1.
Leukotriene
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Leukotrienes use lipid signaling to convey information to either the cell producing them or neighboring cells in order to regulate immune responses. Leukotriene production is accompanied by the production of histamine and prostaglandins. One of their roles is to trigger contractions in the smooth muscles lining the bronchioles, their overproduction is a cause of inflammation in asthma. Leukotriene antagonists are used to treat these disorders by inhibiting the production or activity of leukotrienes, the name leukotriene, introduced by Swedish biochemist Bengt Samuelsson in 1979, comes from the words leukocyte and triene. What would be later named leukotriene C, slow reaction smooth muscle-stimulating substance was originally described between 1938 and 1940 by Feldberg and Kellaway, the researchers isolated SRS from lung tissue after a prolonged period following exposure to snake venom and histamine. Leukotrienes are commercially available to the research community, LTC4, LTD4, LTE4 and LTF4 are often called cysteinyl leukotrienes due to the presence of the amino acid cysteine in their structure. The cysteinyl leukotrienes make up the substance of anaphylaxis. LTF4, like LTD4, is a metabolite of LTC4, but, unlike LTD4, LTB4 is synthesized in vivo from LTA4 by the enzyme LTA4 hydrolase. Its primary function is to recruit neutrophils to areas of tissue damage, drugs that block the actions of LTB4 have shown some efficacy in slowing the progression of neutrophil-mediated diseases. There has also postulated the existence of LTG4, a metabolite of LTE4 in which the cysteinyl moiety has been oxidized to an alpha-keto-acid. Very little is known about this putative leukotriene, leukotrienes originating from the omega-3 class eicosapentanoic acid have diminished inflammatory effects. Leukotrienes are synthesized in the cell from arachidonic acid by arachidonate 5-lipoxygenase, the catalytic mechanism involves the insertion of an oxygen moiety at a specific position in the arachidonic acid backbone. The lipoxygenase pathway is active in leukocytes and other immunocompetent cells, including mast cells, eosinophils, neutrophils, monocytes, when such cells are activated, arachidonic acid is liberated from cell membrane phospholipids by phospholipase A2, and donated by the 5-lipoxygenase-activating protein to 5-lipoxygenase. 5-Lipoxygenase uses FLAP to convert arachidonic acid into 5-hydroperoxyeicosatetraenoic acid, which reduces to 5-hydroxyeicosatetraenoic acid. The enzyme 5-LO acts again on 5-HETE to convert it into leukotriene A4, in cells that express LTC4 synthase, such as mast cells and eosinophils, LTA4 is conjugated with the tripeptide glutathione to form the first of the cysteinyl-leukotrienes, LTC4. Outside the cell, LTC4 can be converted by enzymes to form successively LTD4 and LTE4. Both LTB4 and the cysteinyl-leukotrienes are partly degraded in local tissues, leukotrienes act principally on a subfamily of G protein-coupled receptors. They may also act upon peroxisome proliferator-activated receptors, leukotrienes are involved in asthmatic and allergic reactions and act to sustain inflammatory reactions
2.
Cell signaling
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Cell signaling is part of any communication process that governs basic activities of cells and coordinates all cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, errors in signaling interactions and cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. By understanding cell signaling, diseases may be treated effectively and, theoretically. Traditional work in biology has focused on studying individual parts of cell signaling pathways, systems biology research helps us to understand the underlying structure of cell signaling networks and how changes in these networks may affect the transmission and flow of information. Such networks are complex systems in their organization and may exhibit a number of emergent properties including bistability and ultrasensitivity, analysis of cell signaling networks requires a combination of experimental and theoretical approaches including the development and analysis of simulations and modeling. Long-range allostery is often a significant component of signaling events. Cell signaling has been most extensively studied in the context of human diseases, however, cell signaling may also occur between the cells of two different organisms. In many mammals, early embryo cells exchange signals with cells of the uterus, in the human gastrointestinal tract, bacteria exchange signals with each other and with human epithelial and immune system cells. For the yeast Saccharomyces cerevisiae during mating, some cells send a signal into their environment. The mating factor peptide may bind to a surface receptor on other yeast cells. Cell signaling can be classified to be mechanical and biochemical based on the type of the signal, mechanical signals are the forces exerted on the cell and the forces produced by the cell. These forces can both be sensed and responded by the cells, biochemical signals are the biochemical molecules such as proteins, lipids, ions and gases. These signals can be categorized based on the distance between signaling and responder cells, Signaling within, between, and amongst cells is subdivided into the following classifications, Intracrine signals are produced by the target cell that stay within the target cell. Autocrine signals are produced by the cell, are secreted. Sometimes autocrine cells can target cells close by if they are the type of cell as the emitting cell. An example of this are immune cells and these signals are transmitted along cell membranes via protein or lipid components integral to the membrane and are capable of affecting either the emitting cell or cells immediately adjacent. Paracrine signals target cells in the vicinity of the emitting cell, endocrine cells produce hormones that travel through the blood to reach all parts of the body. Cells communicate with each other via direct contact, over short distances, some cell–cell communication requires direct cell–cell contact
3.
Receptor (biochemistry)
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In biochemistry and pharmacology, a receptor is a protein molecule that receives chemical signals from outside a cell. When such chemical signals bind to a receptor, they cause some form of cellular/tissue response, however, sometimes in pharmacology, the term is also used to include other proteins that are drug targets, such as enzymes, transporters and ion channels. Receptor proteins can be classified by their location, transmembrane receptors include ion channel-linked receptors, G protein-linked hormone receptors, and enzyme-linked hormone receptors. Intracellular receptors are found inside the cell, and include cytoplasmic receptors. The endogenously designated -molecule for a receptor is referred to as its endogenous ligand. E. g. the endogenous ligand for the acetylcholine receptor is acetylcholine but the receptor can also be activated by nicotine. Each receptor is linked to a specific cellular biochemical pathway, while numerous receptors are found in most cells, each receptor will only bind with ligands of a particular structure, much like how locks will only accept specifically shaped keys. When a ligand binds to its receptor, it activates or inhibits the receptors associated biochemical pathway. The ligand-binding cavities are located at the interface between the subunits, type 2, G protein-coupled receptors – This is the largest family of receptors and includes the receptors for several hormones and slow transmitters e. g. dopamine, metabotropic glutamate. They are composed of seven transmembrane alpha helices, the loops connecting the alpha helices form extracellular and intracellular domains. The aforementioned receptors are coupled to different intracellular effector systems via G proteins, the insulin receptor is an example. Type 4, Nuclear receptors – While they are called nuclear receptors, they are located in the cytoplasm. They are composed of a C-terminal ligand-binding region, a core DNA-binding domain, the core region has two zinc fingers that are responsible for recognizing the DNA sequences specific to this receptor. The N terminus interacts with other transcription factors in a ligand-independent manner. Steroid and thyroid-hormone receptors are examples of such receptors, membrane receptors may be isolated from cell membranes by complex extraction procedures using solvents, detergents, and/or affinity purification. The structures and actions of receptors may be studied by using methods such as X-ray crystallography, NMR, circular dichroism. Computer simulations of the behavior of receptors have been used to gain understanding of their mechanisms of action. Ligand binding is an equilibrium process, ligands bind to receptors and dissociate from them according to the law of mass action
4.
Ligand (biochemistry)
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In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein, the binding typically results in a change of conformation of the target protein. In DNA-ligand binding studies, the ligand can be a molecule, ion. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure, the instance of binding occurs over an infinitesimal range of time and space, so the rate constant is usually a very small number. Binding occurs by intermolecular forces, such as bonds, hydrogen bonds. The association of docking is actually reversible through dissociation, measurably irreversible covalent bonding between a ligand and target molecule is atypical in biological systems. In contrast to the definition of ligand in metalorganic and inorganic chemistry, in biochemistry it is whether the ligand generally binds at a metal site. In general, the interpretation of ligand is contextual with regards to what sort of binding has been observed, the etymology stems from ligare, which means to bind. Ligand binding to a receptor protein alters the chemical conformation by affecting the shape orientation. The conformation of a receptor protein composes the functional state, ligands include substrates, inhibitors, activators, and neurotransmitters. The rate of binding is called affinity, and this measurement typifies a tendency or strength of the effect, binding affinity is actualized not only by host-guest interactions, but also by solvent effects that can play a dominant, steric role which drives non-covalent binding in solution. The solvent provides an environment for the ligand and receptor to adapt. Radioligands are radioisotope labeled compounds are used in vivo as tracers in PET studies, the interaction of most ligands with their binding sites can be characterized in terms of a binding affinity. In general, high-affinity binding results in a degree of occupancy for the ligand at its receptor binding site than is the case for low-affinity binding. A ligand that can bind to a receptor, alter the function of the receptor, high-affinity ligand binding implies that a relatively low concentration of a ligand is adequate to maximally occupy a ligand-binding site and trigger a physiological response. The lower the Ki concentration is, the more likely there will be a reaction between the pending ion and the receptive antigen. In the example shown to the right, two different ligands bind to the receptor binding site. Only one of the agonists shown can maximally stimulate the receptor and, thus, an agonist that can only partially activate the physiological response is called a partial agonist
5.
12-Hydroxyeicosatetraenoic acid
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It was first found as a product of arachidonic acid metabolism made by human and bovine platelets through their 12S-lipoxygenase enzyme. The two isomers, either directly or after being metabolized, have been suggested to be involved in a variety of human physiological and pathological reactions. In these roles, they may amplify or dampen, expand or contract cellular, in humans, Arachidonate 12-lipoxygenase is encoded by the ALOX12 gene and expressed primarily in platelets and skin. ALOX12 metabolizes arachidonic acid almost exclusively to 12-hydroperoxy-5Z, 8Z, 10E, Arachidonate 12-lipoxygenase, 12R type, also termed 12RLOX and encoded by the ALOX12B gene, is expressed primarily in skin and cornea, it metabolizes arachidonic acid to 12-HpETE. Mice also express an epidermal type 15-lipoxygenase which has 50. 8% amino acid identity to human 15-LOX-2 and 49. 3% sequence indetity to mouse Arachidonate 8-lipoxygenase. Mouse e-12LO metabolizes arachidonic acid predominantly to 12-HETE and to a lesser extent 15-HETE, in human skin epidermis, 12-HpETE is metabolized by Epidermis-type lipoxygenase, i. e. These decompositions may occur during tissue isolation procedures, in other tissues and animal species, numerous hepoxilins form but the hepoxilin synthase activity responsible for their formation is variable. The majority of reports on hepoxilin formation have not defined the pathways evolved, human and other mammalian cytochome P450 enzymes convert 12-HpETE to 12-oxo-ETE. 12-HETE, 12-HETE, 12-oxo-ETE, hepoxilin B3, and trioxilin B3 are found in the position of phospholipids isolated from normal human epidermis. These acylation reactions may sequester and thereby inactivate or store the metabolites for release during cell stimulation, GPR31 mRNA is expressed at low levels in several human cell lines including K562 cells, Jurkat cells, Hut78 cells, HEK293 cells, MCF7 cells, and EJ cells. Studies have not yet determined the role, if any, in GPR31 receptor in the action of 12-HETE in other cell types, a G protein-coupled receptor for the 5, 12-dihydroxy metabolite of aracidonic acid, Leukotriene B4, vis. Leukotriene B4 receptor 2, but not its Leukotriene B4 receptor 1, mediates responses to 12-HETE, 12-HETE, and 12-oxo-ETE in many cell types. The BLT2 receptor, in contrast to the GPR31 receptor, appears to be expressed at a level in a wide range of tissues including neutrophils, eosinophils, monocytes, spleen, liver. Ultimately, both receptors and all three ligands may prove to be responsible for some tissue responses in vivo, 12-HETE and 12-HETE bind to and act as Competitive antagonists of the Thromboxane receptor which mediates the actions of Thromboxane A2 and Prostaglandin H2. This antagonistic activity was responsible for the ability of 12-HETE and 12-HETE to relax mouse mesenteric arteries pre-constricted with a thromboxane A2 mimetic, 12-HETE binds with high affinity to a 50 kilodalton subunit of a 650 kDa cytosolic and nuclear protein complex. Since it mediates 12-HETE-induced itching in the model, BLT2 rather than GPR31 may mediate human itch in these reactions. These results suggest that the 12-HETE made by prostate cancer tissues serves to promote the growth, further studies in animal models suggest that the 12S-HETE made by pancreatic beta cells orchestrate a local immune response that results in the injury and, when extreme, death of beta cells. These results suggest that the 12-lipoxygenase-12S-HETE pathway is one contributing to immunity-based type I diabetes as well as low insulin output type II diabetes
6.
12-Hydroxyheptadecatrienoic acid
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12-Hydroxyheptadecatrenoic acid is a 17 carbon metabolite of the 20 carbon polyunsaturated fatty acid, arachidonic acid. It was first detected and structurally defined by P. Wlodawer, samuelsson, and M. Hamberg as a product of arachidonic acid metabolism made by microsomes isolated from sheep seminal vesicle glands and by intact human platelets. The metabolite was for years thought to be merely a biologically inactive byproduct of prostaglandin synthesis. More recent studies, however, have attached potentially important activity to it, Thromboxane synthase further metabolizes PGH2 to the 20 carbon product, Thromboxane A2, the 17 carbon product, 12-HHT, and the 3 carbon product Malonyldialdehyde. These effects combine to trigger blood clotting and limiting blood loss, various cytochrome P450 enzymes metabolize PGG2 and PGH2 to 12-HHT and MDA. Future studies, therefore may show that cytochromes are responsible for 12-HHT and this non-enzymatic pathway may explain findings that cells can make 12-HHT in excess of TXA2 and also in the absence of active cycloxygenase and/or thromboxane synthase enzymes. 12-HHT is further metabolized by 15-hydroxyprostaglandin dehydrogenase in a variety of human and other vertebrate cells to its 12-oxo derivative, 12-oxo-5Z, 8E. Pig kidney tissue also converted 12-HHT to 12-keto-5Z, 8E-heptadecadienoic acid, acidic conditions cause 12-HHT to rearrange in a time- and temperature-dependent process to its 5-cis isomer, 12-hydroxy-5E, 8E, 10E-heptadecatrienoic acid. These studies were largely overlooked, in 1998 and 2007 publications, for example and this strategy may be essential for limiting the deleterious thrombotic and vasospastic activities of TXA2. Leukotriene B4 is an arachidonic acid made by the 5-lipoxygenase enzyme pathway. The BLT2 receptors relative affinities for finding LTB4, 12-HETE, 12-HpETE, 12-HETE, 15-HETE, and 20-hydroxy-LTB4 are ~100,10,10,3,3, and 1, respectively. All of these binding affinities are considered to be low and therefore indicating that some unknown ligand might bind BLT2 with high affinity, in 2009, 12-HHT was found to bind to the BLT2 receptor with ~10-fold higher affinity than LTB4, 12-HHT did not bind to the BLT1 receptor. Formyl peptide receptor 2 is a relevant and well-studied example of promiscuous receptors, BLT2 may ultimately prove to have binding specificity for a similarly broad range of agents. Drugs that inhibit LTB4 production or binding to BLT1 are in use or development for the latter diseases, in contrast, the production of 12-HH2 and expression of BLT2 receptors by human tissues is far wider and more robust than that of the LTB4/BLT2 receptor axis. Recent studies indicate that the role of the 12-HHT/BLT2 receptor axis in human physiology and pathology may be different than those of the LTB4/BLT1 axis. These findings suggest that the 12-HHT/BLT2 receptor pathway may support the actions of the LTB4/BLT1 pathway. Furthermore, 12-HHT inhibits HaCaT cells from synthesizing interleukin-6, a pro-inflammatory cytokine associated with cutaneous inflammation and these results suggest that the 12-HHT/BLT2 axis can act to suppress inflammation by promoting the orderly death of damaged cells and blocking IL-6 production. Opposition between the pro-inflammatory LTB4/BLT1 and anti-inflammatory actions of the 12-HHT/BLT2 axes occurs in another setting, also, BLT2 knockout mice exhibited a greatly enhanced response to ovalabumin challenge
7.
15-Hydroxyicosatetraenoic acid
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15-Hydroxyeicosatetraenoic acid is an endogenous eicosanoid, i. e. a metabolite of arachidonic acid. Various cell types and tissues first produce 15-Hydroperoxyicosatetraenoic acid and these initial hydroperoxy products are extremely short lived in cells, if not otherwise metabolized, they are reduced to 15-HETE. The production and actions of these molecules and their metabolites often differ greatly depending on cell-type or tissue-type studied, in many ways they are analogous to the more abundant 5-HETE and 5-HPETE. Its enantiomer is -hydroxy-5Z, 8Z, 11Z, 13E-eicosatetraenoic acid, the substance also has Z- and E-stereoisomers about each of its double bond moieties at carbon positions 5,8,11, and 13. These initial hydroperoxy products are extremely short lived in cells, if not otherwise metabolized, both stereoisomers of 15-HETE and probably also of 15-HpETE have signalling activities, as discussed below. e. g. Human and rat microsomal cytochrome P450s, e. g. CYP2C19, metabolize arachidonic acid to a mixture of 15-HETEs, i. e. 15-HETEs. When pretreated with aspirin, however, COX-1 is inactive while COX-2 attacks arachidonic acid to produce almost exclusively 15-HETE along with its presumed precursor 15-HpETE. The spontaneous and non-enzymatically-induced autooxidation of arachidonic acid yields 15-hydroperoxy-5Z, 8Z, 11Z, b) Is acylated into membrane phospholipids, particularly Phosphatidylinositols and phosphatidylethanolamine. The 15-HpETE is bound primarily at the position of these phospholipids. Phosphotidylinositol phospholipids with 15-HETE in the position can be attacked by phospholipase C to form corresponding diglycerides with 15-HETE at theirsn-2 positions. EXC4 contains glutathione bound in the R configuration to carbon 14, eXC4 is further metabolized by removal of the γ-L-glutamyl residue to form EXD4 which is in turn further metabolized by removal of the glycine residue to form EXE4. These metabolic transformations are similar to those in the pathway that metabolizes arachidonic acid to, the two novel hepoxilins are termed respectively 14, 15-HXA3 and 14, 15-HXB3. e. H) Is metabolized in skin epidermis by Epidermis-type lipoxygenase 3 to make two products, hepoxilin A3 and 15-oxo-ETE), i) Like other hydroperoxy-containing fatty acids, degrades in cells to various bifuctional potentially toxic electrophiles such as 4-hydroxy-2-nonenal and 4-oxo-2-nonenal. J) Is metabolized by cytochrome P450 enzymes such as CYP1A1, CYP1A2, CYP1B1, b) Is acylated into membrane phospholipids, particularly phosphatidylinositol and phosphatidylethanolamine. The phosphatidylethanolamine-bound 15-HETE may be converted to phosphatidylethanolamine-bound 15-oxo-ETE, c) Is oxygenated by 5-lipoxygenase This hydroperoxy precursor of 15-HETE made by COX enzymes degrades to 15-HETE. B) Decomposes to various bifuctional potentially toxic electrophiles such as 4-hydroxy-2-nonenal and 4-oxo-2-nonenal, in this scenario, 15-HETE and one of its formaing enzymes, particularly 15-LOX-2, appear to act as tumor suppressors. These species trigger cells to activate their death programs, i. e. apoptosis, 15-HpETE and 15-HETE inhibit angiogenesis and the growth of cultured human chronic myelogenous leukemia K-562 cells by a mechanism that is associated with the production of reactive oxygen species. Several bifuctional electrophilic breakdown products of 15-HpETE, e. g, similar to 15-HpETE and 15-HETE and with similar potency, 15-HETE binds with and activates peroxisome proliferator-activated receptor gamma. g
8.
Pranlukast
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Pranlukast is a cysteinyl leukotriene receptor-1 antagonist. This drug works similarly to Merck & Co. s montelukast and it is widely used in Japan. Medications of this group are used as an adjunct to the standard therapy of inhaled steroids with inhaled long- and/or short-acting beta-agonists. There are several similar medications in the group, all appear to be equally effective
9.
Cysteinyl leukotriene receptor 2
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Cysteinyl leukotriene receptor 2, also termed CYSLTR2, is a receptor for cysteinyl leukotrienes. CYSLTR2, by binding these cysteinyl LTs contributes to mediating various allergic, however, the first discovered receptor for these CsLTs, cysteinyl leukotriene receptor 1, appears to play the major role in mediating these reactions. The human CysLTR2 gene maps to the arm of chromosome 13 at position 13q14. The gene consists of four exons with all introns located in the genes 5 UTR region, CysLTR2 encodes a protein composed of 347 amino acids and shows only modest similarity to the CysLTR1 gene in that its protein shares only 31% amino acid identity with the CysLTR1 protein. CySLTR2 mRNA is co-expressed along with CysLRR1 in human blood eosinophils and platelets, and tissue mast cells, macrophages, airway epithelial cells, and vascular endothelial cells. It is also expressed without CysLTR1 throughout the heart, including Purkinje cells, adrenal gland, and brain as well as vascular endothelial, airway epithelial. By comparison, the potencies of these CysLTs for CysLTR1 is LTD4>LTC4>LTE4 with LTD4 showing 10-fold greater potency on CysLTR1 than CysLTR2. However, recent studies also working with model cells involved in allergy find that GPR17-bearing cells do not respond to these CysLTs, the latter studies conclude that GPR17 acts to inhibit CysLTR1. There are as yet no selective inhibitors of CysLTR2 that are in clinical use, however, Gemilukast reportedly inhibits both CysLTR1 and CysLTR2. The drug is currently being evaluated in phase II trials for the treatment of asthma, the M201V CysLTR2 variant exhibits decreased responsiveness to LTD4 suggesting that this hypo-responsiveness underlies its asthma transmission-protecting effect. These results suggest that CYSLTR2 contributes to the etiology and development asthma, however, CysLT2 requires 10-fold higher concentrations of LTD4, the most potent cysLT for CysLTR1, to activate CysLTR2. The role of CysLTR2 in the allergic and hypersensitivity diseases of humans must await the development of selective CysLTR2 inhibitors, eicosanoid receptor Cysteinyl leukotriene receptor 1 GPR99 Leukotriene Receptors, CysLT2. IUPHAR Database of Receptors and Ion Channels, international Union of Basic and Clinical Pharmacology. This article incorporates text from the United States National Library of Medicine, which is in the public domain
10.
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
11.
Enzyme inhibitor
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An enzyme inhibitor is a molecule that binds to an enzyme and decreases its activity. Since blocking an enzymes activity can kill a pathogen or correct a metabolic imbalance and they are also used in pesticides. The binding of an inhibitor can stop a substrate from entering the active site and/or hinder the enzyme from catalyzing its reaction. Inhibitor binding is reversible or irreversible. Irreversible inhibitors usually react with the enzyme and change it chemically and these inhibitors modify key amino acid residues needed for enzymatic activity. In contrast, reversible inhibitors bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind to the enzyme, many drug molecules are enzyme inhibitors, so their discovery and improvement is an active area of research in biochemistry and pharmacology. A medicinal enzyme inhibitor is often judged by its specificity and its potency, a high specificity and potency ensure that a drug will have few side effects and thus low toxicity. Enzyme inhibitors also occur naturally and are involved in the regulation of metabolism, for example, enzymes in a metabolic pathway can be inhibited by downstream products. This type of negative feedback slows the production line when products begin to build up and is an important way to maintain homeostasis in a cell, other cellular enzyme inhibitors are proteins that specifically bind to and inhibit an enzyme target. This can help control enzymes that may be damaging to a cell, a well-characterised example of this is the ribonuclease inhibitor, which binds to ribonucleases in one of the tightest known protein–protein interactions. Natural enzyme inhibitors can also be poisons and are used as defences against predators or as ways of killing prey, reversible inhibitors attach to enzymes with non-covalent interactions such as hydrogen bonds, hydrophobic interactions and ionic bonds. Multiple weak bonds between the inhibitor and the active site combine to produce strong and specific binding, in contrast to substrates and irreversible inhibitors, reversible inhibitors generally do not undergo chemical reactions when bound to the enzyme and can be easily removed by dilution or dialysis. There are four kinds of reversible enzyme inhibitors and they are classified according to the effect of varying the concentration of the enzymes substrate on the inhibitor. In competitive inhibition, the substrate and inhibitor cannot bind to the enzyme at the same time, as shown in the figure on the right. This usually results from the inhibitor having an affinity for the site of an enzyme where the substrate also binds. This type of inhibition can be overcome by high concentrations of substrate. However, the apparent Km will increase as it takes a higher concentration of the substrate to reach the Km point, competitive inhibitors are often similar in structure to the real substrate. In uncompetitive inhibition, the inhibitor binds only to the substrate-enzyme complex and this type of inhibition causes Vmax to decrease and Km to decrease
12.
Arachidonate 5-lipoxygenase
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Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme that in humans is encoded by the ALOX5 gene. Arachidonate 5-lipoxygenase is a member of the family of enzymes. It transforms EFA substrates into leukotrienes as well as a range of other biologically active products. ALOX5 is a current target for intervention in a number of diseases. The ALOX5 gene, which occupies 71.9 kilobase pairs on chromosome 10, is composed of 14 exons divided by 13 introns encoding the mature 78 kilodalton ALOX5 protein consisting of 673 amino acids. The gene promoter region of ALOX5 contains 8 GC boxes but lacks TATA boxes or CAT boxes, five of the 8 GC boxes are arranged in tandem and are recognized by the transcription factors Sp1 and Egr-1. A novel Sp1-binding site occurs close to the transcription start site. Platelets, T cells, and erythrocytes are ALOX5-negative, in skin, Langerhans cells strongly express ALOX5. Fibroblasts, smooth muscle cells and endothelial cells express low levels of ALOX5, studies with cultured human cells have found that there are a large number of ALOX5 mRNA splice variants due to Alternative splicing. The physiological and/or pathological consequences of this slicing has yet to be defined, Human ALOX5 is a soluble, monomeric protein consisting of 673 amino acids with a molecular weight of ~78 kDa. The enzyme possesses two catalytic activities as illustrated by its metabolism of arachidonic acid, ALOX5s dioxygenase activity adds a hydroperoxyl residue to arachidonic acid at carbon 5 of its 1,4 diene group to form 5-hydroperoxy-6E, 8Z, 11Z, 14Z-eicosatetraenoic acid. The Glu and Gly residues of LTC4 may be removed step-wise by gamma-glutamyltransferase, to varying extents, the other PUFA substrates of ALOX5 follow similar metabolic pathways to form analogous products. Sub-human mammalian Alox5 enzymes like those in rodents appear to have, at least in general, similar structures, distributions, activities, hence, model Alox5 studies in rodents appear to be valuable for defining the function of ALOX5 in humans. ALOX5 exists primarily in the cytoplasm and nucleoplasm of cells, rises in cytosolic Ca2+, ALOX5s movement to membranes, and ALOX5s interaction with FLAP are critical to the physiological activation of the enzylme. Serine 271 and 663 phosphorylations do not appear to alter ALOX5s activity, serine 523 phosphorylation totally inactivates the enzyme and prevents its nuclear localization, stimuli which cause cells to activate PKA can thereby block production of ALOX5 metaboites. This is accomplished by a family of phospholipase A2 enzymes. The cytosolic PLA2 set of PLA2 enzymes in particular mediates many instances of stimulus-induced release of PUFA in inflammatory cells and this chemotactic factor stimulation concurrently causes the activation of mitogen-activated protein kinases which in turn stimulates the activity of cPLA2α by phosphorylating it on ser-505. These two events allow cPLA2s to release PUFA esterified to membrane phospholipids to FLAP which then presents them to ALOX5 for their metabolism, other factors are known to regulate ALOX5 activity in vitro but have not been fully integrated into its physiological activation during cell stimulation
13.
Baicalein
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Baicalein is a flavone, a type of flavonoid, originally isolated from the roots of Scutellaria baicalensis and Scutellaria lateriflora. It is also reported in Oroxylum indicum or Indian trumpetflower and it is the aglycone of baicalin. Baicalein is one of the ingredients of Sho-Saiko-To, a Japanese herbal supplement believed to enhance liver health. Baicalein, along with its analogue baicalin, is an allosteric modulator of the benzodiazepine site and/or a non-benzodiazepine site of the GABAA receptor. It displays subtype selectivity for α2 and α3 subunit-containing GABAA receptors, in accordance, baicalein shows anxiolytic effects in mice without incidence of sedation or myorelaxation. It is thought that baicalein, along with other flavonoids, may underlie the anxiolytic effects of S. baicalensis, baicalein is also an antagonist of the estrogen receptor, or an antiestrogen. The flavonoid has been shown to inhibit certain types of lipoxygenases and it has antiproliferative effects on ET-1-induced proliferation of pulmonary artery smooth muscle cell proliferation via inhibition of TRPC1 channel expression. Possible antidepressant effects have also attributed to baicalein in animal research. Baicalein is an inhibitor of CYP2C9, an enzyme of the cytochrome P450 system that metabolizes drugs in the body, a derivative of baicalin is a known prolyl endopeptidase inhibitor. Baicalein has been shown to inhibit Staphylococcus aureus biofilm formation and the sensing system in vitro. Tetuin is the 6-glucoside of baicalein, list of compounds with carbon number 15
14.
Caffeic acid
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Caffeic acid is an organic compound that is classified as a hydroxycinnamic acid. This yellow solid consists of both phenolic and acrylic functional groups and it is found in all plants because it is a key intermediate in the biosynthesis of lignin, one of the principal components of plant biomass and its residues. Caffeic acid can be found in the bark of Eucalyptus globulus and it can also be found in the freshwater fern Salvinia molesta or in the mushroom Phellinus linteus. Caffeic acid is found at a very modest level in coffee and it is one of the main natural phenols in argan oil. It is at a high level in black chokeberry and in fairly high level in lingonberry. It is also high in the South American herb yerba mate. It is also found in grain, and in rye grain. Caffeic acid, which is unrelated to caffeine, is biosynthesized by hydroxylation of coumaroyl ester of quinic acid and this hydroxylation produces the caffeic acid ester of shikimic acid, which converts to chlorogenic acid. It is the precursor to acid, coniferyl alcohol, and sinapyl alcohol. The transformation to ferulic acid is catalyzed by the enzyme caffeate O-methyltransferase, caffeic acid and its derivative caffeic acid phenethyl ester are produced in many kinds of plants. Dihydroxyphenylalanine ammonia-lyase was presumed to use 3, 4-dihydroxy-L-phenylalanine to produce trans-caffeate, however, the EC number for this purported enzyme was deleted in 2007, as no evidence has emerged for its existence. Caffeate O-methyltransferase is a responsible for the transformation of caffeic acid into ferulic acid. Caffeic acid and related o-diphenols are rapidly oxidized by o-diphenol oxidases in tissue extracts, caffeate 3, 4-dioxygenase is an enzyme that uses caffeic acid and oxygen to produce 3--cis, cis-muconate. 3-O-caffeoylshikimic acid and its isomers, are enzymic browning substrates found in dates, caffeic acid is an antioxidant in vitro and also in vivo. Caffeic acid also shows immunomodulatory and anti-inflammatory activity, caffeic acid outperformed the other antioxidants, reducing aflatoxin production by more than 95 percent. The studies are the first to show that stress that would otherwise trigger or enhance Aspergillus flavus aflatoxin production can be stymied by caffeic acid. This opens the door to use as a natural fungicide by supplementing trees with antioxidants, studies of the carcinogenicity of caffeic acid have mixed results. Some studies have shown that it inhibits carcinogenesis, and other experiments show carcinogenic effects, oral administration of high doses of caffeic acid in rats has caused stomach papillomas
15.
Curcumin
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Curcumin is a bright yellow chemical produced by some plants. It is the principal curcuminoid of turmeric, a member of the ginger family and it is sold as an herbal supplement, cosmetics ingredient, food flavoring, and food coloring. As a food additive, its E number is E100 and it was isolated in 1815 when Vogel and Pelletier reported the isolation of a yellow coloring-matter from the rhizomes of turmeric and named it curcumin. Although curcumin has been used historically in Ayurvedic medicine, its potential for medicinal properties remains unproven and is doubted as a therapy when used orally, chemically, curcumin is a diarylheptanoid, belonging to the group of curcuminoids, which are natural phenols responsible for turmerics yellow color. It is a tautomeric compound existing in enolic form in organic solvents, the most common applications are as a dietary supplement, in cosmetics, as a food coloring, and as flavoring for foods such as turmeric-flavored beverages. Annual sales of curcumin have increased since 2012, largely due to an increase in its popularity as a dietary supplement and it is increasingly popular in skin care products that are marketed as containing natural ingredients or dyes, especially in Asia. The largest market is in North America, where sales exceeded US$20 million in 2014, curcumin incorporates several functional groups whose structure was first identified in 1910. The aromatic ring systems, which are phenols, are connected by two α, β-unsaturated carbonyl groups, the diketones form stable enols and are readily deprotonated to form enolates, the α, β-unsaturated carbonyl group is a good Michael acceptor and undergoes nucleophilic addition. Curcumin is used as an indicator for boron and it reacts with boric acid to form a red-color compound, rosocyanine. The biosynthetic route of curcumin is uncertain, in 1973, Roughly and Whiting proposed two mechanisms for curcumin biosynthesis. The first mechanism involves a chain reaction by cinnamic acid and 5 malonyl-CoA molecules that eventually arylized into a curcuminoid. The second mechanism involves two cinnamate units coupled together by malonyl-CoA, both use cinnamic acid as their starting point, which is derived from the amino acid phenylalanine. Plant biosyntheses starting with cinnamic acid is rare compared to the more common p-coumaric acid, only a few identified compounds, such as anigorufone and pinosylvin, build from cinnamic acid. In vitro, curcumin exhibits numerous interference properties which may lead to misinterpretation of results, although curcumin has been assessed in numerous laboratory and clinical studies, it has no medical uses established by well-designed clinical research. Cancer studies using curcumin conducted by Bharat Aggarwal, formerly a researcher at the MD Anderson Cancer Center, were deemed fraudulent, curcumin, which shows positive results in most drug discovery assays, may be a false lead that medicinal chemists refer to as pan-assay interference compounds. In vitro, curcumin has been shown to inhibit certain enzymes, transcriptional co-activator proteins. Two preliminary clinical studies in cancer patients consuming high doses of curcumin showed no toxicity, curcumin appears to reduce circulating C-reactive protein in human subjects, although no dose-response relationship was established. Turmeric and curcumin, from Memorial Sloan-Kettering Cancer Center Turmeric, from the University of Maryland Medical Center
16.
Hyperforin
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Hyperforin is a phytochemical produced by some of the members of the plant genus Hypericum, notably Hypericum perforatum. Hyperforin is believed to be one of the three chief active constituents of St. Johns wort -the other two being hypericin and several flavonoid constituents. Hyperforin has only found in significant amounts in Hypericum perforatum with other related species such as Hypericum calycinum containing lower levels of the phytochemical. It is thought to be a reuptake inhibitor and it accumulates in oil glands, pistils, and fruits, probably as a plant defense against herbivory. Other Hypericum species contain low amounts of hyperforin, Hyperforin is a prenylated phloroglucinol derivative. The structure of hyperforin was elucidated by a group from the Shemyakin Institute of Bio-organic Chemistry. A total synthesis of the enantiomer of hyperforin was reported in 2010. Hyperforin is unstable in the presence of light and oxygen, some pharmacokinetic data on hyperforin is available for an extract containing 5% hyperforin. Maximal plasma levels in human volunteers were reached 3. 5h after administration of an extract containing 14.8 mg hyperforin, biological half-life and mean residence time were 9h and 12h respectively with an estimated steady state plasma concentration of 100 ng/mL for 3 doses/d. Linear plasma concentrations were observed within a normal range and no accumulation occurred. In healthy male volunteers,612 mg dry extract of St. Johns wort produced hyperforin pharmacokinetics characterised by a life of 19.64 hours. It appears to be metabolised, at least in part, by CYP3A, Hyperforin is believed to be the primary active constituent responsible for the antidepressant and anxiolytic properties of the extracts of St. Johns wort. Hyperforin also inhibits the reuptake of glycine and choline and it also modulates acetylcholine release in rat hippocampus and facilitates acetylcholine release in the striatum. It appears to exert these effects by activating the transient receptor potential ion channel TRPC6, activation of TRPC6 induces the entry of sodium and calcium into the cell which causes inhibition of monoamine reuptake. It also antagonises the NMDA receptor, AMPA receptor and GABA receptors and its action on the TRPC6 cation channel is also believed to be responsible for its BDNF-like modulation of dendritic spine morphology in hippocampal pyramidal neurons. Nootropic effects of hyperforin have been observed in rats, there is in vivo evidence that it can reduce biomarkers of Alzheimers Disease in animal models and in vitro, an action it seems to share with its analogue, tetrahydrohyperforin. Hyperforin promotes mitochondrial function and the development of oligodendrocytes, Hyperforin also induces cytochrome P450 enzymes CYP3A4 and CYP2C9 by binding to and activating the pregnane X receptor. The induction of CYP3A caused by hypericum perforatum seems to be dependent on its hyperforin content
17.
Hypericum perforatum
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Hypericum perforatum, known as perforate St Johns-wort, common Saint Johns wort and St Johns wort, is a flowering plant in the family Hypericaceae. The common name St Johns wort may be used to refer to any species of the genus Hypericum, therefore, Hypericum perforatum is sometimes called common St Johns wort or perforate St Johns wort in order to differentiate it. It is a herb with antidepressant activity and potent anti-inflammatory properties as an arachidonate 5-lipoxygenase inhibitor. Hypericum perforatum is native to parts of Europe and Asia but has spread to temperate regions worldwide as an invasive weed. The common name St Johns wort comes from its flowering and harvesting on St Johns Day,24 June. The genus name Hypericum is derived from the Greek words hyper and eikon, in reference to the tradition of hanging plants over religious icons in the home during St Johns Day, perforate St Johns wort is a herbaceous perennial plant with extensive, creeping rhizomes. Its stems are erect, branched in the section. It has opposite, stalkless, narrow, oblong leaves that are 1–2 cm long, the leaves are yellow-green in color, with scattered translucent dots of glandular tissue. The dots are conspicuous when held up to the light, giving the leaves the perforated appearance to which the plants Latin name refers, the flowers measure up to 2.5 cm across, have five petals, and are colored bright yellow with conspicuous black dots. The flowers appear in broad cymes at the ends of the upper branches, the sepals are pointed, with black glandular dots. There are many stamens, which are united at the base into three bundles, when flower buds or seed pods are crushed, a reddish/purple liquid is produced. St Johns wort reproduces both vegetatively and sexually and it thrives in areas with either a winter- or summer-dominant rainfall pattern, however, distribution is restricted by temperatures too low for seed germination or seedling survival. Altitudes greater than 1500 m, rainfall less than 500 mm, depending on environmental and climatic conditions, and rosette age, St Johns wort will alter growth form and habit to promote survival. Summer rains are particularly effective in allowing the plant to grow vegetatively, the seeds can persist for decades in the soil seed bank, germinating following disturbance. In pastures, St Johns wort acts as both a toxic and invasive weed and it replaces native plant communities and forage vegetation to the extent of making productive land nonviable or becoming an invasive species in natural habitats and ecosystems. Ingestion by livestock such as horses, sheep, and cattle can cause photosensitization, central nervous system depression, effective herbicides for control of Hypericum include 2, 4-D, picloram, and glyphosate. In western North America three beetles Chrysolina quadrigemina, Chrysolina hyperici and Agrilus hyperici have been introduced as biocontrol agents, studies have supported the efficacy of St Johns wort as a treatment for depression in humans. The authors concluded that it is difficult to assign a place for St and it is proposed that the mechanism of action of St. Johns wort is due to the inhibition of reuptake of certain neurotransmitters
18.
Meclofenamic acid
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Meclofenamic acid is a drug used for joint, muscular pain, arthritis and dysmenorrhea. It is a member of the anthranilic acid derivatives class of NSAID drugs and was approved by the FDA in 1980, like other members of the class, it is a COX inhibitor and prevents formation of prostaglandins. Scientists led by Claude Winder from Parke-Davis invented meclofenamate sodium in 1964, along with members of the class, mefenamic acid in 1961. Patents on the drug expired in 1985 and several generics were introduced in the US and it is not widely used in humans as it has a high rate rate of gastrointestinal side effects. As of 2015 the cost for a course of medication in the United States is 50 to 100 USD. Meclofenamic acid is sold under the trade name Arquel for use in horses and it has a relatively slow onset of action, taking 36–48 hours for full effect, and is most useful for treatment of chronic musculoskeletal disease. It has been found to be beneficial for the treatment of navicular syndrome, laminitis, however, due to cost, it is not routinely used in practice. Toxicity due to excessive dosage is similar to that of phenylbutazone, including depression, anorexia, weight loss, edema, diarrhea, oral ulceration, and decreased hematocrit
19.
ALOX15
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ALOX15 is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically important products. In humans, it is encoded by the ALOX15 gene located on chromosome 17p13.3 and this 11 kilobase pair gene consists of 14 exons and 13 introns coding for a 75 kiloDalton protein composed of 662 amino acids. 15-LO is to be distinguished from another human 15-lipoxygenase enzyme, ALOX15B, orthologs of ALOX15, termed Alox15, are widely distributed in animal and plant species but commonly have different enzyme activities and make somewhat different products than ALOX15. Many of the latter Alox15 enzymes nonetheless possess predominantly or exclusively 12-lipoxygenase rather than 15-lipoxygenase activity, ALOX15 and Alox15 enzymes are non-heme, iron-containing dioxygenases. Rodent Alox15 enzymes, in contrast, produce almost exclusively ω-9 peroxy intermediates, concurrently, ALOX15 and rodent Alox15 enzymes rearrange the carbon-carbon double bonds to bring them into the 1S-hydroxy-2E, 4Z-diene configuration. ALOX15 and Alox15 enzymes act with a degree of Stereospecificity to form products that position the hydroperoxy residue in the S stereoisomer configuration. Eoxins stimulate vascular permeability in an ex vivo human vascular endothelial model system, the PUFA epoxide of arachidonic acid made by ALOX15 may also be conjugated with glutathione to form eoxin A4 which product can be further metabolized to eoxin B4, eoxin C4, and eoxin D4. The human enzyme is active on linoleic acid, preferring it over arachidonic acid it is less active on PUFA that are esters within the cited lipids. Arachidonic acid has double bonds between carbons 5-6, 8-9, 11-12, and 14-15, these bounds are in the cis and its 5-ketone analog. The minor products of ALOX15, 12--HpETE and 12-HETE, possess a range of activities. 12-Oxo-ETE, which along with 12S-HETE, activates the Leukotriene B4 receptor, Leukotriene B4 receptor 2 and this allows the possibility that 12-oxo-ETE contributes to the pro-inflammatory and other activities that BLT2 regulates. Human neutrophils, presumably using their ALOX15, metabolize Dihomo-γ-linolenic acid to 15S-hydroperoxy-8Z, 11Z, 13E-eicosatrienoic acid and 15S-hydroxy-8Z, 11Z and these mice also show an accelerated rate of progression of atherosclerosis whereas mice made to overexpress 12/15-lipoxygenase exhibit a delayed rate of atherosclerosis development. Alox15 overexpressing rabbits exhibited reduced tissue destruction and bone loss in a model of periodontitis, finally, Control mice, but not 12/15-lipoxygense deficient mice responded to eicospentaenoic acid administration by decreasing the number of lesions in a model of endometriosis. These synthetic analogs may prove to be useful for treating the cited human inflammatory diseases. In colorectal, breast, and kidney cancers, 15-LOX-1 levels are low or absent compared to the normal tissue counterparts and/or these levels sharply decline as the cancers progress. These results, as well as a 15-LOX-1 transgene study on colon cancer in mice suggests but do not prove that 15-LOX-1 is a tumor suppressor
20.
Luteolin
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Luteolin is a flavone, a type of flavonoid, with a yellow crystalline appearance. Luteolin is most often found in leaves, but it is seen in rinds, barks, clover blossom. It has also been isolated from the flowering plant, Salvia tomentosa in the mint family. Dietary sources include celery, broccoli, green pepper, parsley, thyme, dandelion, perilla, chamomile tea, carrots, olive oil, peppermint, rosemary, navel oranges and it can also be found in the seeds of the palm Aiphanes aculeata
21.
Leukotriene-A4 hydrolase
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Leukotriene A4 hydrolase, also known as LTA4H is a human gene. The protein encoded by this gene is an enzyme which converts leukotriene A4 to leukotriene B4. This enzyme belongs to the family of hydrolases, specifically those acting on ether bonds, the systematic name of this enzyme class is --5, 6-epoxyicosa-7,9,11, 14-tetraenoate hydrolase. Other names in use include LTA4 hydrolase, LTA4H. This enzyme participates in arachidonic acid metabolism, as of late 2007,4 structures have been solved for this class of enzymes, with PDB accession codes 1GW6, 1H19, 1HS6, and 1SQM. Leukotriene A4 hydrolase at the US National Library of Medicine Medical Subject Headings
22.
Ubenimex
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Ubenimex, also known more commonly as bestatin, is a competitive, reversible protease inhibitor. It is an inhibitor of arginyl aminopeptidase, leukotriene A4 hydrolase, alanyl aminopeptidase, leucyl/cystinyl aminopeptidase and it is being studied for use in the treatment of acute myelocytic leukemia. It is derived from Streptomyces olivoreticuli, ubenimex has been found to inhibit the enzymatic degradation of oxytocin, vasopressin, enkephalins, and various other peptides and compounds. Amastatin Pepstatin The MEROPS online database for peptidases and their inhibitors, Bestatin
23.
Leukotriene C4 synthase
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Leukotriene C4 synthase is an enzyme that in humans is encoded by the LTC4S gene. The protein encoded by this gene, LTC4S is an enzyme that converts leukotriene A4 and this is a member of MAPEG family of transmembrane proteins. A trimer of Leukotriene C4 synthase is localized on the nuclear membrane and endoplasmic reticulum. This protein is related to microsomal glutathione S-transferase. The MAPEG family includes a number of proteins, several of which are involved the production of leukotrienes. This gene encodes an enzyme that catalyzes the first step in the biosynthesis of cysteinyl leukotrienes, leukotrienes have been implicated as mediators of anaphylaxis and inflammatory conditions such as human bronchial asthma. This protein localizes to the envelope and adjacent endoplasmic reticulum
