic processes. The cycle is known as the citric acid cycle or tricarboxylic acid cycle. If insufficient oxygen is available, the acid is broken down anaerobically, creating lactate in animals and ethanol in plants, Pyruvate is a key intersection in the network of metabolic pathways. Pyruvate can be converted into carbohydrates via gluconeogenesis, to fatty acids or energy through acetyl-CoA, to the amino acid alanine, therefore, it unites several key metabolic processes. In glycolysis, phosphoenolpyruvate is converted to pyruvate by pyruvate kinase and this reaction is strongly exergonic and irreversible, in gluconeogenesis, it takes two enzymes, pyruvate carboxylase and PEP carboxykinase, to catalyze the reverse transformation of pyruvate to PEP. Compound C00074 at KEGG Pathway Database, enzyme 2.7.1.40 at KEGG Pathway Database. Compound C00022 at KEGG Pathway Database, click on genes, proteins and metabolites below to link to respective articles. Pyruvate decarboxylation by the pyruvate dehydrogenase complex produces acetyl-CoA, carboxylation by pyruvate carboxylase produces oxaloacetate. Transamination by alanine transaminase produces alanine, reduction by lactate dehydrogenase produces lactate. Pyruvate is sold as a supplement, though evidence supporting this use is lacking
13.
Malic acid
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Malic acid is an organic compound with the molecular formula C4H6O5. It is an acid that is made by all living organisms, contributes to the pleasantly sour taste of fruits. Malic acid has two forms, though only the L-isomer exists naturally. The salts and esters of malic acid are known as malates, the malate anion is an intermediate in the citric acid cycle. L-Malic acid is the naturally occurring form, whereas a mixture of L-, malate plays an important role in biochemistry. In the C4 carbon fixation process, malate is a source of CO2 in the Calvin cycle, in the citric acid cycle, -malate is an intermediate, formed by the addition of an -OH group on the si face of fumarate. It can also be formed from pyruvate via anaplerotic reactions, malate is also synthesized by the carboxylation of phosphoenolpyruvate in the guard cells of plant leaves. Malate, as an anion, often accompanies potassium cations during the uptake of solutes into the guard cells in order to maintain electrical balance in the cell. The accumulation of these solutes within the cell decreases the solute potential, allowing water to enter the cell. Malic acid was first isolated from apple juice by Carl Wilhelm Scheele in 1785, antoine Lavoisier in 1787 proposed the name acide malique, which is derived from the Latin word for apple, mālum—as is its genus name Malus. In German it is named Äpfelsäure after plural or singular of the fruit apple, Malic acid contributes to the sourness of green apples. It is present in grapes and in most wines with concentrations sometimes as high as 5 g/l and it confers a tart taste to wine, although the amount decreases with increasing fruit ripeness. The taste of malic acid is very clear and pure in rhubarb and it is also a component of some artificial vinegar flavors, such as salt and vinegar flavored potato chips. The process of malolactic fermentation converts malic acid to much milder lactic acid, Malic acid occurs naturally in all fruits and many vegetables, and is generated in fruit metabolism. Malic acid, when added to products, is denoted by E number E296. Malic acid is the source of extreme tartness in United States-produced confectionery and it is also used with or in place of the less sour citric acid in sour sweets. These sweets are sometimes labeled with a warning stating that excessive consumption can cause irritation of the mouth and it is approved for use as a food additive in the EU, US and Australia and New Zealand. Malic acid provides 10 kJ of energy per gram during digestion, racemic malic acid is produced industrially by the double hydration of maleic anhydride
14.
Pyruvic acid
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Pyruvic acid is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the base, CH3COCOO−, is a key intermediate in several metabolic pathways. Pyruvic acid can be made from glucose through glycolysis, converted back to carbohydrates via gluconeogenesis and it can also be used to construct the amino acid alanine and can be converted into ethanol or lactic acid via fermentation. Pyruvic acid supplies energy to cells through the citric acid cycle when oxygen is present, pyruvic acid is a colorless liquid with a smell similar to that of acetic acid and is miscible with water. It is the output of the metabolism of known as glycolysis. One molecule of glucose breaks down into two molecules of pyruvate, which are used to provide further energy, in one of two ways. Pyruvate is converted into acetyl-coenzyme A, which is the input for a series of reactions known as the Krebs cycle. Pyruvate is also converted to oxaloacetate by an reaction, which replenishes Krebs cycle intermediates, also. These reactions are named after Hans Adolf Krebs, the biochemist awarded the 1953 Nobel Prize for physiology, jointly with Fritz Lipmann, for research into metabolic processes. The cycle is known as the citric acid cycle or tricarboxylic acid cycle. If insufficient oxygen is available, the acid is broken down anaerobically, creating lactate in animals and ethanol in plants, Pyruvate is a key intersection in the network of metabolic pathways. Pyruvate can be converted into carbohydrates via gluconeogenesis, to fatty acids or energy through acetyl-CoA, to the amino acid alanine, therefore, it unites several key metabolic processes. In glycolysis, phosphoenolpyruvate is converted to pyruvate by pyruvate kinase and this reaction is strongly exergonic and irreversible, in gluconeogenesis, it takes two enzymes, pyruvate carboxylase and PEP carboxykinase, to catalyze the reverse transformation of pyruvate to PEP. Compound C00074 at KEGG Pathway Database, enzyme 2.7.1.40 at KEGG Pathway Database. Compound C00022 at KEGG Pathway Database, click on genes, proteins and metabolites below to link to respective articles. Pyruvate decarboxylation by the pyruvate dehydrogenase complex produces acetyl-CoA, carboxylation by pyruvate carboxylase produces oxaloacetate. Transamination by alanine transaminase produces alanine, reduction by lactate dehydrogenase produces lactate. Pyruvate is sold as a supplement, though evidence supporting this use is lacking
15.
Cofactor (biochemistry)
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A cofactor is a non-protein chemical compound or metallic ion that is required for a proteins biological activity to happen. These proteins are enzymes, and cofactors can be considered helper molecules that assist in biochemical transformations. A coenzyme that is tightly or even covalently bound is termed a prosthetic group, the two subcategories under coenzyme are cosubstrates and prosthetic groups. Cosubstrates are transiently bound to the protein and will be released at some point, the prosthetic groups, on the other hand, are bound permanently to the protein. Both of them have the function, which is to facilitate the reaction of enzymes. Additionally, some sources also limit the use of the cofactor to inorganic substances. An inactive enzyme without the cofactor is called an apoenzyme, while the enzyme with cofactor is called a holoenzyme. Some enzymes or enzyme complexes require several cofactors, organic cofactors are often vitamins or made from vitamins. Many contain the nucleotide adenosine monophosphate as part of their structures, such as ATP, coenzyme A, FAD and this common structure may reflect a common evolutionary origin as part of ribozymes in an ancient RNA world. It has been suggested that the AMP part of the molecule can be considered to be a kind of handle by which the enzyme can grasp the coenzyme to switch it between different catalytic centers. Cofactors can be divided into two groups, organic cofactors, such as flavin or heme, and inorganic cofactors, such as the metal ions Mg2+, Cu+, Mn2+. Organic cofactors are sometimes divided into coenzymes and prosthetic groups. The term coenzyme refers specifically to enzymes and, as such, on the other hand, prosthetic group emphasizes the nature of the binding of a cofactor to a protein and, thus, refers to a structural property. Different sources give different definitions of coenzymes, cofactors. It should be noted that terms are often used loosely. However, the author could not arrive at a single all-encompassing definition of a coenzyme, the study of these cofactors falls under the area of bioinorganic chemistry. In nutrition, the list of essential trace elements reflects their role as cofactors, in humans this list commonly includes iron, magnesium, manganese, cobalt, copper, zinc, and molybdenum. Although chromium deficiency causes impaired glucose tolerance, no human enzyme that uses this metal as a cofactor has been identified, iodine is also an essential trace element, but this element is used as part of the structure of thyroid hormones rather than as an enzyme cofactor
16.
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
17.
Nicotinamide adenine dinucleotide
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Nicotinamide adenine dinucleotide is a coenzyme found in all living cells. The compound is a dinucleotide, because it consists of two nucleotides joined through their phosphate groups, one nucleotide contains an adenine base and the other nicotinamide. Nicotinamide adenine dinucleotide exists in two forms, an oxidized and reduced form abbreviated as NAD+ and NADH respectively, in metabolism, nicotinamide adenine dinucleotide is involved in redox reactions, carrying electrons from one reaction to another. The coenzyme is, therefore, found in two forms in cells, NAD+ is an oxidizing agent – it accepts electrons from other molecules and becomes reduced and this reaction forms NADH, which can then be used as a reducing agent to donate electrons. These electron transfer reactions are the function of NAD. However, it is used in other cellular processes, the most notable one being a substrate of enzymes that add or remove chemical groups from proteins. Because of the importance of these functions, the involved in NAD metabolism are targets for drug discovery. In organisms, NAD can be synthesized from simple building-blocks from the amino acids tryptophan or aspartic acid, in an alternative fashion, more complex components of the coenzymes are taken up from food as the vitamin called niacin. Similar compounds are released by reactions that break down the structure of NAD and these preformed components then pass through a salvage pathway that recycles them back into the active form. Some NAD is also converted into nicotinamide adenine dinucleotide phosphate, the chemistry of this related coenzyme is similar to that of NAD, nicotinamide adenine dinucleotide, like all dinucleotides, consists of two nucleosides joined by a pair of bridging phosphate groups. The nucleosides each contain a ring, one with adenine attached to the first carbon atom. The nicotinamide moiety can be attached in two orientations to this carbon atom. Because of these two structures, the compound exists as two diastereomers. It is the diastereomer of NAD+ that is found in organisms. These nucleotides are joined together by a bridge of two groups through the 5 carbons. In metabolism, the compound accepts or donates electrons in redox reactions, such reactions involve the removal of two hydrogen atoms from the reactant, in the form of a hydride ion, and a proton. The proton is released into solution, while the reductant RH2 is oxidized, the midpoint potential of the NAD+/NADH redox pair is −0.32 volts, which makes NADH a strong reducing agent. The reaction is reversible, when NADH reduces another molecule and is re-oxidized to NAD+
18.
3-hydroxyacyl-CoA dehydrogenase
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This enzyme belongs to the family of oxidoreductases, to be specific those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. It is involved in fatty acid metabolic processes. Specifically it catalyzes the third step of oxidation, the oxidation of L-3-hydroxyacyl CoA by NAD+. The reaction converts the hydroxyl group into a keto group, the end product is 3-ketoacyl CoA. This enzyme participates in 8 metabolic pathways, The systematic name of this class is -3-hydroxyacyl-CoA
19.
3-hydroxybutyryl-CoA dehydrogenase
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This enzyme belongs to the family of oxidoreductases, to be specific those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this class is -3-hydroxybutanoyl-CoA, NADP+ oxidoreductase. This enzyme participates in benzoate degradation via coa ligation and butanoate metabolism, madan VK, Hillmer P, Gottschalk G. Purification and properties of NADP-dependent L-3-hydroxybutyryl-CoA dehydrogenase from Clostridium kluyveri
20.
Alcohol dehydrogenase
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In yeast, plants, and many bacteria, some alcohol dehydrogenases catalyze the opposite reaction as part of fermentation to ensure a constant supply of NAD+. Early on in evolution, a method for eliminating both endogenous and exogenous formaldehyde was important and this capacity has conserved the ancestral ADH-3 through time. Gene duplication of ADH-3, followed by series of mutations, the other ADHs evolved, the ability to produce ethanol from sugar is believed to have initially evolved in yeast. Since rotting fruit can contain more than 4% of ethanol, animals eating the fruit needed a system to metabolize exogenous ethanol. This was thought to explain the conservation of ethanol active ADH in other species than yeast, in the Histidine variant, the enzyme is much more effective at the aforementioned conversion. In humans, various haplotypes arising from this mutation are more concentrated in regions near Eastern China, in regions where rice was cultivated, rice was also fermented into ethanol. The results of increased alcohol availability led to alcoholism and abuse by those able to acquire it and those with the variant allele have little tolerance for alcohol, thus lowering chance of dependence and abuse. Classical Darwinian evolution would act to select against the form of the enzyme because of the lowered reproductive success of individuals carrying the allele. The result would be a frequency of the allele responsible for the His-variant enzyme in regions that had been under selective pressure the longest. The first-ever isolated alcohol dehydrogenase was purified in 1937 from Saccharomyces cerevisiae, many aspects of the catalytic mechanism for the horse liver ADH enzyme were investigated by Hugo Theorell and coworkers. ADH was also one of the first oligomeric enzymes that had its amino acid sequence, in early 1960, it was discovered in fruit flies of the genus Drosophila. In mammals this is a reaction involving the coenzyme nicotinamide adenine dinucleotide. The mechanism in yeast and bacteria is the reverse of this reaction and these steps are supported through kinetic studies. The substrate is coordinated to the zinc and this enzyme has two atoms per subunit. One is the site, which is involved in catalysis. In the active site, the ligands are Cys-46, Cys-174, His-67, the other subunit is involved with structure. In this mechanism, the hydride from the alcohol goes to NAD+, crystal structures indicate that the His-51 deprotonates the nicotinamide ribose, which deprotonates Ser-48. Finally, Ser-48 deprotonates the alcohol, making it an aldehyde, from a mechanistic perspective, if the enzyme adds hydride to the re face of NAD+, the resulting hydrogen is incorporated into the pro-R position
21.
Aldo-keto reductase
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All possess a similar structure, with a beta-alpha-beta fold characteristic of nucleotide binding proteins. The fold comprises a parallel beta-8/alpha-8-barrel, which contains a novel NADP-binding motif, the binding site is located in a large, deep, elliptical pocket in the C-terminal end of the beta sheet, the substrate being bound in an extended conformation. The hydrophobic nature of the pocket favours aromatic and apolar substrates over highly polar ones, binding of the NADPH coenzyme causes a massive conformational change, reorienting a loop, effectively locking the coenzyme in place. This binding is more similar to FAD- than to NAD-binding oxidoreductases, some proteins of this family contain a potassium channel beta chain regulatory domain, these are reported to have oxidoreductase activity. This article incorporates text from the public domain Pfam and InterPro IPR001395
22.
Aldo-keto reductase family 1, member A1
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Alcohol dehydrogenase also known as aldehyde reductase or aldo-keto reductase family 1 member A1 is an enzyme that in humans is encoded by the AKR1A1 gene. AKR1A1 belongs to the aldo-keto reductase superfamily, mutations in the AKR1A1 gene has been found associated with non-Hodgkins lymphoma. The AKR1A1 gene lies on the location of 1p34.1. AKR1A1 consists of 325 amino acids and weighs 36573Da, AKR1A1 gene is found highly expressed in kidney and liver, and moderately expressed in cerebrum, small intestine and testis. Small amounts of AKR1A1 are present in lung, prostate and spleen, however, it is not observed in heart or skeletal muscle. It is also reported to be involved in the metabolism of 4-hydroxynonenal, a SNP in intron 5 of AKR1A1 has been found to be significantly associated with increased risk of non-Hodgkins lymphoma. AKR1A1 could activate procarcinogens, such as polycyclic aromatic hydrocarbon, 4-hydroxynonenal polycyclic aromatic hydrocarbon DAUN AKR1A1 human gene location in the UCSC Genome Browser. AKR1A1 human gene details in the UCSC Genome Browser
23.
AKR1B1
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Aldo-keto reductase family 1, member B1, also known as aldose reductase, is an enzyme that in humans is encoded by the AKR1B1 gene. It is a reduced nicotinamide-adenine dinucleotide phosphate -dependent enzyme catalyzing the reduction of aldehydes and ketones to the corresponding alcohol. The involvement in oxidative stress diseases, cell signal transduction and cell proliferation process endows AKR1B1 the potential as a therapeutic target, the AKR1B1 gene lies on the chromosome location of 7q33 and consists of 10 exons. There are a few putative pseudogenes for this gene, and one of them has been confirmed and mapped to chromosome 3, AKR1B1 consists of 316 amino acid residues and weighs 35853Da. It does not possess the traditional dinucleotide binding fold, the way it binds NADPH differs fro other nucleotide adenine dinucleotide-dependent enzymes. The active site pocket of human aldose reductase is relatively hydrophobic, lined by seven aromatic and it is a reduced nicotinamide-adenine dinucleotide phosphate -dependent enzyme catalyzing the reduction of various aldehydes and ketones to the corresponding alcohol. It also participates in glucose metabolism and osmoregulation and plays a role against toxic aldehydes derived from lipid peroxidation. Under diabetic conditions AR converts glucose into sorbitol, which is converted to fructose. 20466987 It has been found to play an important role in many diabetes complications such as diabetes retinopathy and renopathy and it is also involved in many oxidative stress diseases, cell signal transduction and cell proliferation process including cardiovascular disorders, sepsis, and cancer. Human AR genome location and AR gene details page in the UCSC Genome Browser
24.
AKR1B10
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Aldo-keto reductase family 1 member B10 is an enzyme that in humans is encoded by the AKR1B10 gene. This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and this member can efficiently reduce aliphatic and aromatic aldehydes, and it is less active on hexoses. It is highly expressed in adrenal gland, small intestine, and colon, human AKR1B10 genome location and AKR1B10 gene details page in the UCSC Genome Browser. Human ARL1 genome location and ARL1 gene details page in the UCSC Genome Browser
25.
AKR1C1
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This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors, the enzymes display overlapping but distinct substrate specificity. This enzyme catalyzes the reduction of progesterone to the inactive form 20-alpha-hydroxy-progesterone and this gene shares high sequence identity with three other gene members, and is clustered with those three genes at chromosome 10p15-p14. Human AKR1C1 genome location and AKR1C1 gene details page in the UCSC Genome Browser, human C9 genome location and C9 gene details page in the UCSC Genome Browser
26.
AKR1C3
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Aldo-keto reductase family 1 member C3 is a key steroidogenic enzyme that in humans is encoded by the AKR1C3 gene. This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and these enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity and this enzyme catalyzes the reduction of prostaglandin D2, PGH2 and phenanthrenequinone, and the oxidation of 9alpha, 11beta-PGF2 to PGD2. It may play an important role in the pathogenesis of diseases such as asthma. This gene shares high sequence identity with three other members and is clustered with those three genes at chromosome 10p15-p14. AKR1C3 is overexpressed in cancer and is associated with the development of castration-resistant prostate cancer. In addition, AKR1C3 overexpression may serve as a biomarker for prostate cancer progression. Human AKR1C3 genome location and AKR1C3 gene details page in the UCSC Genome Browser
27.
AKR1C4
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3α-hydroxysteroid dehydrogenase, also known as aldo-keto reductase family 1 member C4, is an enzyme that in humans is encoded by the AKR1C4 gene. It is known to be necessary for the synthesis of the endogenous neurosteroids allopregnanolone, THDOC and it is also known to catalyze the reversible conversion of 3α-androstanediol to dihydrotestosterone and vice versa. This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and these enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity and this enzyme catalyzes the bioreduction of chlordecone, a toxic organochlorine pesticide, to chlordecone alcohol in liver. This gene shares high sequence identity with three other members and is clustered with those three genes at 10p15-p14 on chromosome 10. This action has been implicated in their effectiveness in affective disorders, 3β-Hydroxysteroid dehydrogenase Human AKR1C4 genome location and AKR1C4 gene details page in the UCSC Genome Browser
28.
Aldose reductase
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In enzymology, aldose reductase is a cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides. It is primarily known for catalyzing the reduction of glucose to sorbitol, aldose reductase catalyzes the NADPH-dependent conversion of glucose to sorbitol, the first step in polyol pathway of glucose metabolism. The second and last step in the pathway is catalyzed by sorbitol dehydrogenase, thus, the polyol pathway results in conversion of glucose to fructose with stoichiometric utilization of NADPH and production of NADH. For example, it is used as the first step in a synthesis of fructose from glucose. Liver, Fructose produced from sorbitol can be used as a source for glycolysis and glyconeogenesis. Aldose reductase is also present in the lens, retina, Schwann cells of peripheral nerves, placenta, aldose reductase may be considered a prototypical enzyme of the aldo-keto reductase enzyme superfamily. The enzyme comprises 315 amino acid residues and folds into a structural motif composed of eight parallel β strands. Adjacent strands are connected by eight peripheral α-helical segments running anti-parallel to the β sheet, the catalytic active site situated in the barrel core. The NADPH cofactor is situated at the top of the β/α barrel, with the nicotinamide ring projects down in the center of the barrel, the reaction mechanism of aldose reductase in the direction of aldehyde reduction follows a sequential ordered path where NADPH binds, followed by the substrate. Binding of NADPH induces a change that involves hinge-like movement of a surface loop so as to cover a portion of the NADPH in a manner similar to that of a safety belt. The alcohol product is formed via a transfer of the hydride of NADPH to the re face of the substrates carbonyl carbon. Following release of the product, another conformational change occurs in order to release NADP+. Kinetic studies have shown that reorientation of this loop to permit release of NADP+ appears to represent the rate-limiting step in the direction of aldehyde reduction. As the rate of coenzyme release limits the rate, it can be seen that perturbation of interactions that stabilize coenzyme binding can have dramatic effects on the maximum velocity. The hydride that is transferred from NADP+ to glucose comes from C-4 of the ring at the base of the hydrophobic cavity. Thus, the position of this carbon defines the active site. There exist three residues in the enzyme within a distance of the C-4 that could be potential proton donors, Tyr-48, His-110. Evolutionary, thermodynamic and molecular modeling evidence predicted Tyr-48 as the proton donor and this prediction was confirmed the results of mutagenesis studies
29.
3-oxoacyl-(acyl-carrier-protein) reductase
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This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this class is -3-hydroxyacyl-, NADP+ oxidoreductase. This enzyme participates in fatty acid biosynthesis and polyunsaturated fatty acid biosynthesis, purification and characterizations of beta-Ketoacyl- reductase, beta-hydroxyacyl- dehydrase, and enoyl- reductase from Spinacia oleracea leaves. Studies on the mechanism of fatty acid synthesis, preparation and general properties of beta-ketoacyl acyl carrier protein reductase from Escherichia coli
30.
Carnitine dehydrogenase
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This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this class is carnitine, NAD+ 3-oxidoreductase. Aurich H, Kleber HP, Sorger H, Tauchert H. Reinigung und Eigenschaften der Carnitindehydrogenase aus Pseudomonas aeruginosa, schopp W, Sorger H, Kleber HP, Aurich H. Kinetische Untersuchungen zum Reaktionsmechanismus der Carnitindehydrogenase aus Pseudomonas aeruginosa. Carnitine dehydrogenase at the US National Library of Medicine Medical Subject Headings EC1.1.1.108
31.
DXP reductoisomerase
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DXP reductoisomerase is an enzyme that interconverts 1-deoxy-D-xylulose 5-phosphate and 2-C-methyl-D-erythritol 4-phosphate. It is classified under EC1.1.1.267 and it is part of the nonmevalonate pathway, and it is inhibited by fosmidomycin. It is normally abbreviated DXR, but it is sometimes named IspC and this enzyme is responsible for terpenoid biosynthesis in some organisms. In Arabidopsis thaliana 1-deoxy-D-xylulose 5-phosphate reductoisomerase is the first committed enzyme of the pathway for isoprenoid biosynthesis. The enzyme requires Mn2+, Co2+ or Mg2+ for activity, with Mn2+ being most effective
32.
Glucose-6-phosphate dehydrogenase
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The NADPH in turn maintains the level of glutathione in these cells that helps protect the red blood cells against oxidative damage from compounds like hydrogen peroxide. G6PD reduces NADP+ to NADPH while oxidizing glucose-6-phosphate, clinically, an X-linked genetic deficiency of G6PD predisposes a person to non-immune hemolytic anemia. G6PD is widely distributed in species from bacteria to humans. Multiple sequence alignment of over 100 known G6PDs from different organisms reveal sequence identity ranging from 30% to 94%, human G6PD has over 30% identity in amino acid sequence to G6PD sequences from other species. Humans also have two isoforms of a gene coding for G6PD. Moreover,150 different human G6PD mutants have been documented, some scientists have proposed that some of the genetic variation in human G6PD resulted from generations of adaptation to malarial infection. Other species experience a variation in G6PD as well, in higher plants, several isoforms of G6PDH have been reported, which are localized in the cytosol, the plastidic stroma, and peroxisomes. A modified F420-dependent G6PD is found in Mycobacterium tuberculosis, and is of interest for treating tuberculosis, the bacterial G6PD found in Leuconostoc mesenteroides was shown to be reactive toward 4-Hydroxynonenal, in addition to G6P. G6PD is generally found as a dimer of two identical monomers, depending on conditions, such as pH, these dimers can themselves dimerize to form tetramers. Each monomer in the complex has a binding site that binds to G6P. The evolutionary purpose of the NADP+ structural site is unknown, as for size, each monomers is approximately 500 amino acids long. The proline at position 172 is thought to play a role in positioning Lys171 correctly with respect to the substrate. With access to crystal structures, some scientists have tried to model the structures of other mutants, thus, mutations in these critical areas are possible without completely disrupting the function of G6PD. In fact, it has shown that most disease causing mutations of G6PD occur near the NADP+ structural site. The NADP+ structural site is located greater than 20Å away from the binding site. Its purpose in the catalyzed reaction has been unclear for many years. For some time, it was thought that NADP+ binding to the site was necessary for dimerization of the enzyme monomers. However, this was shown to be incorrect, on the other hand, it was shown that the presence of NADP+ at the structural site promotes the dimerization of dimers to form enzyme tetramers
33.
Glycerol-3-phosphate dehydrogenase
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Glycerol-3-phosphate dehydrogenase is an enzyme that catalyzes the reversible redox conversion of dihydroxyacetone phosphate to sn-glycerol 3-phosphate. Glycerol-3-phosphate dehydrogenase serves as a link between carbohydrate metabolism and lipid metabolism. It is also a contributor of electrons to the electron transport chain in the mitochondria. Older terms for glycerol-3-phosphate dehydrogenase include alpha glycerol-3-phosphate dehydrogenase and glycerolphosphate dehydrogenase, however, glycerol-3-phosphate dehydrogenase is not the same as glyceraldehyde 3-phosphate dehydrogenase, whose substrate is an aldehyde not an alcohol. GPDH plays a role in lipid biosynthesis. Through the reduction of dihydroxyacetone phosphate into glycerol 3-phosphate, GPDH allows the prompt dephosphorylation of glycerol 3-phosphate into glycerol, additionally, GPDH is responsible for maintaining the redox potential across the inner mitochondrial membrane in glycolysis. The NAD+/NADH coenzyme couple act as a reservoir for metabolic redox reactions. Most of these reactions occur in the mitochondria. To regenerate NAD+ for further use, NADH pools in the cytosol must be reoxidized, since the mitochondrial inner membrane is impermeable to both NADH and NAD+, these cannot be freely exchanged between the cytosol and mitochondrial matrix. Simultaneously, NADH is oxidized to NAD+ in the reaction, As a result. GPD1 consists of two subunits, and reacts with dihydroxyacetone phosphate and NAD+ though the interaction, Figure 4. The phosphate group of DHAP is half-encircled by the side-chain of Arg269, the conserved residues Lys204, Asn205, Asp260 and Thr264 form a stable hydrogen bonding network. The other hydrogen bonding network includes residues Lys120 and Asp260, as well as a water molecule. In these two networks, only the ε-NH3+ group of Lys204 is the nearest to the C2 atom of DHAP. GPD2 consists of 4 identical subunits, studies indicate that GPDH is mostly unaffected by pH changes, neither GPD1 or GPD2 is favored under certain pH conditions. At high salt concentrations, GPD1 activity is enhanced over GPD2, changes in temperature do not appear to favor neither GPD1 nor GPD2. The cytosolic together with the mitochondrial glycerol-3-phosphate dehydrogenase work in concert, oxidation of cytoplasmic NADH by the cytosolic form of the enzyme creates glycerol-3-phosphate from dihydroxyacetone phosphate. As a result, there is a net loss in energy, the combined action of these enzymes maintains the NAD+/NADH ratio that allows for continuous operation of metabolism
34.
HMG-CoA reductase
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HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. This enzyme is thus the target of the widely available cholesterol-lowering drugs known collectively as the statins, more recent evidence shows it to contain eight transmembrane domains. In humans, the gene for HMG-CoA reductase is located on the arm of the fifth chromosome. Related enzymes having the function are also present in other animals, plants. The main isoform of HMG-CoA reductase in humans is 888 amino acids long and it is a polytopic transmembrane protein. It contains two domains, an N-terminal sterol-sensing domain, which binds sterol groups. Cholesterol binding at this region inhibits the activity of the catalytic domain, a C-terminal catalytic domain, namely the 3-hydroxy-3-methyl-glutaryl-CoA reductase domain. This domain is required for the enzymatic activity of the protein. Isoform 2 is 835 amino acids long and this variant is shorter because it lacks an exon in the middle region. This does not affect any of the aforementioned domains, HMGCR catalyses the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol. Click on genes, proteins and metabolites below to link to respective articles, drugs that inhibit HMG-CoA reductase, known collectively as HMG-CoA reductase inhibitors, are used to lower serum cholesterol as a means of reducing the risk for cardiovascular disease. These drugs include rosuvastatin, lovastatin, atorvastatin, pravastatin, fluvastatin, pitavastatin, red yeast rice extract, one of the fungal sources from which the statins were discovered, contains several naturally occurring cholesterol-lowering molecules known as monacolins. The most active of these is monacolin K, or lovastatin, HMG-CoA reductase is active when blood glucose is high. The basic functions of insulin and glucagon are to maintain glucose homeostasis and it can be noted that blocking of isoprenoid synthesis by statins has shown promise in treating a mouse model of multiple sclerosis, an inflammatory autoimmune disease. HMG-CoA reductase is an important developmental enzyme, inhibition of its activity and the concomitant lack of isoprenoids that yields can lead to germ cell migration defects as well as intracerebral hemorrhage. Regulation of HMG-CoA reductase is achieved at several levels, transcription, translation, degradation and phosphorylation, transcription of the reductase gene is enhanced by the sterol regulatory element binding protein. This protein binds to the regulatory element, located on the 5 end of the reductase gene. When SREBP is inactive, it is bound to the ER or nuclear membrane with another protein called SREBP cleavage-activating protein, when cholesterol levels fall, SREBP is released from the membrane by proteolysis and migrates to the nucleus, where it binds to the SRE and transcription is enhanced
35.
IMP dehydrogenase
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IMP dehydrogenase is associated with cell proliferation and is a possible target for cancer chemotherapy. Mammalian and bacterial IMPDHs are tetramers of identical chains, there are two IMP dehydrogenase isozymes in humans. IMP dehydrogenase nearly always contains a long insertion that has two CBS domains within it, the structure of this enzyme is composed of a TIM barrel domain with two CBS domains inserted within a loop. It is inhibited by Mycophenolic acid, ribavirin, and 6TGMP, 6TGMP inhibition prevents purine interconversion and thus the synthesis of purine nucleotides. Humans express the following two IMP dehydrogenase isozymes, Purine metabolism This article incorporates text from the public domain Pfam and InterPro IPR001093
