They are categorized under EC number 2.4.1.
|This EC 2.4 enzyme-related article is a stub. You can help Wikipedia by expanding it.|
They are categorized under EC number 2.4.1.
|This EC 2.4 enzyme-related article is a stub. You can help Wikipedia by expanding it.|
1. Transferase – 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
2. Enzyme – 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
3. Glycogen debranching enzyme – A debranching enzyme is a molecule that helps facilitate the breakdown of glycogen, which serves as a store of glucose in the body, through glucosyltransferase and glucosidase activity. Together with phosphorylases, debranching enzymes mobilize glucose reserves from glycogen deposits in the muscles and this constitutes a major source of energy reserves in most organisms. Glycogen breakdown is highly regulated in the body, especially in the liver, by various hormones including insulin and glucagon, when glycogen breakdown is compromised by mutations in the glycogen debranching enzyme, metabolic diseases such as Glycogen storage disease type III can result. Glucosyltransferase and glucosidase are performed by an enzyme in mammals, yeast, and some bacteria. Proteins that catalyze both functions are referred to as glycogen debranching enzymes, when glucosyltransferase and glucosidase are catalyzed by distinct enzymes, glycogen debranching enzyme usually refers to the glucosidase enzyme. In some literature, an enzyme capable only of glucosidase is referred to as a debranching enzyme, together with phosphorylase, glycogen debranching enzymes function in glycogen breakdown and glucose mobilization. When phosphorylase has digested a glycogen branch down to four glucose residues, Glycogen debranching enzymes assist phosphorylase, the primary enzyme involved in glycogen breakdown, mobilize glycogen stores. Phosphorylase can only cleave α-1, 4- glycosidic bond between adjacent glucose molecules in glycogen but branches exist as α-1,6 linkages. The mechanism by which the glucosidase cleaves the α -1, 6-linkage is not fully known because the amino acids in the site have not yet been identified. It is thought to proceed through a two step acid base assistance type mechanism, with an oxocarbenium ion intermediate, and retention of configuration in glucose. This is a method through which to cleave bonds, with an acid below the site of hydrolysis to lend a proton. These acids and bases are amino acid chains in the active site of the enzyme. A scheme for the mechanism is shown in the figure below, thus the debranching enzymes, transferase and α-1, 6- glucosidase converts the branched glycogen structure into a linear one, paving the way for further cleavage by phosphorylase. In E. coli and other bacteria, glucosyltransferase and glucosidase functions are performed by two distinct enzymes, in E. coli, Glucose transfer is performed by 4-alpha-glucanotransferase, a 78.5 kDa protein coded for by the gene malQ. A second protein, referred to as debranching enzyme, performs α-1 and this enzyme has a molecular mass of 73.6 kDa, and is coded for by the gene glgX. Activity of the two enzymes is not always necessarily coupled, in E. coli glgX selectively catalyzes the cleavage of 4-subunit branches, without the action of glucanotransferase. The product of cleavage, maltotetraose, is further degraded by maltodextrin phosphorylase. E. coli GlgX is structurally similar to the protein isoamylase, the monomeric protein contains a central domain in which eight parallel beta-strands are surrounded by eight parallel alpha strands
4. Glucuronosyltransferase – Uridine 5-diphospho-glucuronosyltransferase is a cytosolic glycosyltransferase that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. Alternative names, glucuronyltransferase UDP-glucuronyl transferase UDP-GT Glucuronosyltransferases are responsible for the process of glucuronidation, arguably the most important of the Phase II enzymes, UGTs have been the subject of increasing scientific inquiry since the mid-to-late 1990s. It is also the pathway for foreign chemical removal for most drugs, dietary substances, toxins. UGT is present in humans, other animals, plants, famously, UGT enzymes are not present in the genus Felis, and this accounts for a number of unusual toxicities in the cat family. The resulting glucuronide is more polar and more easily excreted than the substrate molecule, the product solubility in blood is increased allowing it to be eliminated from the body by the kidneys. A deficiency in the specific form of glucuronosyltransferase is thought to be the cause of Gilberts syndrome. It is also associated with Crigler-Najjar syndrome, a serious disorder where the enzymes activity is either completely absent or less than 10% of normal. Infants may have a deficiency in UDP-glucuronyl transferase, and are unable to hepatically metabolize the antibiotic drug chloramphenicol which requires glucuronidation. This leads to a known as gray baby syndrome
5. Glycogen phosphorylase – Glycogen phosphorylase is one of the phosphorylase enzymes. Glycogen phosphorylase catalyzes the rate-limiting step in glycogenolysis in animals by releasing glucose-1-phosphate from the terminal alpha-1, Glycogen phosphorylase is also studied as a model protein regulated by both reversible phosphorylation and allosteric effects. Glycogen phosphorylase breaks up glycogen into glucose subunits, n + Pi ⇌ n-1 + α-D-glucose-1-phosphate, Glycogen is left with one fewer glucose molecule, and the free glucose molecule is in the form of glucose-1-phosphate. In order to be used for metabolism, it must be converted to glucose-6-phosphate by the enzyme phosphoglucomutase, Glycogen phosphorylase can act only on linear chains of glycogen. Its work will come to a halt four residues away from α1-6 branch. In these situations, an enzyme is necessary, which will straighten out the chain in that area. After all this is done, glycogen phosphorylase can continue and this crevice connects the glycogen storage site to the active, catalytic site. Glycogen phosphorylase has a pyridoxal phosphate at each catalytic site, pyridoxal phosphate links with basic residues and covalently forms a Schiff base. There is also a proposed mechanism involving a positively charged oxygen in a half-chair conformation. The glycogen phosphorylase monomer is a protein, composed of 842 amino acids with a mass of 97.434 kDa in muscle cells. While the enzyme can exist as a monomer or tetramer. In mammals, the major isozymes of glycogen phosphorylase are found in muscle, liver, the brain type is predominant in adult brain and embryonic tissues, whereas the liver and muscle types are predominant in adult liver and skeletal muscle, respectively. The glycogen phosphorylase dimer has many regions of biological significance, including sites, glycogen binding sites, allosteric sites. First, the sites are relatively buried, 15Å from the surface of the protein. Perhaps the most important regulatory site is Ser14, the site of reversible phosphorylation very close to the subunit interface. The structural change associated with phosphorylation, and with the conversion of phosphorylase b to phosphorylase a, is the arrangement of the originally disordered residues 10 to 22 into α helices. This change increases phosphorylase activity up to 25% even in the absence of AMP, the allosteric site of AMP binding on muscle isoforms of glycogen phosphorylase are close to the subunit interface just like Ser14. AMP binding rotates the tower helices of the two subunits 50˚ relative to one another through greater organization and intersubunit interactions, the final, perhaps most curious site on the glycogen phosphorylase protein is the so-called glycogen storage site
6. Glycosyltransferase – Glycosyltransferases are enzymes that establish natural glycosidic linkages. The result of transfer can be a carbohydrate, glycoside, oligosaccharide. Some glycosyltransferases catalyse transfer to inorganic phosphate or water, glycosyl transfer can also occur to protein residues, usually to tyrosine, serine, or threonine to give O-linked glycoproteins, or to asparagine to give N-linked glycoproteins. Mannosyl groups may be transferred to tryptophan to generate C-mannosyl tryptophan, transferases may also use lipids as an acceptor, forming glycolipids, and even use lipid-linked sugar phosphate donors, such as dolichol phosphates. Glycosyltransferases that utilize non-nucleotide donors such as dolichol or polyprenol pyrophosphate are non-Leloir glycosyltransferases, the phosphate of these donor molecules are usually coordinated by divalent cations such as manganese, however metal independent enzymes exist. Glycosyltransferases can be segregated into “retaining” or“ inverting” enzymes according to whether the stereochemistry of the donor’s anomeric bond is retained or inverted during the transfer, the inverting mechanism is straightforward, requiring a single nucleophilic attack from the accepting atom to invert stereochemistry. The retaining mechanism has been a matter of debate, but there exists strong evidence against a double displacement mechanism or a dissociative mechanism, sequence-based classification methods have proven to be a powerful way of generating hypotheses for protein function based on sequence alignment to related proteins. The carbohydrate-active enzyme database presents a classification of glycosyltransferases into over 90 families. The same three-dimensional fold is expected to occur within each of the families, in contrast to the diversity of 3D structures observed for glycoside hydrolases, glycosyltransferase have a much smaller range of structures. Many inhibitors of glycosyltransferases are known, some glycosyltransferase inhibitors are of use as drugs or antibiotics. Moenimycin is used in animal feed as a growth promoter, caspofungin has been developed from the echinocandins and is in use as an antifungal agent. Ethambutol is an inhibitor of mycobacterial arabinotransferases and is used for the treatment of tuberculosis, lufenuron is an inhibitor of insect chitin synthases and is used to control fleas in animals. The ABO blood group system is determined by type of glucosyltransferases are expressed in the body. The ABO gene locus expressing the glucosyltransferases has three main forms, A, B, and O. The A allele encodes 1-3-N-acetylgalactosaminyltransferase that bonds α-N-acetylgalactosamine to D-galactose end of H antigen, the B allele encodes 1-3-galactosyltransferase that joins α-D-galactose bonded to D-galactose end of H antigen, creating the B antigen. In case of O allele the exon 6 contains a deletion that results in a loss of enzymatic activity, the O allele differs slightly from the A allele by deletion of a single nucleotide - Guanine at position 261. The deletion causes a frameshift and results in translation of an almost entirely different protein that lacks enzymatic activity and this results in H antigen remaining unchanged in case of O groups. The combination of glucosyltransferases by both present in each person determines whether there is an AB, A, B or O blood type
7. Glycogen synthase – Glycogen synthase is a key enzyme in glycogenesis, the conversion of glucose into glycogen. It is a glycosyltransferase that catalyses the reaction of UDP-glucose and n to yield UDP, in other words, this enzyme combines excess glucose residues one by one into a polymeric chain for storage as glycogen. Glycogen synthase concentration is highest in the bloodstream 30 to 60 minutes following intense exercise, much research has been done on glycogen degradation through studying the structure and function of glycogen phosphorylase, the key regulatory enzyme of glycogen degradation. On the other hand, much less is known about the structure of glycogen synthase, the crystal structure of glycogen synthase from Agrobacterium tumefaciens, however, has been determined at 2.3 A resolution. In its asymmetric form, glycogen synthase is found as a dimer and this structural property, among others, is shared with related enzymes, such as glycogen phosphorylase and other glycosyltransferases of the GT-B superfamily. Nonetheless, a more recent characterization of the Saccharomyces cerevisiae glycogen synthase crystal structure reveals that the dimers may actually interact to form a tetramer, since the structure of eukaryotic glycogen synthase is highly conserved among species, glycogen synthase likely forms a tetramer in humans as well. Glycogen synthase can be classified in two protein families. The first family, which is from mammals and yeast, is approximately 80 kDa, uses UDP-glucose as a sugar donor, the second family, which is from bacteria and plants, is approximately 50 kDA, uses ADP-glucose as a sugar donor, and is unregulated. Glycogen synthase catalyzes the conversion of the moiety of uridine diphosphate glucose into glucose to be incorporated into glycogen via an α glycosidic bond. However, since glycogen synthase requires an oligosaccharide primer as a glucose acceptor, in a recent study of transgenic mice, an overexpression of glycogen synthase and an overexpression of phosphatase both resulted in excess glycogen storage levels. This suggests that glycogen synthase plays an important biological role in regulating glycogen/glucose levels and is activated by dephosphorylation, in humans, there are two paralogous isozymes of glycogen synthase, The liver enzyme expression is restricted to the liver, whereas the muscle enzyme is widely expressed. Liver glycogen serves as a pool to maintain the blood glucose level during fasting. The role of muscle glycogen is as a reserve to provide energy during bursts of activity, meanwhile, the muscle isozyme plays a major role in the cellular response to long-term adaptation to hypoxia. Notably, hypoxia only induces expression of the muscle isozyme and not the liver isozyme, however, muscle-specific glycogen synthase activation may lead to excessive accumulation of glycogen, leading to damage in the heart and central nervous system following ischemic insults. Phosphorylation of glycogen synthase decreases its activity, the enzyme also cleaves the ester bond between the C1 position of glucose and the pyrophosphate of UDP itself. The control of glycogen synthase is a key step in regulating glycogen metabolism, glycogen synthase is directly regulated by glycogen synthase kinase 3, AMPK, protein kinase A, and casein kinase 2. Each of these protein kinases lead to phosphorylated and catalytically inactive glycogen synthase, the phosphorylation sites of glycogen synthase are summarized below. For enzymes in the GT3 family, these regulatory kinases inactivate glycogen synthase by phosphorylating it at the N-terminal of the 25th residue, glycogen synthase is also regulated by protein phosphatase 1, which activates glycogen synthase via dephosphorylation
8. Myophosphorylase – Myophosphorylase is the muscle isoform of the enzyme glycogen phosphorylase. This enzyme helps break down glycogen into glucose-1-phosphate, so that it can be utilized within the muscle cell, a deficiency is associated with Glycogen storage disease type V, also known as McArdles Syndrome. A case study suggested that a deficiency in myophosphorylase may be linked with cognitive impairment, besides muscle, this isoform is present in astrocytes, where it plays a key role in neural energy metabolism. A 55-year-old woman with McArdle disease has expressed cognitive impairment with bilateral dysfunction of prefrontal and frontal cortex, further studies are needed to assess the validity of this claim. Myophosphorylase at the US National Library of Medicine Medical Subject Headings
9. Glycogen branching enzyme – Glycogen branching enzyme is an enzyme that adds branches to the growing glycogen molecule during the synthesis of glycogen, a storage form of glucose. More specifically, during synthesis, a glucose 1-phosphate molecule reacts with uridine triphosphate to become UDP-glucose. Importantly, glycogen synthase can only catalyze the synthesis of α-1, branching also importantly increases the solubility and decreases the osmotic strength of glycogen. This enzyme belongs to the family of transferases, to be specific, the systematic name of this enzyme class is 1, 4-alpha-D-glucan,1, 4-alpha-D-glucan 6-alpha-D--transferase. This enzyme participates in starch and sucrose metabolism, GBE is encoded by the GBE1 gene. Through southern blot analysis of DNA derived from human/rodent somatic cell hybrids, the human GBE gene was also isolated by a function complementation of the Saccharomyces cerevisiae GBE deficiency. From the isolated cDNA, the length of the gene was found to be approximately 3 kb, additionally, the coding sequence was found to comprise 2,106 base pairs and encode a 702-amino acid long GBE. The molecular mass of human GBE was calculated to be 80,438 Da, glycogen branching enzyme belongs to the α-amylase family of enzymes, which include α-amylases, pullulanas/isoamylase, cyclodextrin glucanotransferase, and branching enzyme. While the central domain is common in members of the α-amylase family. Additionally, there are striking differences between the loops connecting elements of the secondary structure among these various α-amylase members, especially around the active site. In comparison to the family members, glycogen binding enzyme has shorter loops. These residues are implicated in catalysis and substrate binding, glycogen binding enzymes in other organisms have also been crystallized and structurally determined, demonstrating both similarity and variation to GBE found in Escherichia coli. In glycogen, every 10 to 14 glucose units, a branch with an additional chain of glucose units occurs. The side chain attaches at carbon atom 6 of a glucose unit and this connection is catalyzed by a branching enzyme, generally given the name α-glucan branching enzyme. A branching enzyme attaches a string of seven glucose units to the carbon at the C-6 position on the unit, forming the α-1. The specific nature of this means that this chain of 7 carbons is usually attached to a glucose molecule that is in position three from the non-reducing end of another chain. Mutations in this gene are associated with glycogen storage disease type IV in newborns, approximately 40 mutations in the GBE1 gene, most resulting in a point mutation in the glycogen branching enzyme, have led to the early childhood disorder, glycogen storage disease type IV. This disease is characterized by a severe depletion or complete absence of GBE, resulting in the accumulation of abnormally structured glycogen, glycogen buildup leads to increased osmotic pressure resulting in cellular swelling and death