BioPAX pathway converted from "Synthesis of Leukotrienes (LT) and Eoxins (EX)" in the Reactome database. Synthesis of Leukotrienes (LT) and Eoxins (EX) Synthesis of Leukotrienes (LT) and Eoxins (EX) Leukotrienes (LTs) are biologically active molecules formed in response to inflammatory stimuli. They cause contraction of bronchial smooth muscles, stimulation of vascular permeability, and attraction and activation of leukocytes. LTs were discovered in 1938 and were termed the "slow release substance" (SRS) until their structures were determined in 1979 and they were then renamed to leukotrienes. LTs are derived from arachidonic acid through action by arachidonate 5-lipoxygenase (ALOX5). Cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are generated as products derived from leukotriene A4 (LTA4). Eoxins are generated from leukotrienes (LTs) and resemble cysteinyl leukotrienes but have a different three-dimensional structure (Murphy & Gijon 2007, Hammarstrom 1983, MA.Claesson 2009, Vance & Vance 2008, Buczynski et al. 2009). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 2.7.11.1 ALOX5 is phosphorylated by MAPKAP2 ALOX5 is phosphorylated by MAPKAP2 Arachidonate 5-lipoxygenase (ALOX5) catalyzes the first step in leukotriene biosynthesis and has a key role in inflammatory processes. ALOX5 is phosphorylated by MAPKAPK2; MAPKAPK2 is stimulated by arachidonic acid. Authored: Jupe, S, 2009-07-14 Reviewed: Rush, MG, 2012-11-10 Edited: Jupe, S, 2010-05-06 Reactome DB_ID: 2237880 1 cytosol GO 0005829 ALOX5:Ca2+:Fe2+ [cytosol] ALOX5:Ca2+:Fe2+ ALOX5 (iron, calcium cofactors) Reactome DB_ID: 71067 1 iron(2+) [ChEBI:29033] iron(2+) FE (II) ION Fe(2+) Fe(II) Ferrous ion Fe2+ iron ion(2+) Reactome http://www.reactome.org ChEBI 29033 Reactome DB_ID: 429010 1 UniProt:P09917 ALOX5 ALOX5 LOG5 ALOX5 FUNCTION Catalyzes the oxygenation of arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) to 5-hydroperoxyeicosatetraenoate (5-HPETE) followed by the dehydration to 5,6- epoxyeicosatetraenoate (Leukotriene A4/LTA4), the first two steps in the biosynthesis of leukotrienes, which are potent mediators of inflammation (PubMed:8631361, PubMed:21233389, PubMed:22516296, PubMed:24282679, PubMed:19022417, PubMed:23246375, PubMed:8615788, PubMed:24893149, PubMed:31664810). Also catalyzes the oxygenation of arachidonate into 8-hydroperoxyicosatetraenoate (8-HPETE) and 12-hydroperoxyicosatetraenoate (12-HPETE) (PubMed:23246375). Displays lipoxin synthase activity being able to convert (15S)-HETE into a conjugate tetraene (PubMed:31664810). Although arachidonate is the preferred substrate, this enzyme can also metabolize oxidized fatty acids derived from arachidonate such as (15S)-HETE, eicosapentaenoate (EPA) such as (18R)- and (18S)-HEPE or docosahexaenoate (DHA) which lead to the formation of specialized pro-resolving mediators (SPM) lipoxin and resolvins E and D respectively, therefore it participates in anti-inflammatory responses (PubMed:21206090, PubMed:31664810, PubMed:8615788, PubMed:17114001, PubMed:32404334). Oxidation of DHA directly inhibits endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor gamma (PPARgamma) (By similarity). It does not catalyze the oxygenation of linoleic acid and does not convert (5S)-HETE to lipoxin isomers (PubMed:31664810). In addition to inflammatory processes, it participates in dendritic cell migration, wound healing through an antioxidant mechanism based on heme oxygenase-1 (HO-1) regulation expression, monocyte adhesion to the endothelium via ITGAM expression on monocytes (By similarity). Moreover, it helps establish an adaptive humoral immunity by regulating primary resting B cells and follicular helper T cells and participates in the CD40-induced production of reactive oxygen species (ROS) after CD40 ligation in B cells through interaction with PIK3R1 that bridges ALOX5 with CD40 (PubMed:21200133). May also play a role in glucose homeostasis, regulation of insulin secretion and palmitic acid-induced insulin resistance via AMPK (By similarity). Can regulate bone mineralization and fat cell differentiation increases in induced pluripotent stem cells (By similarity).ACTIVITY REGULATION Undergoes a sequential loss of the oxygenase and pseudoperoxidase activities which is dependent on the structural characteristics of the substrate for the reaction, on oxygen concentration and on exposure to phospholipids and calcium (PubMed:8631361). 15-HETE and other 15-mono-hydroxyeicosanoids exhibit the highest inhibitory potencies in their capability of suppressing 5-lipoxygenation of arachidonic acid, whereas the other HETEs, (5S,15S)-dihydroxy-(6E,8Z,11Z,13E)-eicosatetraenoic acid (5,15-diHETE) as well as octadecanoids, are modest or poor inhibitors (PubMed:8615788). The formation of (5S)-hydroperoxy-(15S)-hydroxy-(6E,8Z,11Z,13E)-eicosatetraenoate is strongly stimulated by either hydroperoxypolyenoic fatty acids or arachidonic acid (PubMed:8615788). Arachidonate 5-lipoxygenase and leukotriene A4 synthase activities are allosterically increased by ATP (PubMed:24893149).PATHWAY Lipid metabolism; leukotriene A4 biosynthesis.SUBUNIT Homodimer (PubMed:22516296, PubMed:21233389). Interacts with ALOX5AP and LTC4S (PubMed:19233132). Interacts with COTL1, the interaction is required for stability and efficient catalytic activity (PubMed:19807693). Interacts with PIK3R1; this interaction bridges ALOX5 with CD40 after CD40 ligation in B cells and leads to the production of reactive oxygen species (ROS) (PubMed:21200133). Interacts (via PLAT domain) with DICER1 (via Dicer dsRNA-binding fold domain); this interaction enhances arachidonate 5-lipoxygenase activity and modifies the miRNA precursor processing activity of DICER1 (PubMed:19022417).PTM Serine phosphorylation by MAPKAPK2 is stimulated by arachidonic acid (PubMed:11844797, PubMed:18978352). Phosphorylation on Ser-524 by PKA has an inhibitory effect (PubMed:15280375). Phosphorylation on Ser-272 prevents export from the nucleus (PubMed:11844797, PubMed:18978352). Phosphorylation at Ser-524 is stimulated by 8-bromo-3',5'-cyclic AMP or prostaglandin E2 (PubMed:26210919).SIMILARITY Belongs to the lipoxygenase family. Homo sapiens NCBI Taxonomy 9606 UniProt P09917 Chain Coordinates 2 EQUAL 674 EQUAL Reactome DB_ID: 74016 2 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI 29108 Reactome Database ID Release 82 2237880 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2237880 Reactome R-HSA-2237880 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2237880.1 Reactome DB_ID: 113592 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 265277 1 p-S272-ALOX5:Ca2+:Fe2+ [cytosol] p-S272-ALOX5:Ca2+:Fe2+ ALOX5 (iron, calcium cofactors) Reactome DB_ID: 71067 1 Reactome DB_ID: 265276 1 O-phospho-L-serine at 272 272 EQUAL O-phospho-L-serine [MOD:00046] 2 EQUAL 674 EQUAL Reactome DB_ID: 74016 2 Reactome Database ID Release 82 265277 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265277 Reactome R-HSA-265277 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-265277.1 Reactome DB_ID: 29370 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 187760 UniProt:P49137 MAPKAPK2 MAPKAPK2 MAPKAPK2 FUNCTION Stress-activated serine/threonine-protein kinase involved in cytokine production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling, DNA damage response and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. Phosphorylates ALOX5, CDC25B, CDC25C, CEP131, ELAVL1, HNRNPA0, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Phosphorylates HSF1; leading to the interaction with HSP90 proteins and inhibiting HSF1 homotrimerization, DNA-binding and transactivation activities (PubMed:16278218). Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to the dissociation of HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impairment of their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins ELAVL1, HNRNPA0, PABPC1 and TTP/ZFP36, leading to the regulation of the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity, leading to inhibition of dependent degradation of ARE-containing transcripts. Phosphorylates CEP131 in response to cellular stress induced by ultraviolet irradiation which promotes binding of CEP131 to 14-3-3 proteins and inhibits formation of novel centriolar satellites (PubMed:26616734). Also involved in late G2/M checkpoint following DNA damage through a process of post-transcriptional mRNA stabilization: following DNA damage, relocalizes from nucleus to cytoplasm and phosphorylates HNRNPA0 and PARN, leading to stabilization of GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3.ACTIVITY REGULATION Activated following phosphorylation by p38-alpha/MAPK14 following various stresses. Inhibited following sumoylation. Specifically inhibited by pyrrolopyridine inhibitors.SUBUNIT Heterodimer with p38-alpha/MAPK14; this heterodimer forms a stable complex: molecules are positioned 'face to face' so that the ATP-binding sites of both kinases are at the heterodimer interface (PubMed:12171911, PubMed:17576063, PubMed:17255097, PubMed:17480064, PubMed:17449059, PubMed:17395714). Interacts with PHC2 (PubMed:15094067). Interacts with HSF1 (PubMed:16278218).TISSUE SPECIFICITY Expressed in all tissues examined.PTM Sumoylation inhibits the protein kinase activity.PTM Phosphorylated and activated by MAP kinase p38-alpha/MAPK14 at Thr-222, Ser-272 and Thr-334.SIMILARITY Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. UniProt P49137 O-phospho-L-threonine at 222 222 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-serine at 272 272 EQUAL O-phospho-L-threonine at 334 334 EQUAL 1 EQUAL 400 EQUAL GO 0004674 GO molecular function Reactome Database ID Release 82 429015 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=429015 Reactome Database ID Release 82 429016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=429016 Reactome R-HSA-429016 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-429016.2 10779545 Pubmed 2000 5-lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinases Werz, O Klemm, J Samuelsson, B Rådmark, O Proc Natl Acad Sci U S A 97:5261-6 11844797 Pubmed 2002 Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2) Werz, O Szellas, D Steinhilber, D Rådmark, O J Biol Chem 277:14793-800 1.13.11.34 Arachidonic acid is oxidised to 5S-HpETE by ALOX5 Arachidonic acid is oxidised to 5S-HpETE by ALOX5 Oxidation of arachidonic acid to 5-HpETE Arachidonate 5-lipoxygenase (ALOX5) catalyzes the formation of leukotriene A4 (LTA4) from arachidonic acid in a two-step process. First, arachidonic acid AA is oxidized to form 5S-hydroperoxyeicosatetranoic acid (5S-HpETE) (Rouzer et al. 1988, Rouzer & Samuelsson 1987, Rouzer et al. 1986). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 29368 1 dioxygen [ChEBI:15379] dioxygen ChEBI 15379 Reactome DB_ID: 29768 1 arachidonate [ChEBI:32395] arachidonate (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate (20:4n6) (5Z,8Z,11Z,14Z)-eicosatetraenoate ChEBI 32395 Reactome DB_ID: 266010 1 5(S)-HPETE [ChEBI:15632] 5(S)-HPETE ChEBI 15632 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2318764 nuclear envelope GO 0005635 ALOX5:ALOX5AP:LTC4S [nuclear envelope] ALOX5:ALOX5AP:LTC4S ALOX5:FLAP:LTC4S Reactome DB_ID: 2318770 1 ALOX5AP trimer [nuclear envelope] ALOX5AP trimer FLAP trimer Reactome DB_ID: 2318768 3 UniProt:P20292 ALOX5AP ALOX5AP FLAP ALOX5AP FUNCTION Required for leukotriene biosynthesis by ALOX5 (5-lipoxygenase). Anchors ALOX5 to the membrane. Binds arachidonic acid, and could play an essential role in the transfer of arachidonic acid to ALOX5. Binds to MK-886, a compound that blocks the biosynthesis of leukotrienes.SUBUNIT Homotrimer. Interacts with LTC4S and ALOX5.DOMAIN The C-terminal part after residue 140 is mostly unstructured.DISEASE Genetic variations in ALOX5AP may be associated with susceptibility to myocardial infarction. Involvement in myocardial infarction is however unclear: according to some authors (PubMed:14770184), a 4-SNP haplotype in ALOX5AP confers risk of myocardial infarction, while according to other (PubMed:17304054) ALOX5AP is not implicated in this condition.SIMILARITY Belongs to the MAPEG family. UniProt P20292 1 EQUAL 161 EQUAL Reactome Database ID Release 82 2318770 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318770 Reactome R-HSA-2318770 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318770.1 Reactome DB_ID: 2318769 1 p-S272-ALOX5:Ca2+:Fe2+ [nuclear envelope] p-S272-ALOX5:Ca2+:Fe2+ ALOX5 (iron, calcium cofactors) Reactome DB_ID: 2318767 2 Reactome DB_ID: 2318766 1 Reactome DB_ID: 2318765 1 O-phospho-L-serine at 272 272 EQUAL 2 EQUAL 674 EQUAL Reactome Database ID Release 82 2318769 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318769 Reactome R-HSA-2318769 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318769.1 Reactome DB_ID: 2142729 1 LTC4S trimer [nuclear envelope] LTC4S trimer LTC4 synthase homotrimer Reactome DB_ID: 266025 3 UniProt:Q16873 LTC4S LTC4S LTC4S FUNCTION Catalyzes the conjugation of leukotriene A4 with reduced glutathione (GSH) to form leukotriene C4 with high specificity (PubMed:7937884, PubMed:27791009, PubMed:27365393, PubMed:9153254, PubMed:23409838). Can also catalyze the transfer of a glutathionyl group from glutathione (GSH) to 13(S),14(S)-epoxy-docosahexaenoic acid to form maresin conjugate in tissue regeneration 1 (MCTR1), a bioactive lipid mediator that possess potent anti-inflammatory and proresolving actions (PubMed:27791009).ACTIVITY REGULATION Inhibited by MK886.PATHWAY Lipid metabolism; leukotriene C4 biosynthesis.SUBUNIT Homotrimer (PubMed:17632548, PubMed:17632546). Interacts with ALOX5AP and ALOX5 (PubMed:19233132).TISSUE SPECIFICITY Detected in lung, platelets and the myelogenous leukemia cell line KG-1 (at protein level). LTC4S activity is present in eosinophils, basophils, mast cells, certain phagocytic mononuclear cells, endothelial cells, vascular smooth muscle cells and platelets.PTM Phosphorylation at Ser-36 by RPS6KB1 inhibits the leukotriene-C4 synthase activity.DISEASE LTC4 synthase deficiency is associated with a neurometabolic developmental disorder characterized by muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly.SIMILARITY Belongs to the MAPEG family. UniProt Q16873 1 EQUAL 150 EQUAL Reactome Database ID Release 82 2142729 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142729 Reactome R-HSA-2142729 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142729.1 Reactome Database ID Release 82 2318764 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318764 Reactome R-HSA-2318764 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318764.1 GO 0004051 GO molecular function Reactome Database ID Release 82 265275 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265275 Reactome Database ID Release 82 265296 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265296 Reactome R-HSA-265296 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-265296.1 3164719 Pubmed 1988 Characterization of cloned human leukocyte 5-lipoxygenase expressed in mammalian cells Rouzer, CA Rands, E Kargman, S Jones, RE Register, RB Dixon, RA J Biol Chem 263:10135-40 3006030 Pubmed 1986 Single protein from human leukocytes possesses 5-lipoxygenase and leukotriene A4 synthase activities Rouzer, CA Matsumoto, T Samuelsson, B Proc Natl Acad Sci U S A 83:857-61 3118366 Pubmed 1987 Reversible, calcium-dependent membrane association of human leukocyte 5-lipoxygenase Rouzer, CA Samuelsson, B Proc Natl Acad Sci U S A 84:7393-7 ALOX5 binds ALOX5 inhibitors ALOX5 binds ALOX5 inhibitors Eicosanoids, oxygenated, 20-carbon fatty acids, are autocrine and paracrine signaling molecules that modulate physiological processes including pain, fever, inflammation, blood clot formation, smooth muscle contraction and relaxation, and the release of gastric acid. Eicosanoids are synthesized in humans primarily from arachidonic acid (AA) that is released from membrane phospholipids. Once released, AA can be acted on by various enzymes to form different eicosanoids. Arachidonate lipoxygenase 5 (ALOX)5 form leukotrienes (LTs) and eicosatetraenoic acids (ETEs) from AA. LTs and ETEs are biologically active molecules formed in response to inflammatory stimuli. They cause contraction of bronchial smooth muscles, stimulation of vascular permeability, and attraction and activation of leukocytes. When produced in excess, these molecules may contribute to a wide range of pathological inflammatory responses.<br><br>ALOX5 inhibitors are compounds that slow or stop the action of the ALOX5 enzyme, which is responsible for the production of inflammatory LTs and ETEs. Zileuton blocks the activity of ALOX5 (Carter et al. 1991). Zileuton is used in the treatment of acne vulgaris (Zouboulis 2005, Zouboulis et al. 2009) and for the prophylaxis and chronic treatment of allergic asthma (Bruno et al. 2018, Morina et al. 2016). Meclofenamic acid is a non-steroidal anti-inflammatory drug (NSAID) used for the relief of mild to moderate pain, for the treatment of primary dysmenorrhea and for the treatment of idiopathic heavy menstrual blood loss. It is also used for relief of the signs and symptoms of acute and chronic rheumatoid arthritis and osteoarthritis. In vitro meclofenamic acid was found to be an inhibitor of human ALOX5 activity (Boctor et al. 1986). Balsalazide, olsalazine and sulfasalazine are all pro-drugs that are enzymatically cleaved in the colon to produce the anti-inflammatory agent mesalazine (5-aminosalicylic acid, 5-ASA, mesalazine (Klotz 1985, Selby et al. 1985, Sharon et al. 1978, Hawkey et al. 1985, Neilsen et al. 1987). Once metabolised, 5-ASA acts locally in the colon to reduce inflammation in conditions such as inflammatory bowel disease and ulcerative colitis (Wiggins & Rajapakse 2009, Rask-Madsen et al. 1992, Singer et al. 2006, Hoult 1986, Feagan & Macdonald 2012). Authored: Jassal, Bijay, 2021-03-25 Reviewed: Huddart, Rachel, 2022-03-01 Edited: Jassal, Bijay, 2021-10-27 Edited: Matthews, Lisa, 2022-05-10 Reactome DB_ID: 2318764 1 Converted from EntitySet in Reactome Reactome DB_ID: 9707237 1 ALOX5 inhibitors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity balsalazide [cytosol] olsalazine [cytosol] zileuton [cytosol] sulfasalazine [cytosol] meclofenamic acid [cytosol] Guide to Pharmacology 11569 Guide to Pharmacology 11578 Guide to Pharmacology 5297 Guide to Pharmacology 4840 Guide to Pharmacology 7219 Reactome DB_ID: 9707188 1 ALOX5:ALOX5 inhibitors [nuclear envelope] ALOX5:ALOX5 inhibitors Reactome DB_ID: 2318764 1 Converted from EntitySet in Reactome Reactome DB_ID: 9707237 1 Reactome Database ID Release 82 9707188 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9707188 Reactome R-HSA-9707188 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9707188.1 Reactome Database ID Release 82 9707186 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9707186 Reactome R-HSA-9707186 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9707186.1 20436887 Pubmed 2009 Zileuton, a new efficient and safe systemic anti-acne drug Zouboulis, Christos C Dermatoendocrinol 1:188-92 2866075 Pubmed 1985 Modulation of human colonic arachidonic acid metabolism by sulfasalazine Hawkey, C J Boughton-Smith, N K Whittle, B J Dig Dis Sci 30:1161-5 2877850 Pubmed 1986 Pharmacological and biochemical actions of sulphasalazine Hoult, J R Drugs 32:18-26 29133059 Pubmed 2018 Recent advances in the search for novel 5-lipoxygenase inhibitors for the treatment of asthma Bruno, Ferdinando Spaziano, Giuseppe Liparulo, Angela Roviezzo, Fiorentina Nabavi, Seyed Mohammed Sureda, Antoni Filosa, Rosanna D'Agostino, Bruno Eur J Med Chem 153:65-72 23076889 Pubmed 2012 Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis Feagan, Brian G Macdonald, John K Cochrane Database Syst Rev 10:CD000543 1848634 Pubmed 1991 5-lipoxygenase inhibitory activity of zileuton Carter, G W Young, P R Albert, D H Bouska, J Dyer, R Bell, R L Summers, J B Brooks, D W J Pharmacol Exp Ther 256:929-37 3933675 Pubmed 1985 Olsalazine in active ulcerative colitis Selby, W S Barr, G D Ireland, A Mason, C H Jewell, D P Br Med J (Clin Res Ed) 291:1373-5 27046942 Pubmed 2016 Maximum Time of the Effect of Antileukotriene - Zileuton in Treatment of Patients with Bronchial Asthma Morina, Naim Boçari, Gëzim Iljazi, Ali Hyseini, Kadir Halac, Gunay Acta Inform Med 24:16-9 3020588 Pubmed 1986 Meclofenamate sodium is an inhibitor of both the 5-lipoxygenase and cyclooxygenase pathways of the arachidonic acid cascade in vitro Boctor, A M Eickholt, M Pugsley, T A Prostaglandins Leukot Med 23:229-38 16795963 Pubmed 2006 Efficacy and tolerability of olsalazine (dipentum) in the treatment of patients with ulcerative colitis--results of a field study Singer, M V Schmausser, H Schönfeld, G Hepatogastroenterology 53:317-21 2882965 Pubmed 1987 Inhibition of 5-lipoxygenase pathway of arachidonic acid metabolism in human neutrophils by sulfasalazine and 5-aminosalicylic acid Nielsen, O H Bukhave, K Elmgreen, J Ahnfelt-Rønne, I Dig Dis Sci 32:577-82 2864155 Pubmed 1985 Clinical pharmacokinetics of sulphasalazine, its metabolites and other prodrugs of 5-aminosalicylic acid Klotz, U Clin Pharmacokinet 10:285-302 15604543 Pubmed 2005 Zileuton, an oral 5-lipoxygenase inhibitor, directly reduces sebum production Zouboulis, Ch C Saborowski, A Boschnakow, A Dermatology 210:36-8 1359745 Pubmed 1992 5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease Rask-Madsen, J Bukhave, K Laursen, L S Lauritsen, K Agents ActionsC37-46 30669 Pubmed 1978 Role of prostaglandins in ulcerative colitis. Enhanced production during active disease and inhibition by sulfasalazine Sharon, P Ligumsky, M Rachmilewitz, D Zor, U Gastroenterology 75:638-40 19743890 Pubmed 2009 Balsalazide: a novel 5-aminosalicylate prodrug for the treatment of active ulcerative colitis Wiggins, Jon Brendan Rajapakse, Ramona Expert Opin Drug Metab Toxicol 5:1279-84 1.13.11.34 5S-HpETE is dehydrated to LTA4 by ALOX5 5S-HpETE is dehydrated to LTA4 by ALOX5 Dehydration of 5-HpETE to leukotriene A4 In the second step of the formation of leukotriene A4 (LTA4) from arachidonic acid, arachidonate 5-lipoxygenase (ALOX5) converts 5S-hydroperoxyeicosatetranoic acid (5S-HpETE) to an allylic epoxide, leukotriene A4 (LTA4) (Rouzer et al. 1988, Rouzer & Samuelsson 1987, Rouzer et al. 1986). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Reviewed: Hansen, Trond Vidar, 2018-02-21 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 266010 1 Reactome DB_ID: 265281 1 leukotriene A4 [ChEBI:15651] leukotriene A4 ChEBI 15651 Reactome DB_ID: 29356 1 water [ChEBI:15377] water ChEBI 15377 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2318764 Reactome Database ID Release 82 266051 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266051 Reactome R-HSA-266051 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-266051.2 3.3.2.6 LTA4 is hydolysed to LTB4 by LTA4H LTA4 is hydolysed to LTB4 by LTA4H LTA4 is hydrolyzed to LTB4 Leukotriene A4 hydrolase (LTA4H) is a monomeric, soluble enzyme that catalyzes the hydrolysis of the allylic epoxide leukotriene A4 (LTA4) to the dihydroxy acid leukotriene B4 (LTB4) (Radmark et al. 1984, McGee & Fitzpatrick 1985). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 265281 1 Reactome DB_ID: 29356 1 Reactome DB_ID: 266056 1 leukotriene B4 [ChEBI:15647] leukotriene B4 ChEBI 15647 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 266038 LTA4H:Zn2+ [cytosol] LTA4H:Zn2+ LTA4 hydrolase (Zinc cofactor) Reactome DB_ID: 29426 1 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI 29105 Reactome DB_ID: 266022 1 UniProt:P09960 LTA4H LTA4H LTA4 LTA4H FUNCTION Bifunctional zinc metalloenzyme that comprises both epoxide hydrolase (EH) and aminopeptidase activities. Acts as an epoxide hydrolase to catalyze the conversion of LTA4 to the pro-inflammatory mediator leukotriene B4 (LTB4) (PubMed:11917124, PubMed:12207002, PubMed:15078870, PubMed:18804029, PubMed:1897988, PubMed:1975494, PubMed:2244921). Has also aminopeptidase activity, with high affinity for N-terminal arginines of various synthetic tripeptides (PubMed:20813919, PubMed:18804029). In addition to its pro-inflammatory EH activity, may also counteract inflammation by its aminopeptidase activity, which inactivates by cleavage another neutrophil attractant, the tripeptide Pro-Gly-Pro (PGP), a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP9) and prolylendopeptidase (PREPL) (PubMed:20813919, PubMed:24591641). Involved also in the biosynthesis of resolvin E1 and 18S-resolvin E1 from eicosapentaenoic acid, two lipid mediators that show potent anti-inflammatory and pro-resolving actions (PubMed:21206090).ACTIVITY REGULATION Inhibited by bestatin (PubMed:11175901). The epoxide hydrolase activity is restrained by suicide inactivation that involves binding of LTA4 to Tyr-379 (PubMed:7667299). 4-(4-benzylphenyl)thiazol-2-amine (ARM1) selectively inhibits the epoxide hydrolase activity (PubMed:24591641).PATHWAY Lipid metabolism; leukotriene B4 biosynthesis.SUBUNIT Monomer.TISSUE SPECIFICITY Isoform 1 and isoform 2 are expressed in monocytes, lymphocytes, neutrophils, reticulocytes, platelets and fibroblasts.PTM Phosphorylation at Ser-416 inhibits leukotriene-A4 hydrolase activity.SIMILARITY Belongs to the peptidase M1 family. UniProt P09960 2 EQUAL 611 EQUAL Reactome Database ID Release 82 266038 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266038 Reactome R-HSA-266038 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-266038.1 GO 0004463 GO molecular function Reactome Database ID Release 82 266024 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266024 Reactome Database ID Release 82 266072 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266072 Reactome R-HSA-266072 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-266072.1 2995393 Pubmed 1985 Enzymatic hydration of leukotriene A4. Purification and characterization of a novel epoxide hydrolase from human erythrocytes McGee, J Fitzpatrick, F J Biol Chem 260:12832-7 6490615 Pubmed 1984 Leukotriene A4 hydrolase in human leukocytes. Purification and properties Rådmark, O Shimizu, T Jörnvall, H Samuelsson, B J Biol Chem 259:12339-45 LTB4 is oxidised to 12-oxoLTB4 by PTGR1 LTB4 is oxidised to 12-oxoLTB4 by PTGR1 Prostaglandin reductase 1 (PTGR1) aka LTB4DH metabolizes eicosanoids by catalysing the oxidation of leukotriene B4 (LTB4) to form 12-oxo-Leukotriene B4 (12-oxoLTB4) aka 12-Keto-LTB4. The gene was originally cloned as leukotriene B4 12-hydroxydehydrogenase (LTB4DH) but was later discovered to have dual functionality as a prostaglandin reductase (Yokomizo et al. 1996). This reaction has been inferred from a reaction in pigs (Yokomizo et al. 1993, Ensor et al. 1998). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 266056 1 Reactome DB_ID: 29366 1 NADP(3-) [ChEBI:58349] NADP(3-) NADP(+) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADP trianion ChEBI 58349 Reactome DB_ID: 29364 1 NADPH(4-) [ChEBI:57783] NADPH(4-) NADPH 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADPH tetraanion ChEBI 57783 Reactome DB_ID: 70106 1 hydron [ChEBI:15378] hydron ChEBI 15378 Reactome DB_ID: 2142810 1 12-dehydro-leukotriene B4 [ChEBI:27814] 12-dehydro-leukotriene B4 ChEBI 27814 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142671 UniProt:Q14914 PTGR1 PTGR1 LTB4DH PTGR1 FUNCTION NAD(P)H-dependent oxidoreductase involved in metabolic inactivation of pro- and anti-inflammatory eicosanoids: prostaglandins (PG), leukotrienes (LT) and lipoxins (LX) (PubMed:25619643). Catalyzes with high efficiency the reduction of the 13,14 double bond of 15-oxoPGs, including 15-oxo-PGE1, 15-oxo-PGE2, 15-oxo-PGF1-alpha and 15-oxo-PGF2-alpha (PubMed:25619643). Catalyzes with lower efficiency the oxidation of the hydroxyl group at C12 of LTB4 and its derivatives, converting them into biologically less active 12-oxo-LTB4 metabolites (PubMed:25619643) (By similarity). Reduces 15-oxo-LXA4 to 13,14 dihydro-15-oxo-LXA4, enhancing neutrophil recruitment at the inflammatory site (By similarity). May play a role in metabolic detoxification of alkenals and ketones. Reduces alpha,beta-unsaturated alkenals and ketones, particularly those with medium-chain length, showing highest affinity toward (2E)-decenal and (3E)-3-nonen-2-one (PubMed:25619643). May inactivate 4-hydroxy-2-nonenal, a cytotoxic lipid constituent of oxidized low-density lipoprotein particles (By similarity).SUBUNIT Monomer or homodimer.TISSUE SPECIFICITY High expression in the kidney, liver, and intestine but not in leukocytes.SIMILARITY Belongs to the NADP-dependent oxidoreductase L4BD family. UniProt Q14914 1 EQUAL 329 EQUAL GO 0097257 GO molecular function Reactome Database ID Release 82 2161632 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161632 Reactome Database ID Release 82 2161567 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161567 Reactome R-HSA-2161567 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161567.2 9461497 Pubmed 1998 Purification, cDNA cloning and expression of 15-oxoprostaglandin 13-reductase from pig lung Ensor, CM Zhang, H Tai, HH Biochem J 330:103-8 8394361 Pubmed 1993 Enzymatic inactivation of leukotriene B4 by a novel enzyme found in the porcine kidney. Purification and properties of leukotriene B4 12-hydroxydehydrogenase Yokomizo, T Izumi, T Takahashi, T Kasama, T Kobayashi, Y Sato, F Taketani, Y Shimizu, T J Biol Chem 268:18128-35 8576264 Pubmed 1996 cDNA cloning, expression, and mutagenesis study of leukotriene B4 12-hydroxydehydrogenase Yokomizo, T Ogawa, Y Uozumi, N Kume, K Izumi, T Shimizu, T J Biol Chem 271:2844-50 1.14.14.94 CYP4F2, 4F3 20-hydroxylate LTB4 CYP4F2, 4F3 20-hydroxylate LTB4 CYP4F2 omega-hydroxylates leukotriene B4, thus inactivating it Leukotriene B4 (LTB4) is formed from arachidonic acid and is a potent inflammatory mediator. LTB4's activity is terminated by formation of its omega hydroxylated metabolite, 20-hydroxyleukotriene B4 (20OH-LTB4), catalysed by CYP4F2 primarily in human liver (Jin et al. 1998) and also by CYP4F3 (Kikuta et al. 1998). Authored: Jassal, Bijay, 2008-05-19 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, Bijay, 2008-05-19 Reactome DB_ID: 29364 1 Reactome DB_ID: 266056 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 29356 1 Reactome DB_ID: 2161636 1 20-hydroxy-leukotriene B4 [ChEBI:15646] 20-hydroxy-leukotriene B4 ChEBI 15646 Reactome DB_ID: 29366 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161611 endoplasmic reticulum membrane GO 0005789 Cytochrome P450 (CYP4F2/4F3 based) [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CYP4F2 [endoplasmic reticulum membrane] CYP4F3 [endoplasmic reticulum membrane] UniProt P78329 UniProt Q08477 GO 0050051 GO molecular function Reactome Database ID Release 82 2162138 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162138 Reactome Database ID Release 82 211873 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211873 Reactome R-HSA-211873 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-211873.1 9539102 Pubmed 1998 Human leukotriene B4 omega-hydroxylase (CYP4F3) gene: molecular cloning and chromosomal localization Kikuta, Y Kato, M Yamashita, Y Miyauchi, Y Tanaka, K Kamada, N Kusunose, M DNA Cell Biol 17:221-30 9799565 Pubmed 1998 Role of human CYP4F2 in hepatic catabolism of the proinflammatory agent leukotriene B4 Jin, R Koop, DR Raucy, JL Lasker, JM Arch Biochem Biophys 359:89-98 20oh-LTB4 is oxidised to 20cho-LTB4 by CYP4F2/4F3 20oh-LTB4 is oxidised to 20cho-LTB4 by CYP4F2/4F3 The cytochrome P450s 4F2 (CYP4F2) and F3 (CYP4F3) oxidise the omega hydroxylated metabolite, 20-hydroxyleukotriene B4 (20oh-LTB4) to form 20-aldehyde leukotriene B4 (20cho-LTB4) (Soberman et al. 1988). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29364 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 2161636 1 Reactome DB_ID: 2142740 1 20-oxoleukotriene B4 [ChEBI:63979] 20-oxoleukotriene B4 ChEBI 63979 Reactome DB_ID: 29356 2 Reactome DB_ID: 29366 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161611 GO 0097258 GO molecular function Reactome Database ID Release 82 2161740 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161740 Reactome Database ID Release 82 2161745 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161745 Reactome R-HSA-2161745 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161745.2 2836406 Pubmed 1988 The identification and formation of 20-aldehyde leukotriene B4 Soberman, RJ Sutyak, JP Okita, RT Wendelborn, DF Roberts LJ, 2nd Austen, KF J Biol Chem 263:7996-8002 20cho-LTB4 is oxidised to 20cooh-LTB4 by CYP4F2/4F3 20cho-LTB4 is oxidised to 20cooh-LTB4 by CYP4F2/4F3 The cytochrome P450s 4F2 (CYP4F2) and F3 (CYP4F3) oxidise 20-aldehyde leukotriene B4 (20cho-LTB4) to form 20-carboxy leukotriene B4 (20cooh-LTB4) (Soberman et al. 1988). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29364 1 Reactome DB_ID: 2142740 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 2161582 1 20-hydroxy-20-oxoleukotriene B4 [ChEBI:27562] 20-hydroxy-20-oxoleukotriene B4 ChEBI 27562 Reactome DB_ID: 29356 1 Reactome DB_ID: 29366 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161611 GO 0097259 GO molecular function Reactome Database ID Release 82 2161602 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161602 Reactome Database ID Release 82 2161792 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161792 Reactome R-HSA-2161792 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161792.2 20cho-LTB4 is oxidised to 20cooh-LTB4 by ALDH 20cho-LTB4 is oxidised to 20cooh-LTB4 by ALDH An aldehyde dehydrogenase (ALDH) yet to be cloned in humans has been observed to oxidise 20-aldehyde leukotriene B4 (20cho-LTB4) to form 20-carboxy leukotriene B4 (20cooh-LTB4) (Sutyak et al. 1989). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29364 1 Reactome DB_ID: 2142740 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 2161582 1 Reactome DB_ID: 29356 1 Reactome DB_ID: 29366 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2161598 ALDH [cytosol] ALDH Aldehyde dehydrogenase Reactome Database ID Release 82 2161683 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161683 Reactome Database ID Release 82 2161979 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161979 Reactome R-HSA-2161979 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161979.2 2549038 Pubmed 1989 Identification of an aldehyde dehydrogenase in the microsomes of human polymorphonuclear leukocytes that metabolizes 20-aldehyde leukotriene B4 Sutyak, J Austen, KF Soberman, RJ J Biol Chem 264:14818-23 20cooh-LTB4 is converted to 18cooh-LTB4 20cooh-LTB4 is converted to 18cooh-LTB4 Once omega-oxidation has occurred, 20-carboxy leukotriene B4 (20cooh-LTB4) can be further metabolized by beta-oxidation at its omega end into 18-carboxy-LTB4 (18cooh-LTB4) (Berry et al. 2003, Wheelan et al. 1999). The actual human enzyme or enzymes involved have yet to be identified. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 2161582 1 Reactome DB_ID: 2142676 1 18-hydroxy-18-oxo-dinorleukotriene B4 [ChEBI:63980] 18-hydroxy-18-oxo-dinorleukotriene B4 ChEBI 63980 Reactome Database ID Release 82 2161790 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161790 Reactome R-HSA-2161790 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161790.2 9862787 Pubmed 1999 Metabolic transformations of leukotriene B4 in primary cultures of human hepatocytes Wheelan, P Hankin, JA Bilir, B Guenette, D Murphy, RC J Pharmacol Exp Ther 288:326-34 12709426 Pubmed 2003 Urinary metabolites of leukotriene B4 in the human subject Berry, KA Borgeat, P Gosselin, J Flamand, L Murphy, RC J Biol Chem 278:24449-60 4.4.1.20 LTA4 is converted to LTC4 by LTC4S LTA4 is converted to LTC4 by LTC4S LTA4 conjugates with glutathione to form LTC4 Leukotriene A4 conjugates with reduced glutathione (GSH) to produce leukotriene C4 (LTC4). This conjugation is mediated by the homodimeric, perinuclear membrane-bound enzyme leukotriene C4 synthase (LTC4S) (Lam et al. 1994, Welsch et al. 1994). LTC4S differs from cytosolic and microsomal GSH-S-transferases by having a very narrow substrate specificity and the inability to conjugate xenobiotics. Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 265281 1 Reactome DB_ID: 29450 1 glutathionate(1-) [ChEBI:57925] glutathionate(1-) glutathionate anion glutathionate ion glutathione glutathionate ChEBI 57925 Reactome DB_ID: 266066 1 leukotriene C4 [ChEBI:16978] leukotriene C4 ChEBI 16978 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2318764 GO 0004464 GO molecular function Reactome Database ID Release 82 266055 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266055 Reactome Database ID Release 82 266050 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266050 Reactome R-HSA-266050 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-266050.1 8052639 Pubmed 1994 Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4 Lam, Bing K Penrose, JF Freeman, GJ Austen, KF Proc Natl Acad Sci U S A 91:7663-7 7937884 Pubmed 1994 Molecular cloning and expression of human leukotriene-C4 synthase Welsch, DJ Creely, DP Hauser, SD Mathis, KJ Krivi, GG Isakson, PC Proc Natl Acad Sci U S A 91:9745-9 LTC4 is exported from the cytosol by ABCC1 LTC4 is exported from the cytosol by ABCC1 ABCC1 mediates LTC4 export from the cell On formation, leukotriene C4 (LTC4) is exported to the extracellular region by the ABCC1 transporter (Sjolinder et al. 1999, Lam et al. 1989) and processed further by cleavage reactions. Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 266066 1 Reactome DB_ID: 266013 1 extracellular region GO 0005576 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 266068 plasma membrane GO 0005886 UniProt:P33527 ABCC1 ABCC1 ABCC1 MRP1 MRP FUNCTION Mediates export of organic anions and drugs from the cytoplasm (PubMed:7961706, PubMed:16230346, PubMed:9281595, PubMed:10064732, PubMed:11114332). Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics (PubMed:7961706, PubMed:16230346, PubMed:9281595, PubMed:10064732, PubMed:11114332). Confers resistance to anticancer drugs by decreasing accumulation of drug in cells, and by mediating ATP- and GSH-dependent drug export (PubMed:9281595). Hydrolyzes ATP with low efficiency (PubMed:16230346). Catalyzes the export of sphingosine 1-phosphate from mast cells independently of their degranulation (PubMed:17050692). Participates in inflammatory response by allowing export of leukotriene C4 from leukotriene C4-synthezing cells (By similarity).ACTIVITY REGULATION MK 571 inhibits sphingosine 1-phosphate and leukotriene C4 export.TISSUE SPECIFICITY Lung, testis and peripheral blood mononuclear cells.SIMILARITY Belongs to the ABC transporter superfamily. ABCC family. Conjugate transporter (TC 3.A.1.208) subfamily. UniProt P33527 1 EQUAL 1531 EQUAL GO 0140359 GO molecular function Reactome Database ID Release 82 266058 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266058 Reactome Database ID Release 82 266070 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266070 Reactome R-HSA-266070 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-266070.1 10064732 Pubmed 1999 Characterization of a leukotriene C4 export mechanism in human platelets: possible involvement of multidrug resistance-associated protein 1 Sjölinder, Mikael Tornhamre, S Claesson, HE Hydman, J Lindgren, J J Lipid Res 40:439-46 2753893 Pubmed 1989 The identification of a distinct export step following the biosynthesis of leukotriene C4 by human eosinophils Lam, Bing K Owen WF, Jr Austen, KF Soberman, RJ J Biol Chem 264:12885-9 3.4.19.13 GGT1, 5 dimers hydrolyse LTC4 to LTD4 GGT1, 5 dimers hydrolyse LTC4 to LTD4 Cleavage of the gamma-glutamyl bond of LTC4 forms LTD4 The reversible conversion of leukotriene C4 (LTC4) to leukotriene D4 (LTD4) is catalysed by gamma-glutamyl transferases 1 (GGT1) and 5 (GGT5). GGTs are present on the outer surface of plasma membranes and are a heterodimer of a heavy and a light chain. Its action involves the hydrolysis of the gamma-glutamyl peptide bond of glutathione and glutathione conjugates, releasing glutamate. In this example, LTC4 is a glutathione conjugate that is hydrolysed to LTD4 (Anderson et al. 1982, Wickham et al. 2011). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 266013 1 Reactome DB_ID: 109276 1 Reactome DB_ID: 210382 1 L-glutamate(1-) [ChEBI:29985] L-glutamate(1-) C5H8NO4 WHUUTDBJXJRKMK-VKHMYHEASA-M (2S)-2-ammoniopentanedioate 146.12136 L-glutamate hydrogen L-glutamate InChI=1S/C5H9NO4/c6-3(5(9)10)1-2-4(7)8/h3H,1-2,6H2,(H,7,8)(H,9,10)/p-1/t3-/m0/s1 L-glutamic acid, ion(1-) [NH3+][C@@H](CCC([O-])=O)C([O-])=O L-glutamic acid monoanion ChEBI 29985 Reactome DB_ID: 266074 1 leukotriene D4 [ChEBI:28666] leukotriene D4 ChEBI 28666 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2162130 GGT1, 5 dimers [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0036374 GO molecular function Reactome Database ID Release 82 266030 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266030 Reactome Database ID Release 82 266046 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266046 Reactome R-HSA-266046 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-266046.4 21447318 Pubmed 2011 Gamma-glutamyl compounds: substrate specificity of gamma-glutamyl transpeptidase enzymes Wickham, S West, MB Cook, PF Hanigan, MH Anal Biochem 414:208-14 6122208 Pubmed 1982 Interconversion of leukotrienes catalyzed by purified gamma-glutamyl transpeptidase: concomitant formation of leukotriene D4 and gamma-glutamyl amino acids Anderson, ME Allison, RD Meister, Alton Proc Natl Acad Sci U S A 79:1088-91 3.4.13.21 3.4.13.18 LTD4 is converted to LTE4 by DPEP1/2 LTD4 is converted to LTE4 by DPEP1/2 Further cleavage of LTD4 forms LTE4 Another outer surface membrane-bound, homodimeric enzyme, dipeptidase, existing in two forms DPEP1 (Adachi et al. 1989) and DPEP2 (Lee et al. 1983, Raulf et al. 1987), further hydrolyses leukotriene D4 (LTD4) to leukotriene E4 (LTE4), cleaving a glycine residue in the process. Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 109276 1 Reactome DB_ID: 266074 1 Reactome DB_ID: 266033 1 leukotriene E4 [ChEBI:15650] leukotriene E4 ChEBI 15650 Reactome DB_ID: 266029 1 glycine zwitterion [ChEBI:57305] glycine zwitterion glycine DHMQDGOQFOQNFH-UHFFFAOYSA-N C2H5NO2 2-azaniumylacetate [NH3+]CC([O-])=O InChI=1S/C2H5NO2/c3-1-2(4)5/h1,3H2,(H,4,5) 75.06660 ChEBI 57305 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2162149 DPEP1,2,3 dimers [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0016805 GO molecular function Reactome Database ID Release 82 266039 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266039 Reactome Database ID Release 82 266012 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266012 Reactome R-HSA-266012 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-266012.3 3563417 Pubmed 1987 Release and functional characterization of the leukotriene D4-metabolizing enzyme (dipeptidase) from human polymorphonuclear leucocytes Raulf, M König, W Köller, M Stüning, M Scand J Immunol 25:305-13 6293969 Pubmed 1983 Conversion of leukotriene D4 to leukotriene E4 by a dipeptidase released from the specific granule of human polymorphonuclear leucocytes Lee, CW Lewis, RA Corey, EJ Austen, KF Immunology 48:27-35 2768222 Pubmed 1989 Purification and characterization of human microsomal dipeptidase Adachi, Hideki Kubota, I Okamura, N Iwata, H Tsujimoto, M Nakazato, H Nishihara, T Noguchi, T J Biochem 105:957-61 LTA4 is hydrolysed to 6t-/6t,12epi-LTB4 LTA4 is hydrolysed to 6t-/6t,12epi-LTB4 Non-enzymatic hydrolysis of the leukotriene A4 (LTA4) epoxide bond creates 6-trans leukotriene B4 (6t-LTB4) and 6-trans,12-epi leukotriene B4 (6t,12epi-LTB4) stereoisomers (Mansour & Agha 1999, Sirois et al. 1985). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 265281 1 Reactome DB_ID: 29356 1 Converted from EntitySet in Reactome Reactome DB_ID: 2161801 1 6t/6t,12epi-LTB4 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 6t-LTB4 [cytosol] 6t,12epi-LTB4 [cytosol] ChEBI 63981 ChEBI 63982 Reactome Database ID Release 82 2161962 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161962 Reactome R-HSA-2161962 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161962.2 10741385 Pubmed 1999 Inhibition of calcium ionophore-stimulated leukotriene generation from intact human neutrophils by captopril Mansour, M Agha, A Res Commun Mol Pathol Pharmacol 104:345-60 2998743 Pubmed 1985 Metabolism of leukotrienes by adult and fetal human lungs Sirois, P Brousseau, Y Chagnon, M Gentile, J Gladu, M Salari, H Borgeat, P Exp Lung Res 9:17-30 LTA4 is converted to EXA4 by ALOX15 LTA4 is converted to EXA4 by ALOX15 Analogous to arachidonate 5-lipoxygenase (ALOX5) biosynthesis of leukotriene A4 (LTA4), arachidonate 15-lipoxygenase (ALOX15) can form an epoxide across C-14 and C-15 to form 14,15-LTA4 aka eoxin A4 (EXA4) (Feltenmark et al. 2008, Claesson et al. 2008). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 265281 1 Reactome DB_ID: 2142772 1 eoxin A4 [ChEBI:63983] eoxin A4 ChEBI 63983 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142744 ALOX15:Fe2+ [cytosol] ALOX15:Fe2+ Reactome DB_ID: 71067 1 Reactome DB_ID: 2142838 1 UniProt:P16050 ALOX15 ALOX15 ALOX15 LOG15 FUNCTION Non-heme iron-containing dioxygenase that catalyzes the stereo-specific peroxidation of free and esterified polyunsaturated fatty acids generating a spectrum of bioactive lipid mediators (PubMed:1944593, PubMed:8334154, PubMed:17052953, PubMed:24282679, PubMed:25293588, PubMed:32404334). It inserts peroxyl groups at C12 or C15 of arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) producing both 12-hydroperoxyeicosatetraenoate/12-HPETE and 15-hydroperoxyeicosatetraenoate/15-HPETE (PubMed:1944593, PubMed:8334154, PubMed:17052953, PubMed:24282679). It may then act on 12-HPETE to produce hepoxilins, which may show pro-inflammatory properties (By similarity). Can also peroxidize linoleate ((9Z,12Z)-octadecadienoate) to 13-hydroperoxyoctadecadienoate/13-HPODE (PubMed:8334154). May participate in the sequential oxidations of DHA ((4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate) to generate specialized pro-resolving mediators (SPMs)like resolvin D5 ((7S,17S)-diHPDHA) and (7S,14S)-diHPDHA, that actively down-regulate the immune response and have anti-aggregation properties with platelets (PubMed:32404334). Can convert epoxy fatty acids to hydroperoxy-epoxides derivatives followed by an intramolecular nucleophilic substitution leading to the formation of monocyclic endoperoxides (PubMed:25293588). Plays an important role during the maintenance of self-tolerance by peroxidizing membrane-bound phosphatidylethanolamine which can then signal the sorting process for clearance of apoptotic cells during inflammation and prevent an autoimmune response. In addition to its role in the immune and inflammatory responses, this enzyme may play a role in epithelial wound healing in the cornea through production of lipoxin A4 (LXA(4)) and docosahexaenoic acid-derived neuroprotectin D1 (NPD1; 10R,17S-HDHA), both lipid autacoids exhibit anti-inflammatory and neuroprotective properties. Furthermore, it may regulate actin polymerization which is crucial for several biological processes such as the phagocytosis of apoptotic cells. It is also implicated in the generation of endogenous ligands for peroxisome proliferator activated receptor (PPAR-gamma), hence modulating macrophage development and function. It may also exert a negative effect on skeletal development by regulating bone mass through this pathway. As well as participates in ER stress and downstream inflammation in adipocytes, pancreatic islets, and liver (By similarity). Finally, it is also involved in the cellular response to IL13/interleukin-13 (PubMed:21831839).ACTIVITY REGULATION Activity is increased by binding phosphatidylinositol phosphates, especially phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 4,5-bisphosphate (PubMed:17052953). Inactivated at 37 degrees Celsius by (13S)-hydroperoxy-(9Z,11E)-octadecadienoate (PubMed:8334154).PATHWAY Lipid metabolism; hydroperoxy eicosatetraenoic acid biosynthesis.SUBUNIT Interacts with PEBP1; in response to IL13/interleukin-13, prevents the interaction of PEBP1 with RAF1 to activate the ERK signaling cascade.TISSUE SPECIFICITY Detected in monocytes and eosinophils (at protein level). Expressed in airway epithelial cells.INDUCTION Up-regulated by UV-irradiation.DOMAIN The PLAT domain can bind calcium ions; this promotes association with membranes.DISEASE Disease susceptibility may be associated with variants affecting the gene represented in this entry. Met at position 560 may confer interindividual susceptibility to coronary artery disease (CAD) (PubMed:17959182).SIMILARITY Belongs to the lipoxygenase family. UniProt P16050 2 EQUAL 662 EQUAL Reactome Database ID Release 82 2142744 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142744 Reactome R-HSA-2142744 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142744.1 GO 0097260 GO molecular function Reactome Database ID Release 82 2161993 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161993 Reactome Database ID Release 82 2162019 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162019 Reactome R-HSA-2162019 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2162019.2 18184802 Pubmed 2008 Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells Feltenmark, S Gautam, N Brunnström, A Griffiths, W Backman, L Edenius, C Lindbom, L Björkholm, M Claesson, HE Proc Natl Acad Sci U S A 105:680-5 18647347 Pubmed 2008 Hodgkin Reed-Sternberg cells express 15-lipoxygenase-1 and are putative producers of eoxins in vivo: novel insight into the inflammatory features of classical Hodgkin lymphoma Claesson, HE Griffiths, WJ Brunnström, A Schain, F Andersson, E Feltenmark, S Johnson, HA Porwit, A Sjöberg, J Björkholm, M FEBS J 275:4222-34 EXA4 is converted to EXC4 by LTC4S EXA4 is converted to EXC4 by LTC4S In addition to its role converting leukotriene A4 (LTA4) into leukotriene C4 (LTC4), the enzyme leukotriene C4 synthase (LTC4S) analogously converts eoxin A4 (EXA4), with reduced glutathione (GSH), to eoxin C4 (EXC4) (Feltenmark et al. 2008, Claesson et al. 2008). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29450 1 Reactome DB_ID: 2142772 1 Reactome DB_ID: 2142726 1 eoxin C4 [ChEBI:63984] eoxin C4 ChEBI 63984 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2318764 GO 0097261 GO molecular function Reactome Database ID Release 82 2161978 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161978 Reactome Database ID Release 82 2161768 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161768 Reactome R-HSA-2161768 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161768.2 EXC4 is converted to EXD4 by GGT EXC4 is converted to EXD4 by GGT In an analogous reaction to the formation of leukotriene D4 (LTD4), eoxin C4 (EXC4) is converted to eoxin D4 (EXD4) by a class of gamma-glutamyltransferase (GGT) (Feltenmark et al. 2008, Claesson et al. 2008) which has not yet been identified. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 2142726 1 Reactome DB_ID: 2142758 1 eoxin D4 [ChEBI:63985] eoxin D4 ChEBI 63985 Reactome DB_ID: 29404 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2161915 GGT [cytosol] GGT gamma-glutamyltransferase GO 0097262 GO molecular function Reactome Database ID Release 82 2161784 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161784 Reactome Database ID Release 82 2161945 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161945 Reactome R-HSA-2161945 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161945.2 EXD4 is converted to EXE4 by DPEP EXD4 is converted to EXE4 by DPEP In an analogous reaction to the formation of leukotriene E4 (LTE4), eoxin D4 (EXD4) is converted to eoxin E4 (EXE4) by a dipeptidase (DPEP) (Feltenmark et al. 2008, Claesson et al. 2008) which has not yet been identified. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29356 1 Reactome DB_ID: 2142758 1 Reactome DB_ID: 2142730 1 eoxin E4 [ChEBI:63986] eoxin E4 ChEBI 63986 Reactome DB_ID: 29424 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2161751 DPEP [cytosol] DPEP Dipeptidase GO 0097263 GO molecular function Reactome Database ID Release 82 2161981 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161981 Reactome Database ID Release 82 2161868 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161868 Reactome R-HSA-2161868 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161868.2 Reactome Database ID Release 82 2142691 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142691 Reactome R-HSA-2142691 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142691.2 19130894 Pubmed 2009 On the biosynthesis and biological role of eoxins and 15-lipoxygenase-1 in airway inflammation and Hodgkin lymphoma Claesson, HE Prostaglandins Other Lipid Mediat 89:120-5 19244215 Pubmed 2009 Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology Buczynski, MW Dumlao, DS Dennis, EA J Lipid Res 50:1015-38 978-0-444-53219-0 ISBN 2008 The eicosanoids: cyclooxygenase, lipoxygenase, and epoxygenase pathways Smith, William L Murphy, RC Biochemistry of Lipids, Lipoproteins and Membranes, 5th Edition (Book): 331-362 17623009 Pubmed 2007 Biosynthesis and metabolism of leukotrienes Murphy, RC Gijon, MA Biochem J 405:379-95 6311078 Pubmed 1983 Leukotrienes Hammarström, Sven Annu Rev Biochem 52:355-77 GO 0006691 GO biological process