1.
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
2.
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
3.
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
4.
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
5.
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
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.
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
8.
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
9.
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
10.
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
11.
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
