BioPAX pathway converted from "Arachidonic acid metabolism" in the Reactome database.
Arachidonic acid metabolism
Arachidonic acid metabolism
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 (all-cis 5,8,11,14-eicosatetraenoic acid) that is released from membrane phospholipids. Once released, arachidonic acid is acted on by prostaglandin G/H synthases (PTGS, also known as cyclooxygenases (COX)) to form prostaglandins and thromboxanes, by arachidonate lipoxygenases (ALOX) to form leukotrienes, epoxygenases (cytochrome P450s and epoxide hydrolase) to form epoxides such as 15-eicosatetraenoic acids, and omega-hydrolases (cytochrome P450s) to form hydroxyeicosatetraenoic acids (Buczynski et al. 2009, Vance & Vance 2008).<br>Levels of free arachidonic acid in the cell are normally very low so the rate of synthesis of eicosanoids is determined primarily by the activity of phospholipase A2, which mediates phospholipid cleavage to generate free arachidonic acid. The enzymes involved in arachidonic acid metabolism are typically constitutively expressed so the subset of these enzymes expressed by a cell determines the range of eicosanoids it can synthesize.<br>Eicosanoids are unstable, undergoing conversion to inactive forms with half-times under physiological conditions of seconds or minutes. Many of these reactions appear to be spontaneous.
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Hydrolysis of phosphatidylcholine
Hydrolysis of phosphatidylcholine
Once bound to the membrane, cPLA2 hydrolyzes phosphatidylcholine to produce arachidonic acid (AA), a precursor to inflammatory mediators. While several phospholipases can catalyze this reaction in cells overexpressing the enzymes, PLA2G4A is the major enzyme that catalyzes this reaction in vivo (Reed et al. 2011). At the same time, possible physiological roles have been described for soluble phospholipases (sPLA) in the mobilization of arachidonic acid in some cell types or under some physiological conditions (Murakami et al. 2011). Here, the major role of PLA2G4A has been annotated.
Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05
Reviewed: Rush, MG, 2012-11-10
Edited: Jassal, Bijay, 2008-11-06
Reactome DB_ID: 426925
1
endoplasmic reticulum membrane
GO
0005789
1,2-diacyl-sn-glycero-3-phosphocholine [ChEBI:57643]
1,2-diacyl-sn-glycero-3-phosphocholine
1,2-diacyl-sn-glycero-3-phosphocholine betaine
PC
1,2-diacyl-sn-glycero-3-phosphocholines
3-sn-phosphatidylcholine
Diacyl PC
Phosphatidylcholine
3-sn-phosphatidylcholines
lecithin
a 1,2-diacyl-sn-glycero-3-phosphocholine
Reactome
http://www.reactome.org
ChEBI
57643
Reactome DB_ID: 29356
1
cytosol
GO
0005829
water [ChEBI:15377]
water
ChEBI
15377
Reactome DB_ID: 428981
1
1-O-acyl-sn-glycero-3-phosphocholine(1+) [ChEBI:17504]
1-O-acyl-sn-glycero-3-phosphocholine(1+)
ChEBI
17504
Reactome DB_ID: 140356
1
endoplasmic reticulum lumen
GO
0005788
arachidonate [ChEBI:32395]
arachidonate
(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate
(20:4n6)
(5Z,8Z,11Z,14Z)-eicosatetraenoate
ChEBI
32395
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 111860
Active PLA2:phosphatidylcholine [endoplasmic reticulum membrane]
Active PLA2:phosphatidylcholine
Reactome DB_ID: 426925
1
Reactome DB_ID: 111859
1
UniProt:P47712 PLA2G4A
PLA2G4A
CPLA2
PLA2G4A
PLA2G4
FUNCTION Has primarily calcium-dependent phospholipase and lysophospholipase activities, with a major role in membrane lipid remodeling and biosynthesis of lipid mediators of the inflammatory response (PubMed:7794891, PubMed:8619991, PubMed:8702602, PubMed:9425121, PubMed:10358058, PubMed:14709560, PubMed:16617059, PubMed:17472963, PubMed:27642067, PubMed:18451993). Plays an important role in embryo implantation and parturition through its ability to trigger prostanoid production (By similarity). Preferentially hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity) (PubMed:7794891, PubMed:8619991, PubMed:9425121, PubMed:10358058, PubMed:17472963, PubMed:18451993). Selectively hydrolyzes sn-2 arachidonoyl group from membrane phospholipids, providing the precursor for eicosanoid biosynthesis via the cyclooxygenase pathway (PubMed:18451993, PubMed:7794891, PubMed:9425121, PubMed:10358058, PubMed:17472963). In an alternative pathway of eicosanoid biosynthesis, hydrolyzes sn-2 fatty acyl chain of eicosanoid lysophopholipids to release free bioactive eicosanoids (PubMed:27642067). Hydrolyzes the ester bond of the fatty acyl group attached at sn-1 position of phospholipids (phospholipase A1 activity) only if an ether linkage rather than an ester linkage is present at the sn-2 position. This hydrolysis is not stereospecific (PubMed:7794891). Has calcium-independent phospholipase A2 and lysophospholipase activities in the presence of phosphoinositides (PubMed:12672805). Has O-acyltransferase activity. Catalyzes the transfer of fatty acyl chains from phospholipids to a primary hydroxyl group of glycerol (sn-1 or sn-3), potentially contributing to monoacylglycerol synthesis (PubMed:7794891).ACTIVITY REGULATION Activated by cytosolic calcium, which is necessary for binding to membrane lipids (PubMed:12672805). Activated by phosphorylation in response to mitogenic stimuli (PubMed:8381049). Activated by ceramide-1-phosphate. Binding (via C2 domain) to ceramide-1-phosphate increases the affinity for membrane lipids (PubMed:17472963). Can be activated by phosphoinositides in the absence of calcium (PubMed:12672805). Inhibited by ANXA5 in a calcium- and substrate-dependent way (PubMed:9425121).PATHWAY Membrane lipid metabolism; glycerophospholipid metabolism.PATHWAY Lipid metabolism; arachidonate metabolism.PATHWAY Lipid metabolism; prostaglandin biosynthesis.PATHWAY Lipid metabolism; leukotriene B4 biosynthesis.SUBUNIT Interacts with KAT5.TISSUE SPECIFICITY Expressed in various cells and tissues such as macrophages, neutrophils, fibroblasts and lung endothelium. Expressed in platelets (at protein level) (PubMed:25102815).DOMAIN The N-terminal C2 domain associates with lipid membranes upon calcium binding. It modulates enzyme activity by presenting the active site to its substrate in response to elevations of cytosolic calcium (PubMed:9430701, PubMed:9665851, PubMed:11375391). In the presence of phosphoinositides, regulates phospholipase A2 and lysophospholipase activities in a calcium-independent way (PubMed:12672805).PTM Phosphorylated at both Ser-505 and Ser-727 in response to mitogenic stimuli.
Homo sapiens
NCBI Taxonomy
9606
UniProt
P47712
O-phospho-L-serine at 505
505
EQUAL
O-phospho-L-serine [MOD:00046]
O-phospho-L-serine at 727
727
EQUAL
Chain Coordinates
1
EQUAL
749
EQUAL
Reactome DB_ID: 74016
1
calcium(2+) [ChEBI:29108]
calcium(2+)
ChEBI
29108
Reactome Database ID Release 81
111860
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=111860
Reactome
R-HSA-111860
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-111860.1
GO
0047498
GO molecular function
Reactome Database ID Release 81
111882
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=111882
Reactome Database ID Release 81
111883
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=111883
Reactome
R-HSA-111883
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-111883.3
21247147
Pubmed
2011
Functional characterization of mutations in inherited human cPLA? deficiency
Reed, Kathleen A
Tucker, Dawn E
Aloulou, Ahmed
Adler, David
Ghomashchi, Farideh
Gelb, Michael H
Leslie, Christina C
Oates, John A
Boutaud, Olivier
Biochemistry 50:1731-8
21746768
Pubmed
2011
Secreted phospholipase A2 revisited
Murakami, Makoto
Taketomi, Yoshitaka
Sato, Hiroyasu
Yamamoto, Kei
J. Biochem. 150:233-55
Arachidonate diffuses across the ER membrane
Arachidonate diffuses across the ER membrane
Arachidonate released by phospholipases diffuses within the membrane and out of the membrane into the ER lumen and cytosol. The relatively low level of arachidonate in the cytoplasm is probably due to reesterification into complex lipids by acyl transferases.
Authored: Jupe, S, 2009-07-14
Reviewed: Rush, MG, 2012-11-10
Edited: Jupe, S, 2009-07-14
Reactome DB_ID: 140356
1
Reactome DB_ID: 29768
1
Reactome Database ID Release 81
428990
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=428990
Reactome
R-HSA-428990
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-428990.3
6810878
Pubmed
1982
How is the level of free arachidonic acid controlled in mammalian cells?
Irvine, RF
Biochem J 204:3-16
6146314
Pubmed
1984
Inositol trisphosphate and diacylglycerol as second messengers
Berridge, MJ
Biochem J 220:345-60
2.3.1.75
AWAT1 transfers acyl group from acyl-CoA to ARACOH, forming wax esters
AWAT1 transfers acyl group from acyl-CoA to ARACOH, forming wax esters
Arachidyl alcohol (ARACOH) is straight-chain fatty alcohol of C20 length used as an emollient in cosmetics. Esterification of alcohols with fatty acids represents the formation of both storage and cytoprotective molecules in the body. Overproduction of these esters is associated with several disease pathologies, including atherosclerosis and obesity. The ER membrane-associated acyl-CoA wax alcohol acyltransferase 1 (AWAT1) mediates the esterification of its preferred substrate ARACOH (Turkish et al. 2005).
Authored: Jassal, Bijay, 2015-05-29
Reviewed: D'Eustachio, Peter, 2015-06-26
Edited: Jassal, Bijay, 2015-05-29
Reactome DB_ID: 5696426
1
icosan-1-ol [ChEBI:75627]
icosan-1-ol
arachidyl alcohol
eicosyl alcohol
eicosan-1-ol
arachidic alcohol
1-eicosanol
ChEBI
75627
Reactome DB_ID: 192172
1
acyl-CoA [ChEBI:17984]
acyl-CoA
ChEBI
17984
Reactome DB_ID: 162743
1
coenzyme A(4-) [ChEBI:57287]
coenzyme A(4-)
CoA
3'-phosphonatoadenosine 5'-{3-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-({3-oxo-3-[(2-sulfanylethyl)amino]propyl}amino)butyl] diphosphate}
ChEBI
57287
Reactome DB_ID: 5696412
1
wax ester [ChEBI:10036]
wax ester
Wax esters
ChEBI
10036
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 5696425
UniProt:Q58HT5 AWAT1
AWAT1
AWAT1
DGAT2L3
DGA2
FUNCTION Acyltransferase that catalyzes the formation of ester bonds between fatty alcohols and fatty acyl-CoAs to form wax monoesters (PubMed:15671038). Shows a strong preference for decyl alcohol (C10), with less activity towards C16 and C18 alcohols (PubMed:15671038). Shows a strong preference for saturated acyl-CoAs (PubMed:15671038).TISSUE SPECIFICITY Predominantly expressed in skin, where it is limited to the sebaceous gland. Expressed in more mature, centrally located cells just before their rupture and sebum release. Also expressed in all tissues except spleen. Expressed at higher level in thymus, prostate and testis.SIMILARITY Belongs to the diacylglycerol acyltransferase family.
UniProt
Q58HT5
1
EQUAL
328
EQUAL
GO
0047196
GO molecular function
Reactome Database ID Release 81
5696418
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=5696418
Reactome Database ID Release 81
5696424
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=5696424
Reactome
R-HSA-5696424
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-5696424.2
15671038
Pubmed
2005
Identification of two novel human acyl-CoA wax alcohol acyltransferases: members of the diacylglycerol acyltransferase 2 (DGAT2) gene superfamily
Turkish, Aaron R
Henneberry, Annette L
Cromley, Debra
Padamsee, Mahajabeen
Oelkers, P
Bazzi, Hisham
Christiano, Angela M
Billheimer, JT
Sturley, Stephen L
J. Biol. Chem. 280:14755-64
FAAH hydrolyses AEA to AA and ETA
FAAH hydrolyses AEA to AA and ETA
Fatty acid amides are a class of lipid transmitters that include the endogenous cannabinoid anandamide (AEA) and the sleep-inducing chemical oleamide. The magnitude and duration of their signalling are controlled by enzymatic hydrolysis mediated by fatty-acid amide hydrolases 1 and 2 (FAAH, H2). Hydrolysis of AEA is described here (Wei et al. 2006). FAAH is localised to the ER membrane whereas FAAH2 is localised to lipid droplets (Kaczocha et al. 2010).
Authored: Jassal, Bijay, 2015-05-18
Reviewed: D'Eustachio, Peter, 2015-06-26
Edited: Jassal, Bijay, 2015-05-18
Reactome DB_ID: 29356
1
Reactome DB_ID: 5693754
1
anandamide [ChEBI:2700]
anandamide
ChEBI
2700
Reactome DB_ID: 1498751
1
ethanolamine [ChEBI:16000]
ethanolamine
ChEBI
16000
Reactome DB_ID: 29768
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 5693746
UniProt:O00519 FAAH
FAAH
FAAH
FAAH1
FUNCTION Catalyzes the hydrolysis of endogenous amidated lipids like the sleep-inducing lipid oleamide ((9Z)-octadecenamide), the endocannabinoid anandamide (N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine), as well as other fatty amides, to their corresponding fatty acids, thereby regulating the signaling functions of these molecules (PubMed:9122178, PubMed:17015445, PubMed:19926788). Hydrolyzes polyunsaturated substrate anandamide preferentially as compared to monounsaturated substrates (PubMed:9122178, PubMed:17015445). It can also catalyze the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol) (PubMed:21049984). FAAH cooperates with PM20D1 in the hydrolysis of amino acid-conjugated fatty acids such as N-fatty acyl glycine and N-fatty acyl-L-serine, thereby acting as a physiological regulator of specific subsets of intracellular, but not of extracellular, N-fatty acyl amino acids (By similarity).ACTIVITY REGULATION Inhibited by O-aryl carbamates and alpha-keto heterocycles (PubMed:17015445). Inhibited by trifluoromethyl ketone (PubMed:9122178).SUBUNIT Homodimer.TISSUE SPECIFICITY Highly expressed in the brain, small intestine, pancreas, skeletal muscle and testis. Also expressed in the kidney, liver, lung, placenta and prostate.POLYMORPHISM Genetic variations in FAAH can be associated with susceptibility to polysubstance abuse [MIM:606581]. At homozygosity, variant Thr-129 is strongly associated with drug and alcohol abuse, and methamphetamine dependence.SIMILARITY Belongs to the amidase family.
UniProt
O00519
1
EQUAL
579
EQUAL
GO
0017064
GO molecular function
Reactome Database ID Release 81
5693749
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=5693749
Reactome Database ID Release 81
5693742
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=5693742
Reactome
R-HSA-5693742
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-5693742.1
19926788
Pubmed
2010
Lipid droplets are novel sites of N-acylethanolamine inactivation by fatty acid amide hydrolase-2
Kaczocha, Martin
Glaser, Sherrye T
Chae, Janiper
Brown, Deborah A
Deutsch, Dale G
J. Biol. Chem. 285:2796-806
17015445
Pubmed
2006
A second fatty acid amide hydrolase with variable distribution among placental mammals
Wei, Binqing Q
Mikkelsen, Tarjei S
McKinney, Michele K
Lander, Eric S
Cravatt, BF
J. Biol. Chem. 281:36569-78
FAAH2 hydrolyses AEA to AA and ETA
FAAH2 hydrolyses AEA to AA and ETA
Fatty acid amides are a class of lipid transmitters that include the endogenous cannabinoid anandamide (AEA) and the sleep-inducing chemical oleamide. The magnitude and duration of their signalling are controlled by enzymatic hydrolysis mediated by fatty-acid amide hydrolases 1 and 2 (FAAH, H2). Hydrolysis of AEA is described here (Wei et al. 2006). FAAH is localised to the ER membrane whereas FAAH2 is localised to lipid droplets (Kaczocha et al. 2010).
Authored: Jassal, Bijay, 2015-05-18
Reviewed: D'Eustachio, Peter, 2015-06-26
Edited: Jassal, Bijay, 2015-05-18
Reactome DB_ID: 5693752
1
lipid droplet
GO
0005811
Reactome DB_ID: 5693747
1
Reactome DB_ID: 5693736
1
Reactome DB_ID: 5693733
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 5693745
UniProt:Q6GMR7 FAAH2
FAAH2
AMDD
FAAH2
FUNCTION Catalyzes the hydrolysis of endogenous amidated lipids like the sleep-inducing lipid oleamide ((9Z)-octadecenamide), the endocannabinoid anandamide (N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine), as well as other fatty amides, to their corresponding fatty acids, thereby regulating the signaling functions of these molecules (PubMed:17015445, PubMed:19926788). Hydrolyzes monounsaturated substrate anandamide preferentially as compared to polyunsaturated substrates.ACTIVITY REGULATION Inhibited by O-aryl carbamates and alpha-keto heterocytes.SUBUNIT Homodimer.TISSUE SPECIFICITY Expressed in kidney, liver, lung, prostate, heart and ovary.SIMILARITY Belongs to the amidase family.
UniProt
Q6GMR7
1
EQUAL
532
EQUAL
Reactome Database ID Release 81
5693738
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=5693738
Reactome Database ID Release 81
5693751
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=5693751
Reactome
R-HSA-5693751
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-5693751.1
Synthesis of Prostaglandins (PG) and Thromboxanes (TX)
Synthesis of Prostaglandins (PG) and Thromboxanes (TX)
The bioactive prostaglandin (PG) signalling molecules, including PGA2, PGE2, PGF2a, and PGI2 (prostacyclin) are synthesised from arachidonic acid and its products by various prostaglandin synthase type enzymes. Prostaglandin H2 (PGH2) is the starting point for the synthesis of Thromboxanes (TXs) (Buczynski et al. 2009, Vance & Vance 2008). PGs and TXs are collectively known as the prostanoids.<br>Two enzymes, PTGS1 and 2 (COX1 and 2) both catalyze the two-step conversion of arachidonic acid to PGH2. PTGS1 is constitutively expressed in many cell types while PTGS2 is induced in response to stress and mediates the syntheses of prostaglandins associated with pain, fever, and inflammation. Aspirin irreversibly inactivates both enzymes (though it acts more efficiently on PTGS1), explaining both its antiinflammatory effects and side effects like perturbed gastic acid secretion. Drugs like celecoxib, by specifically inhibiting PTGS2, have a strong anti-inflammatory effect with fewer side effects. These PTGS2-specific drugs, however, probably because of their effects on the balance of prostaglandin synthesis in platelets and endothelial cells, can also promote blood clot formation (Buczynski et al. 2009; Stables & Gilroy 2011).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
PTGS2 dimer binds PTGS2 inhibitors
PTGS2 dimer binds PTGS2 inhibitors
While closely similar, PTGS1 and 2 differ sufficiently in the structures of their active sites so that the latter enzyme selectively binds and is inhibited by PTGS2 inhibitors (benzquinamide, carprofen, celecoxib, etodolac, etoricoxib, lumiracoxib, rofecoxib, valdecoxib) (Luong et al. 1996; Smith et al. 2000; Dong et al. 2011).
Authored: D'Eustachio, P, 2012-06-05
Reviewed: Rush, MG, 2012-11-10
Edited: D'Eustachio, P, 2012-06-05
Reactome DB_ID: 140491
1
PTGS2 dimer [endoplasmic reticulum membrane]
PTGS2 dimer
PGHS2 dimer
Reactome DB_ID: 2311355
1
heme b [ChEBI:26355]
heme b
protoheme
heme
[3,7,12,17-tetramethyl-8,13-divinylporphyrin-2,18-dipropanoato(2-)]iron
haem b
PROTOPORPHYRIN IX CONTAINING FE
protoheme IX
(7,12-diethenyl-3,8,13,17-tetramethylporphyrin-2,18-dipropanoato)iron
ChEBI
26355
Reactome DB_ID: 61605
2
UniProt:P35354 PTGS2
PTGS2
COX2
PTGS2
FUNCTION Dual cyclooxygenase and peroxidase in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate, with a particular role in the inflammatory response (PubMed:7947975, PubMed:7592599, PubMed:9261177, PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593, PubMed:11939906, PubMed:19540099). The cyclooxygenase activity oxygenates arachidonate (AA, C20:4(n-6)) to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide PGH2, the precursor of all 2-series prostaglandins and thromboxanes (PubMed:7947975, PubMed:7592599, PubMed:9261177, PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593). This complex transformation is initiated by abstraction of hydrogen at carbon 13 (with S-stereochemistry), followed by insertion of molecular O2 to form the endoperoxide bridge between carbon 9 and 11 that defines prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase activity) yields a hydroperoxy group in PGG2 that is then reduced to PGH2 by two electrons (PubMed:7947975, PubMed:7592599, PubMed:9261177, PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593). Similarly catalyzes successive cyclooxygenation and peroxidation of dihomo-gamma-linoleate (DGLA, C20:3(n-6)) and eicosapentaenoate (EPA, C20:5(n-3)) to corresponding PGH1 and PGH3, the precursors of 1- and 3-series prostaglandins (PubMed:11939906, PubMed:19540099). In an alternative pathway of prostanoid biosynthesis, converts 2-arachidonoyl lysophopholipids to prostanoid lysophopholipids, which are then hydrolyzed by intracellular phospholipases to release free prostanoids (PubMed:27642067). Metabolizes 2-arachidonoyl glycerol yielding the glyceryl ester of PGH2, a process that can contribute to pain response (PubMed:22942274). Generates lipid mediators from n-3 and n-6 polyunsaturated fatty acids (PUFAs) via a lipoxygenase-type mechanism. Oxygenates PUFAs to hydroperoxy compounds and then reduces them to corresponding alcohols (PubMed:11034610, PubMed:11192938, PubMed:9048568, PubMed:9261177). Plays a role in the generation of resolution phase interaction products (resolvins) during both sterile and infectious inflammation (PubMed:12391014). Metabolizes docosahexaenoate (DHA, C22:6(n-3)) to 17R-HDHA, a precursor of the D-series resolvins (RvDs) (PubMed:12391014). As a component of the biosynthetic pathway of E-series resolvins (RvEs), converts eicosapentaenoate (EPA, C20:5(n-3)) primarily to 18S-HEPE that is further metabolized by ALOX5 and LTA4H to generate 18S-RvE1 and 18S-RvE2 (PubMed:21206090). In vascular endothelial cells, converts docosapentaenoate (DPA, C22:5(n-3)) to 13R-HDPA, a precursor for 13-series resolvins (RvTs) shown to activate macrophage phagocytosis during bacterial infection (PubMed:26236990). In activated leukocytes, contributes to oxygenation of hydroxyeicosatetraenoates (HETE) to diHETES (5,15-diHETE and 5,11-diHETE) (PubMed:22068350, PubMed:26282205). During neuroinflammation, plays a role in neuronal secretion of specialized preresolving mediators (SPMs) 15R-lipoxin A4 that regulates phagocytic microglia (By similarity).ACTIVITY REGULATION The cyclooxygenase activity is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, ibuprofen, flurbiprofen, celecoxib, flufenamic, mefenamic and tolfenamic acids as well as by hydroperoxide scavenger erythrocyte glutathione peroxidase GPX1 (PubMed:26859324, PubMed:27226593, PubMed:7592599, PubMed:9048568). Aspirin triggers enzyme acetylation turning off its ability to generate proinflammatory prostaglandins, but switches on its capacity to produce anti-inflammatory lipid mediators involved in inflammation resolution (PubMed:11034610, PubMed:12391014). Aspirin enhances lipoxygenase-type activity toward production of epimers with R stereochemistry such as 15R-HETE, 18R-HEPE, 15R-HEPE and 17R-HDHA (PubMed:11034610, PubMed:11192938, PubMed:22068350, PubMed:12391014, PubMed:9048568, PubMed:21206090). Atorvastatin, a cholesterol-lowering drug, triggers enzyme S-nitrosylation increasing production of 13-series resolvins (RvTs) (PubMed:26236990).PATHWAY Lipid metabolism; prostaglandin biosynthesis.SUBUNIT Homodimer.INDUCTION By cytokines and mitogens. Up-regulated by IL1B (PubMed:26282205, PubMed:9545330). Up-regulated by lipopolysaccharide (LPS) (PubMed:9545330).PTM S-nitrosylation by NOS2 (iNOS) activates enzyme activity. S-nitrosylation may take place on different Cys residues in addition to Cys-526.PTM Acetylated at Ser-565 by SPHK1. During neuroinflammation, acetylation by SPHK1 promotes neuronal secretion of specialized preresolving mediators (SPMs), especially 15-R-lipoxin A4, which results in an increase of phagocytic microglia.MISCELLANEOUS The conversion of arachidonate to prostaglandin H2 is a 2 step reaction: a cyclooxygenase (COX) reaction which converts arachidonate to prostaglandin G2 (PGG2) and a peroxidase reaction in which PGG2 is reduced to prostaglandin H2 (PGH2). The cyclooxygenase reaction occurs in a hydrophobic channel in the core of the enzyme. The peroxidase reaction occurs at a heme-containing active site located near the protein surface. The nonsteroidal anti-inflammatory drugs (NSAIDs) binding site corresponds to the cyclooxygenase active site.MISCELLANEOUS Conversion of arachidonate to prostaglandin H2 is mediated by 2 different isozymes: the constitutive PTGS1 and the inducible PTGS2. PTGS1 is expressed constitutively and generally produces prostanoids acutely in response to hormonal stimuli to fine-tune physiological processes requiring instantaneous, continuous regulation (e.g. hemostasis). PTGS2 is inducible and typically produces prostanoids that mediate responses to physiological stresses such as infection and inflammation.MISCELLANEOUS PTGS1 and PTGS2 are the targets of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin and ibuprofen (PubMed:27710942, PubMed:26859324, PubMed:27226593). Aspirin is able to produce an irreversible inactivation of the enzyme through a serine acetylation (PubMed:26859324). Inhibition of the PGHSs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces fatal thrombotic events, as well as the development of colon cancer and Alzheimer's disease. PTGS2 is the principal isozyme responsible for production of inflammatory prostaglandins. New generation PTGSs inhibitors strive to be selective for PTGS2, to avoid side effects such as gastrointestinal complications and ulceration.SIMILARITY Belongs to the prostaglandin G/H synthase family.
UniProt
P35354
18
EQUAL
604
EQUAL
Reactome Database ID Release 81
140491
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=140491
Reactome
R-HSA-140491
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-140491.1
Converted from EntitySet in Reactome
Reactome DB_ID: 9716714
1
PTGS2 inhibitors [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
valdecoxib [cytosol]
carprofen [cytosol]
rofecoxib [cytosol]
etodolac [cytosol]
benzquinamide [cytosol]
celecoxib [cytosol]
etoricoxib [cytosol]
lumiracoxib [cytosol]
Guide to Pharmacology
2894
Guide to Pharmacology
7141
Guide to Pharmacology
2893
Guide to Pharmacology
7185
Guide to Pharmacology
7124
Guide to Pharmacology
2892
Guide to Pharmacology
2896
Guide to Pharmacology
2897
Reactome DB_ID: 2309778
1
PTGS2 dimer:PTGS2 inhibitors [endoplasmic reticulum membrane]
PTGS2 dimer:PTGS2 inhibitors
Reactome DB_ID: 140491
1
Converted from EntitySet in Reactome
Reactome DB_ID: 9716714
1
Reactome Database ID Release 81
2309778
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=2309778
Reactome
R-HSA-2309778
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-2309778.3
Reactome Database ID Release 81
2309779
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=2309779
Reactome
R-HSA-2309779
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-2309779.4
10966456
Pubmed
2000
Cyclooxygenases: structural, cellular, and molecular biology
Smith, William L
DeWitt, David L
Garavito, R Michael
Annu Rev Biochem 69:145-82
8901870
Pubmed
1996
Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2
Luong, Christine
Miller, Aaron
Barnett, Jim
Chow, Joan
Ramesha, Chakk
Browner, Michelle F
Nat. Struct. Biol. 3:927-33
21467029
Pubmed
2011
Human cyclooxygenase-2 is a sequence homodimer that functions as a conformational heterodimer
Dong, Liang
Vecchio, Alex J
Sharma, Narayan P
Jurban, Brice J
Malkowski, Michael G
Smith, William L
J. Biol. Chem. 286:19035-46
ASA- acetylates PTGS1
ASA- acetylates PTGS1
The ionized form of aspirin, acetylsalicylate (ASA-) reacts spontaneously with one subunit of PTGS1 dimer to acetylate serine residue 516. The modified enzyme is no longer capable of catalyzing the conversion of arachidonic acid to PGH2. The identity of the acetylated residue is inferred from data for the humann PTGS2 enzyme (Lecomte et al. 1994) and the ovine PGHS1 enzyme (Loll et al. 1995).
Authored: D'Eustachio, P, 2012-06-07
Reviewed: Rush, MG, 2012-11-10
Edited: D'Eustachio, P, 2012-06-07
Reactome DB_ID: 428986
1
PTGS1 dimer [endoplasmic reticulum membrane]
PTGS1 dimer
PGHS1 homodimer
COX1
Reactome DB_ID: 2311355
1
Reactome DB_ID: 428931
2
UniProt:P23219 PTGS1
PTGS1
COX1
PTGS1
FUNCTION Dual cyclooxygenase and peroxidase in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate, with a particular role in the inflammatory response. The cyclooxygenase activity oxygenates arachidonate (AA, C20:4(n-6)) to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide PGH2, the precursor of all 2-series prostaglandins and thromboxanes. This complex transformation is initiated by abstraction of hydrogen at carbon 13 (with S-stereochemistry), followed by insertion of molecular O2 to form the endoperoxide bridge between carbon 9 and 11 that defines prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase activity) yields a hydroperoxy group in PGG2 that is then reduced to PGH2 by two electrons (PubMed:7947975). Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the generation of thromboxane A2 (TXA2), which promotes platelet activation and aggregation, vasoconstriction and proliferation of vascular smooth muscle cells (Probable).ACTIVITY REGULATION The cyclooxygenase activity is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) including ibuprofen, flurbiprofen, ketoprofen, naproxen, flurbiprofen, anirolac, fenclofenac and diclofenac.PATHWAY Lipid metabolism; prostaglandin biosynthesis.SUBUNIT Homodimer.MISCELLANEOUS The conversion of arachidonate to prostaglandin H2 is a 2 step reaction: a cyclooxygenase (COX) reaction which converts arachidonate to prostaglandin G2 (PGG2) and a peroxidase reaction in which PGG2 is reduced to prostaglandin H2 (PGH2). The cyclooxygenase reaction occurs in a hydrophobic channel in the core of the enzyme. The peroxidase reaction occurs at a heme-containing active site located near the protein surface. The nonsteroidal anti-inflammatory drugs (NSAIDs) binding site corresponds to the cyclooxygenase active site.MISCELLANEOUS Conversion of arachidonate to prostaglandin H2 is mediated by 2 different isozymes: the constitutive PTGS1 and the inducible PTGS2. PTGS1 is expressed constitutively and generally produces prostanoids acutely in response to hormonal stimuli to fine-tune physiological processes requiring instantaneous, continuous regulation (e.g. hemostasis). PTGS2 is inducible and typically produces prostanoids that mediate responses to physiological stresses such as infection and inflammation.MISCELLANEOUS PTGS1 and PTGS2 are the targets of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin and ibuprofen. Aspirin is able to produce an irreversible inactivation of the enzyme through a serine acetylation. Inhibition of the PGHSs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces fatal thrombotic events, as well as the development of colon cancer and Alzheimer's disease. PTGS2 is the principal isozyme responsible for production of inflammatory prostaglandins. New generation PTGSs inhibitors strive to be selective for PTGS2, to avoid side effects such as gastrointestinal complications and ulceration.SIMILARITY Belongs to the prostaglandin G/H synthase family.
UniProt
P23219
24
EQUAL
599
EQUAL
Reactome Database ID Release 81
428986
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=428986
Reactome
R-HSA-428986
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-428986.1
Reactome DB_ID: 2314693
1
acetylsalicylate [ChEBI:13719]
acetylsalicylate
ChEBI
13719
Reactome DB_ID: 2314695
1
Ac-PTGS1 dimer [endoplasmic reticulum membrane]
Ac-PTGS1 dimer
Reactome DB_ID: 2311355
1
Reactome DB_ID: 428931
1
24
EQUAL
599
EQUAL
Reactome DB_ID: 2314694
1
O-acetyl-L-serine at 529
529
EQUAL
O-acetyl-L-serine
24
EQUAL
599
EQUAL
Reactome Database ID Release 81
2314695
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=2314695
Reactome
R-HSA-2314695
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-2314695.1
Reactome DB_ID: 2314690
1
salicylate [ChEBI:30762]
salicylate
o-hydroxybenzoate
2-hydroxybenzoic acid ion(1-)
sal
ChEBI
30762
Reactome Database ID Release 81
2314678
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=2314678
Reactome
R-HSA-2314678
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-2314678.4
7552725
Pubmed
1995
The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase
Loll, Patrick J
Picot, Daniel
Garavito, R Michael
Nat. Struct. Biol. 2:637-43
8175750
Pubmed
1994
Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin
Lecomte, Marc
Laneuville, Odette
Ji, Chuan
DeWitt, David L
Smith, William L
J. Biol. Chem. 269:13207-15
ASA- acetylates PTGS2
ASA- acetylates PTGS2
The ionized form of aspirin, acetylsalicylate (ASA-) reacts spontaneously with one subunit of PTGS2 dimer (Dong et al. 2011) to acetylate serine residue 516 (Lecomte et al. 1994). The modified enzyme is no longer capable of catalyzing the conversion of arachidonic acid to PGH2, but acquires the ability to convert it to 15R-HETE.
Authored: D'Eustachio, P, 2012-06-07
Reviewed: Rush, MG, 2012-11-10
Edited: D'Eustachio, P, 2012-06-07
Reactome DB_ID: 140491
1
Reactome DB_ID: 2314693
1
Reactome DB_ID: 2314687
1
Ac-PTGS2 dimer [endoplasmic reticulum membrane]
Ac-PTGS2 dimer
Reactome DB_ID: 2311355
1
Reactome DB_ID: 2161824
1
O-acetyl-L-serine at 516
516
EQUAL
18
EQUAL
604
EQUAL
Reactome DB_ID: 61605
1
18
EQUAL
604
EQUAL
Reactome Database ID Release 81
2314687
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=2314687
Reactome
R-HSA-2314687
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-2314687.1
Reactome DB_ID: 2314690
1
Reactome Database ID Release 81
2314686
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=2314686
Reactome
R-HSA-2314686
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-2314686.3
1.14.99.1
Arachidonic acid is oxidised to PGG2 by PTGS1
Arachidonic acid is oxidised to PGG2 by PTGS1
Arachidonic acid oxidised to PGG2
Prostaglandin G/H synthase PTGS1 exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The cyclooxygenase function catalyzes the initial conversion of arachidonic acid to an intermediate, prostaglandin G2 (PGG2) (Hamberg et al. 1974, Nugteren 1973).
Authored: Jassal, Bijay, 2008-10-01
Reviewed: Rush, MG, 2012-11-10
Edited: Jassal, B, 2008-05-28 09:06:10
Edited: Jassal, Bijay, 2008-05-19
Reactome DB_ID: 140356
1
Reactome DB_ID: 113534
2
dioxygen [ChEBI:15379]
dioxygen
ChEBI
15379
Reactome DB_ID: 140357
1
prostaglandin G2 [ChEBI:27647]
prostaglandin G2
ChEBI
27647
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 428986
GO
0004666
GO molecular function
Reactome Database ID Release 81
140354
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=140354
Reactome Database ID Release 81
140355
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=140355
Reactome
R-HSA-140355
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-140355.1
4521806
Pubmed
1974
Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation
Hamberg, M
Svensson, J
Wakabayashi, T
Samuelsson, B
Proc Natl Acad Sci U S A 71:345-9
4776443
Pubmed
1973
Isolation and properties of intermediates in prostaglandin biosynthesis
Nugteren, DH
Hazelhof, E
Biochim Biophys Acta 326:448-61
PTGS1 dimer binds PTGS1 Inhibitors
PTGS1 dimer binds PTGS1 Inhibitors
Prostaglandins are involved in physiological functions such as protecting the stomach mucosa, platelet aggregation and regulating kidney function. They also play pathological roles in inflammation, fever and pain (Ricciotti & FitzGerald 2011). Cyclooxygenase enzymes mediate the production of protaglandins. Prostaglandin G/H synthase 1 (PTGS1, cyclooxygenase 1, COX1) is a mainly constitutively expressed enzyme that acts in a 'housekeeping' fashion producing prostaglandins for physiological functions whereas prostaglandin G/H synthase 2 (PTGS2, cyclooxygenase 2, COX2) is an inducible form which mediates protaglandin production for inflammation.<br><br>In 1971, John R Vane showed that the pharmacological actions of aspirin and similar nonsteroid anti-inflammatory drugs (NSAIDs) were due to the inhibition of cyclooxygenase (Vane 1971). Thus, aspirin-like drugs exert their anti-inflammatory, antipyretic and analgesic effects by the inhibition of cyclooxygenase (Vane & Botting 1997, Botting 2006). The beneficial actions of NSAIDs can be associated with inhibition of COX2 whereas their harmful side effects are associated with inhibition of COX1 therefore developing drugs with a high COX2 specificity is advantageous (Cryer & Feldman 1998, Warner et al. 1999, GarcÃa-Rayado et al. 2018, Saad & Matthew 2020).<br><br>Most NSAIDs possess some or all of antipyretic, analgesic and anti-inflammatory properties and are used to treat rheumatic and osteoarthritic conditions, pain, inflammation and fever (Botting 2006, Crofford 2013).
Authored: Jassal, Bijay, 2020-03-05
Reviewed: Huddart, Rachel, 2022-03-01
Edited: Jassal, Bijay, 2020-03-05
Edited: Matthews, Lisa, 2022-05-10
Converted from EntitySet in Reactome
Reactome DB_ID: 9677343
1
PTGS1 Inhibitors [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
indomethacin [cytosol]
APAP [cytosol]
meloxicam [cytosol]
nimesulide [cytosol]
fenoprofen [cytosol]
bromfenac [cytosol]
Guide to Pharmacology
1909
Guide to Pharmacology
5239
Guide to Pharmacology
7220
Guide to Pharmacology
7401
Guide to Pharmacology
4820
Guide to Pharmacology
7131
Reactome DB_ID: 428986
1
Reactome DB_ID: 9677354
1
PTGS1 dimer:PTGS1 Inhibitors [endoplasmic reticulum membrane]
PTGS1 dimer:PTGS1 Inhibitors
Converted from EntitySet in Reactome
Reactome DB_ID: 9677343
1
Reactome DB_ID: 428986
1
Reactome Database ID Release 81
9677354
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=9677354
Reactome
R-HSA-9677354
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-9677354.1
Reactome Database ID Release 81
9677320
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=9677320
Reactome
R-HSA-9677320
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-9677320.1
10377455
Pubmed
1999
Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis
Warner, T D
Giuliano, F
Vojnovic, I
Bukasa, A
Mitchell, J A
Vane, J R
Proc. Natl. Acad. Sci. U.S.A. 96:7563-8
5284360
Pubmed
1971
Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs
Vane, J R
Nature New Biol. 231:232-5
17218763
Pubmed
2006
Inhibitors of cyclooxygenases: mechanisms, selectivity and uses
Botting, R M
J. Physiol. Pharmacol. 57:113-24
24267197
Pubmed
2013
Use of NSAIDs in treating patients with arthritis
Crofford, Leslie J
Arthritis Res. Ther. 15:S2
30139288
Pubmed
2018
NSAID induced gastrointestinal damage and designing GI-sparing NSAIDs
GarcÃa-Rayado, Guillermo
Navarro, Mercedes
Lanas, Angel
Expert Rev Clin Pharmacol 11:1031-1043
21508345
Pubmed
2011
Prostaglandins and inflammation
Ricciotti, Emanuela
FitzGerald, Garret A
Arterioscler. Thromb. Vasc. Biol. 31:986-1000
9219313
Pubmed
1997
Mechanism of action of aspirin-like drugs
Vane, J R
Botting, R M
Semin. Arthritis Rheum. 26:2-10
9626023
Pubmed
1998
Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs
Cryer, B
Feldman, M
Am. J. Med. 104:413-21
30252262
Pubmed
2020
Nonsteroidal Anti-Inflammatory Drugs (NSAID) Toxicity
Saad, Jennifer
Mathew, Dana
1.14.99.1
Arachidonic acid is oxidised to PGG2 by PTGS2
Arachidonic acid is oxidised to PGG2 by PTGS2
Arachidonic acid oxidised to PGG2
Prostaglandin G/H synthase PTGS2 exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The cyclooxygenase function catalyzes the initial conversion of arachidonic acid to an intermediate, prostaglandin G2 (PGG2) (Hamberg et al. 1974, Nugteren 1973).
Authored: Jassal, Bijay, 2008-10-01
Reviewed: Rush, MG, 2012-11-10
Edited: Jassal, B, 2008-05-28 09:06:10
Edited: Jassal, Bijay, 2008-05-19
Reactome DB_ID: 140356
1
Reactome DB_ID: 113534
2
Reactome DB_ID: 140357
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 140491
Reactome Database ID Release 81
2309772
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=2309772
Reactome Database ID Release 81
2309787
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=2309787
Reactome
R-HSA-2309787
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-2309787.1
1.11.1.7
PGG2 is reduced to PGH2 by PTGS1
PGG2 is reduced to PGH2 by PTGS1
Peroxidative reduction of PGG2 to PGH2
Prostaglandin G/H synthase 1 (PTGS1) exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The peroxidase function converts prostaglandin G2 (PGG2) to prostaglandin H2 (PGH2) via a two-electron reduction (Hamberg et al. 1973, Hla & Neilson 1992, Swinney et al. 1997, Barnett et al. 1994).
Authored: Jassal, Bijay, 2008-10-01
Reviewed: Rush, MG, 2012-11-10
Edited: Jassal, Bijay, 2008-05-19
Reactome DB_ID: 156540
2
hydron [ChEBI:15378]
hydron
ChEBI
15378
Reactome DB_ID: 76342
2
electron [ChEBI:10545]
electron
ChEBI
10545
Reactome DB_ID: 140357
1
Reactome DB_ID: 113519
1
Reactome DB_ID: 30138
1
prostaglandin H2 [ChEBI:15554]
prostaglandin H2
ChEBI
15554
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 428986
GO
0004601
GO molecular function
Reactome Database ID Release 81
140358
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=140358
Reactome Database ID Release 81
140359
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=140359
Reactome
R-HSA-140359
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-140359.1
1380156
Pubmed
1992
Human cyclooxygenase-2 cDNA
Hla, T
Neilson, K
Proc Natl Acad Sci U S A 89:7384-8
9139685
Pubmed
1997
Differential allosteric regulation of prostaglandin H synthase 1 and 2 by arachidonic acid
Swinney, DC
Mak, AY
Barnett, J
Ramesha, CS
J Biol Chem 272:12393-8
4514999
Pubmed
1973
Detection and isolation of an endoperoxide intermediate in prostaglandin biosynthesis
Hamberg, M
Samuelsson, B
Proc Natl Acad Sci U S A 70:899-903
7947975
Pubmed
1994
Purification, characterization and selective inhibition of human prostaglandin G/H synthase 1 and 2 expressed in the baculovirus system
Barnett, J
Chow, J
Ives, D
Chiou, M
Mackenzie, R
Osen, E
Nguyen, B
Tsing, S
Bach, C
Freire, J
Biochim Biophys Acta 1209:130-9
1.11.1.7
PGG2 is reduced to PGH2 by PTGS2
PGG2 is reduced to PGH2 by PTGS2
Peroxidative reduction of PGG2 to PGH2
Prostaglandin G/H synthase 2 (PTGS2) exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The peroxidase function converts prostaglandin G2 (PGG2) to prostaglandin H2 (PGH2) via a two-electron reduction (Hamberg et al. 1973, Hla & Neilson 1992, Swinney et al. 1997, Barnett et al. 1994).
Authored: Jassal, Bijay, 2008-10-01
Reviewed: Rush, MG, 2012-11-10
Edited: Jassal, Bijay, 2008-05-19
Reactome DB_ID: 156540
2
Reactome DB_ID: 76342
2
Reactome DB_ID: 140357
1
Reactome DB_ID: 113519
1
Reactome DB_ID: 30138
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 140491
Reactome Database ID Release 81
2309777
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=2309777
Reactome Database ID Release 81
2309773
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=2309773
Reactome
R-HSA-2309773
6
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-2309773.6
ACTIVATION
Reactome Database ID Release 81
5362144
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=5362144
Reactome
R-HSA-5362144
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-5362144.1
Reactome DB_ID: 549282
1-methylnicotinamide [ChEBI:16797]
1-methylnicotinamide
ChEBI
16797
INHIBITION
Reactome Database ID Release 81
9677534
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=9677534
Reactome DB_ID: 2309778
PGH2 diffuses from the endoplasmic reticulum lumen to the cytosol
PGH2 diffuses from the endoplasmic reticulum lumen to the cytosol
PGH2 moves from the endoplasmic reticulum to the cytosol. The mechanism of this movement has not been determined and could could simply be diffusion through the ER membrane.
Authored: D'Eustachio, P, 2012-06-04
Reviewed: Rush, MG, 2012-11-10
Reactome DB_ID: 30138
1
Reactome DB_ID: 265283
1
Reactome Database ID Release 81
2299725
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=2299725
Reactome
R-HSA-2299725
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-2299725.3
20346915
Pubmed
2010
The prostaglandin transporter PGT transports PGH(2)
Chi, Yuling
Schuster, Victor L
Biochem. Biophys. Res. Commun. 395:168-72
PGH2 is reduced to PGF2a by AKR1C3
PGH2 is reduced to PGF2a by AKR1C3
Aldo-keto reductase family 1 member C3 (AKR1C3) aka PGFS is responsible for the reduction of prostaglandin H2 (PGH2) to prostaglandin F2alpha (PGF2a) (Suzuki-Yamamoto et al. 1999, Komoto et al. 2004, Komoto et al. 2006). There is an additional way of achieving this reaction involving the prostamide/prostaglandin F synthase, FAM213B and thioredoxin (TRX).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 265283
1
Reactome DB_ID: 70106
1
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: 879535
1
prostaglandin F2alpha [ChEBI:15553]
prostaglandin F2alpha
ChEBI
15553
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
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2142714
UniProt:P42330 AKR1C3
AKR1C3
PGFS
KIAA0119
DDH1
AKR1C3
HSD17B5
FUNCTION Cytosolic aldo-keto reductase that catalyzes the NADH and NADPH-dependent reduction of ketosteroids to hydroxysteroids. Acts as a NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductase on the steroid nucleus and side chain and regulates the metabolism of androgens, estrogens and progesterone (PubMed:10622721, PubMed:11165022, PubMed:7650035, PubMed:9415401, PubMed:9927279). Displays the ability to catalyze both oxidation and reduction in vitro, but most probably acts as a reductase in vivo since the oxidase activity measured in vitro is inhibited by physiological concentration of NADPH (PubMed:14672942, PubMed:11165022). Acts preferentially as a 17-ketosteroid reductase and has the highest catalytic efficiency of the AKR1C enzyme for the reduction of delta4-androstenedione to form testosterone (PubMed:20036328). Reduces prostaglandin (PG) D2 to 11beta-prostaglandin F2, progesterone to 20alpha-hydroxyprogesterone and estrone to 17beta-estradiol (PubMed:15047184, PubMed:20036328, PubMed:10622721, PubMed:11165022, PubMed:10998348, PubMed:19010934). Catalyzes the transformation of the potent androgen dihydrotestosterone (DHT) into the less active form, 5-alpha-androstan-3-alpha,17-beta-diol (3-alpha-diol) (PubMed:10998348, PubMed:14672942, PubMed:11165022, PubMed:7650035, PubMed:9415401, PubMed:10557352). Displays also retinaldehyde reductase activity toward 9-cis-retinal (PubMed:21851338).ACTIVITY REGULATION Strongly inhibited by nonsteroidal anti-inflammatory drugs (NSAID) including flufenamic acid and indomethacin. Also inhibited by the flavinoid, rutin, and by selective serotonin inhibitors (SSRIs) (PubMed:14979715, PubMed:14996743, PubMed:10557352). The oxidation reaction is inhibited by low micromolar concentrations of NADPH (PubMed:14672942).PATHWAY Steroid metabolism.TISSUE SPECIFICITY Expressed in many tissues including adrenal gland, brain, kidney, liver, lung, mammary gland, placenta, small intestine, colon, spleen, prostate and testis. High expression in prostate and mammary gland. In the prostate, higher levels in epithelial cells than in stromal cells. In the brain, expressed in medulla, spinal cord, frontotemporal lobes, thalamus, subthalamic nuclei and amygdala. Weaker expression in the hippocampus, substantia nigra and caudate.SIMILARITY Belongs to the aldo/keto reductase family.
UniProt
P42330
1
EQUAL
323
EQUAL
GO
0036130
GO molecular function
Reactome Database ID Release 81
2161558
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=2161558
Reactome Database ID Release 81
2161549
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=2161549
Reactome
R-HSA-2161549
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-2161549.2
16475787
Pubmed
2006
Prostaglandin F2alpha formation from prostaglandin H2 by prostaglandin F synthase (PGFS): crystal structure of PGFS containing bimatoprost
Komoto, J
Yamada, T
Watanabe, K
Woodward, DF
Takusagawa, F
Biochemistry 45:1987-96
14979715
Pubmed
2004
Crystal structure of human prostaglandin F synthase (AKR1C3)
Komoto, J
Yamada, T
Watanabe, K
Takusagawa, F
Biochemistry 43:2188-98
10622721
Pubmed
1999
cDNA cloning, expression and characterization of human prostaglandin F synthase
Suzuki-Yamamoto, T
Nishizawa, M
Fukui, M
Okuda-Ashitaka, E
Nakajima, T
Ito, S
Watanabe, K
FEBS Lett 462:335-40
1.11.1
PGH2 is reduced to PGF2a by FAM213B
PGH2 is reduced to PGF2a by FAM213B
Prostamide/prostaglandin F synthase, FAM213B and thioredoxin (TXN) are the proteins involved in the reduction of prostaglandin H2 (PGH2) to prostaglandin F2alpha (PGF2a) (Moriuchi et al. 2008, Yoshikawa et al. 2011). This reaction has been inferred from an event in mice. An additional way of achieving this reaction involves the protein aldo-keto reductase family 1 member C3 (AKR1C3) aka PGFS.
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 265283
1
Reactome DB_ID: 2142774
1
thioredoxin dithiol [ChEBI:15967]
thioredoxin dithiol
ChEBI
15967
Reactome DB_ID: 879535
1
Reactome DB_ID: 2142833
1
thioredoxin disulfide [ChEBI:18191]
thioredoxin disulfide
ChEBI
18191
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2142703
UniProt:Q8TBF2 PRXL2B
PRXL2B
FAM213B
PRXL2B
C1orf93
FUNCTION Catalyzes the reduction of prostaglandin-ethanolamide H(2) (prostamide H(2)) to prostamide F(2alpha) with NADPH as proton donor. Also able to reduce prostaglandin H(2) to prostaglandin F(2alpha) (By similarity).SIMILARITY Belongs to the peroxiredoxin-like PRXL2 family. Prostamide/prostaglandin F synthase subfamily.
UniProt
Q8TBF2
1
EQUAL
198
EQUAL
GO
0008379
GO molecular function
Reactome Database ID Release 81
2161731
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=2161731
Reactome Database ID Release 81
2161612
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=2161612
Reactome
R-HSA-2161612
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-2161612.2
20950588
Pubmed
2011
Preferential localization of prostamide/prostaglandin F synthase in myelin sheaths of the central nervous system
Yoshikawa, K
Takei, S
Hasegawa-Ishii, S
Chiba, Y
Furukawa, A
Kawamura, N
Hosokawa, M
Woodward, DF
Watanabe, K
Shimada, A
Brain Res 1367:22-32
18006499
Pubmed
2008
Molecular characterization of a novel type of prostamide/prostaglandin F synthase, belonging to the thioredoxin-like superfamily
Moriuchi, H
Koda, N
Okuda-Ashitaka, E
Daiyasu, H
Ogasawara, K
Toh, H
Ito, S
Woodward, DF
Watanabe, K
J Biol Chem 283:792-801
5.3.99.3
PGH2 is isomerised to PGE2 by PTGES
PGH2 is isomerised to PGE2 by PTGES
Prostaglandin E synthase (PTGES) requires glutathione (GSH) as an essential cofactor for its enzymatic activity, and together they isomerise prostaglandin H2 (PGH2) to prostaglandin E2 (PGE2) (Jegerschold et al. 2008). After PGH2 has been produced by the prostaglandin G/H synthases (PTGS1 and 2) on the lumenal side of the endoplasmic reticulum, it diffuses through the membrane to the active site of PTGES located on the cytoplasmic side.
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 265283
1
Reactome DB_ID: 265287
1
prostaglandin E2 [ChEBI:15551]
prostaglandin E2
ChEBI
15551
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2142686
PTGES trimer [endoplasmic reticulum membrane]
PTGES trimer
Prostaglandin E synthase homotrimer
Reactome DB_ID: 2142717
3
UniProt:O14684 PTGES
PTGES
PGES
MPGES1
PIG12
MGST1L1
PTGES
FUNCTION Terminal enzyme of the cyclooxygenase (COX)-2-mediated prostaglandin E2 (PGE2) biosynthetic pathway. Catalyzes the glutathione-dependent oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2) in response to inflammatory stimuli (PubMed:18682561, PubMed:10377395, PubMed:12672824, PubMed:12460774, PubMed:10869354, PubMed:12244105). Plays a key role in inflammation response, fever and pain (By similarity). Catalyzes also the oxidoreduction of endocannabinoids into prostaglandin glycerol esters and PGG2 into 15-hydroperoxy-PGE2 (PubMed:12244105, PubMed:12672824). In addition, displays low glutathione transferase and glutathione-dependent peroxidase activities, toward 1-chloro-2,4-dinitrobenzene and 5-hydroperoxyicosatetraenoic acid (5-HPETE), respectively (PubMed:12672824).ACTIVITY REGULATION Induced by interleukin IL1B.PATHWAY Lipid metabolism; prostaglandin biosynthesis.SUBUNIT Homotrimer.INDUCTION Induced by the interleukin IL1B (PubMed:10377395, PubMed:10760517). Induced By p53/TP53 (PubMed:9305847).SIMILARITY Belongs to the MAPEG family.
UniProt
O14684
1
EQUAL
152
EQUAL
Reactome DB_ID: 2239524
3
glutathione [ChEBI:16856]
glutathione
ChEBI
16856
Reactome Database ID Release 81
2142686
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=2142686
Reactome
R-HSA-2142686
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-2142686.1
GO
0050220
GO molecular function
Reactome Database ID Release 81
2161577
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=2161577
Reactome Database ID Release 81
2161660
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=2161660
Reactome
R-HSA-2161660
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-2161660.3
18682561
Pubmed
2008
Structural basis for induced formation of the inflammatory mediator prostaglandin E2
Jegerschöld, C
Pawelzik, SC
Purhonen, P
Bhakat, P
Gheorghe, KR
Gyobu, N
Mitsuoka, K
Morgenstern, R
Jakobsson, PJ
Hebert, H
Proc Natl Acad Sci U S A 105:11110-5
5.3.99.3
Prostaglandin E synthase isomerizes PGH2 to PGE2
Prostaglandin E synthase isomerizes PGH2 to PGE2
Prostaglandin E2 (PGE2) is the most abundant prostanoid in the body and is a major mediator of inflammation in diseases such as osteoarthritis and rheumatoid arthritis. The product of arachidonic acid, prostaglandin H2 (PGH2) serves as the substrate for the isomerization to PGE2. The conversion is carried out by prostaglandin E synthases. Of the three forms, two are predominanly cytosolic. Prostaglandin E synthase 3 (PTGES3) is also called cytosolic prostaglandin E2 synthase (cPGES). Prostaglandin E synthase 2 (mPGES-2, PTGES2) is synthesized as a Golgi membrane-associated protein which undergoes a spontaneous cleavage of the N-terminal hydrophobic domain leading to a truncated mature cytosolic protein.
Authored: Jassal, Bijay, 2008-10-01
Reviewed: Rush, MG, 2012-11-10
Reactome DB_ID: 265283
1
Reactome DB_ID: 265287
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 8864254
PTGES2(88-377), PTGES3 [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
PTGES3 [cytosol]
PTGES2(88-377) [cytosol]
UniProt
Q15185
UniProt
Q9H7Z7
Reactome Database ID Release 81
265290
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=265290
Reactome Database ID Release 81
265295
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=265295
Reactome
R-HSA-265295
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-265295.2
10922363
Pubmed
2000
Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis
Tanioka, T
Nakatani, Y
Semmyo, N
Murakami, M
Kudo, I
J Biol Chem 275:32775-82
12835322
Pubmed
2003
Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2
Murakami, Makoto
Nakashima, Karin
Kamei, Daisuke
Masuda, Seiko
Ishikawa, Yukio
Ishii, Toshiharu
Ohmiya, Yoshihiro
Watanabe, Kikuko
Kudo, Ichiro
J. Biol. Chem. 278:37937-47
1.1.1.189
PGE2 is converted to PGF2a by CBR1
PGE2 is converted to PGF2a by CBR1
Carbonyl reductase (CBR1) aka prostaglandin 9-keto reductase inactivates prostaglandin E2 (PGE2) by converting it to prostaglandin F2alpha (PGF2a) (Wermuth 1981, Miura et al. 2008).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 70106
1
Reactome DB_ID: 29364
1
Reactome DB_ID: 265287
1
Reactome DB_ID: 879535
1
Reactome DB_ID: 29366
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2142784
UniProt:P16152 CBR1
CBR1
CBR1
CBR
SDR21C1
CRN
FUNCTION NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. Catalyzes the reduction of the antitumor anthracyclines doxorubicin and daunorubicin to the cardiotoxic compounds doxorubicinol and daunorubicinol (PubMed:18449627, PubMed:15799708, PubMed:17912391, PubMed:7005231). Can convert prostaglandin E to prostaglandin F2-alpha (By similarity). Can bind glutathione, which explains its higher affinity for glutathione-conjugated substrates. Catalyzes the reduction of S-nitrosoglutathione (PubMed:18826943, PubMed:17344335).ACTIVITY REGULATION Inhibited by quercetin, rutenin and its derivatives.SUBUNIT Monomer.TISSUE SPECIFICITY Expressed in kidney (at protein level).SIMILARITY Belongs to the short-chain dehydrogenases/reductases (SDR) family.
UniProt
P16152
2
EQUAL
277
EQUAL
GO
0050221
GO molecular function
Reactome Database ID Release 81
2161655
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=2161655
Reactome Database ID Release 81
2161651
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=2161651
Reactome
R-HSA-2161651
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-2161651.2
18493841
Pubmed
2008
Different functions between human monomeric carbonyl reductase 3 and carbonyl reductase 1
Miura, T
Nishinaka, T
Terada, T
Mol Cell Biochem 315:113-21
7005231
Pubmed
1981
Purification and properties of an NADPH-dependent carbonyl reductase from human brain. Relationship to prostaglandin 9-ketoreductase and xenobiotic ketone reductase
Wermuth, B
J Biol Chem 256:1206-13
PGE2 is dehydrated to PGA2
PGE2 is dehydrated to PGA2
Cyclopentenone prostaglandins comprise a family of molecules that are formed by dehydration of hydroxyl moieties in prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2). Dehydration of PGE2 leads to prostaglandin A2 (PGA2) (Hamberg & Samuelsson B 1966, Amin 1989).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 265287
1
Reactome DB_ID: 2299726
1
prostaglandin A2 [ChEBI:27820]
prostaglandin A2
ChEBI
27820
Reactome DB_ID: 29356
1
Reactome Database ID Release 81
2161659
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=2161659
Reactome
R-HSA-2161659
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-2161659.2
2717650
Pubmed
1989
Simultaneous determination of prostaglandins (PG) E2, A2 and B2 and stability studies of PGE2 in pharmaceutical preparations by ion-pair reversed phase HPLC
Amin, M
Pharm Acta Helv 64:45-50
5903721
Pubmed
1966
Prostaglandins in human seminal plasma. Prostaglandins and related factors 46
Hamberg, M
Samuelsson, B
J Biol Chem 241:257-63
PGA2 is isomerised to PGC2
PGA2 is isomerised to PGC2
Dehydration in the cyclopentane ring of prostaglandin E2 (PGE2) yields prostaglandin A2 (PGA2) followed by isomerization of the double bond to yield the unstable compound prostaglandin C2 (PGC2) (Straus & Glass, 2001).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 2299726
1
Reactome DB_ID: 2299724
1
prostaglandin C2 [ChEBI:27555]
prostaglandin C2
ChEBI
27555
Reactome Database ID Release 81
2161666
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=2161666
Reactome
R-HSA-2161666
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-2161666.2
11301410
Pubmed
2001
Cyclopentenone prostaglandins: new insights on biological activities and cellular targets
Straus, DS
Glass, CK
Med Res Rev 21:185-210
PGC2 is isomerised to PGB2
PGC2 is isomerised to PGB2
Isomerization of the double bond in prostaglandin A2 (PGA2) forms prostaglandin C2 (PGC2). This is an unstable compound which undergoes a second isomerization to yield prostaglandin B2 (PGB2) (Straus & Glass, 2001).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 2299724
1
Reactome DB_ID: 2299721
1
prostaglandin B2 [ChEBI:28099]
prostaglandin B2
ChEBI
28099
Reactome Database ID Release 81
2161735
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=2161735
Reactome
R-HSA-2161735
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-2161735.2
PGA2 is dehydrated to 15d-PGA2
PGA2 is dehydrated to 15d-PGA2
The non-enzymatic dehydration of prostaglandin A2 (PGA2) into 15-deoxy prostaglandin A2 (15d-PGA2) which occurs in mice (Petrova et al. 1999) is inferred in humans.
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 2299726
1
Reactome DB_ID: 2299722
1
15-deoxy-Delta(12,14)-prostaglandin A2 [ChEBI:63975]
15-deoxy-Delta(12,14)-prostaglandin A2
ChEBI
63975
Reactome DB_ID: 29356
1
Reactome Database ID Release 81
2161668
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=2161668
Reactome
R-HSA-2161668
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-2161668.2
10200320
Pubmed
1999
Cyclopentenone prostaglandins suppress activation of microglia: down-regulation of inducible nitric-oxide synthase by 15-deoxy-Delta12,14-prostaglandin J2
Petrova, TV
Akama, KT
Van Eldik, LJ
Proc Natl Acad Sci U S A 96:4668-73
5.3.99.2
PGH2 is isomerised to PGD2 by PTGDS
PGH2 is isomerised to PGD2 by PTGDS
Prostaglandin D2 (PGD2) is a structural isomer of prostaglandin E2 (PGE2). There is a 9-keto and 11-hydroxy group on PGE2 with these substituents reversed on PGD2. PGD2 is formed by two evolutionarily distinct, but functionally convergent, prostaglandin D synthases: lipocalin-type prostaglandin-D synthase aka Prostaglandin-H2 D-isomerase (PTDGS) and hematopoietic prostaglandin D synthase (HPGDS). One of the main differences between these two proteins is that HPGDS requires glutathione (GSH) for catalysis while PTDGS can function without this cofactor. Here, PTDGS promotes the isomerisation of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2) (Zhou et al. 2010).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 30138
1
Reactome DB_ID: 2161634
1
prostaglandin D2 [ChEBI:15555]
prostaglandin D2
ChEBI
15555
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2142814
UniProt:P41222 PTGDS
PTGDS
PTGDS
PDS
FUNCTION Catalyzes the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation (PubMed:20667974). Involved in a variety of CNS functions, such as sedation, NREM sleep and PGE2-induced allodynia, and may have an anti-apoptotic role in oligodendrocytes. Binds small non-substrate lipophilic molecules, including biliverdin, bilirubin, retinal, retinoic acid and thyroid hormone, and may act as a scavenger for harmful hydrophobic molecules and as a secretory retinoid and thyroid hormone transporter. Possibly involved in development and maintenance of the blood-brain, blood-retina, blood-aqueous humor and blood-testis barrier. It is likely to play important roles in both maturation and maintenance of the central nervous system and male reproductive system (PubMed:20667974, PubMed:9475419). Involved in PLA2G3-dependent maturation of mast cells. PLA2G3 is secreted by immature mast cells and acts on nearby fibroblasts upstream to PTDGS to synthesize PGD2, which in turn promotes mast cell maturation and degranulation via PTGDR (By similarity).SUBUNIT Monomer.TISSUE SPECIFICITY Abundant in the brain and CNS, where it is expressed in tissues of the blood-brain barrier and secreted into the cerebro-spinal fluid. Abundantly expressed in the heart. In the male reproductive system, it is expressed in the testis, epididymis and prostate, and is secreted into the seminal fluid. Expressed in the eye and secreted into the aqueous humor. Lower levels detected in various tissue fluids such as serum, normal urine, ascitic fluid and tear fluid. Also found in a number of other organs including ovary, fimbriae of the fallopian tubes, kidney, leukocytes.DEVELOPMENTAL STAGE Expression in the amniotic fluid increases dramatically during weeks 12 to 25 of pregnancy. Levels decrease slowly after 25 weeks.INDUCTION By IL1B/interleukin-1 beta and thyroid hormone. Probably induced by dexamethasone, dihydrotestosterone (DHT), progesterone, retinoic acid and retinal. Repressed by the Notch-Hes signaling pathway.DOMAIN Forms a beta-barrel structure that accommodates hydrophobic ligands in its interior.PTM N- and O-glycosylated. Both N-glycosylation recognition sites are almost quantitatively occupied by N-glycans of the biantennary complex type, with a considerable proportion of structures bearing a bisecting GlcNAc. N-glycan at Asn-78: dHex1Hex5HexNAc4. Agalacto structure as well as sialylated and nonsialylated oligosaccharides bearing alpha2-3- and/or alpha2-6-linked NeuNAc are present.MISCELLANEOUS It has been proposed that the urinary and serum levels may provide a sensitive indicator of renal damage in diabetes mellitus and hypertension. Elevated levels in the coronary circulation may also be associated with angina. Changes in charge and molecular weight microheterogeneity, due to modification of the N-linked oligosaccharides, may be associated with neurodegenerative disease and multiple sclerosis. Detected in meningioma but not in other brain tumors and may be considered a specific cell marker for meningioma. Expression levels in amniotic fluid are altered in abnormal pregnancies. Levels are lower in pregnancies with trisomic fetuses and fetuses with renal abnormalities.SIMILARITY Belongs to the calycin superfamily. Lipocalin family.
UniProt
P41222
23
EQUAL
190
EQUAL
GO
0004667
GO molecular function
Reactome Database ID Release 81
2161647
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=2161647
Reactome Database ID Release 81
2161620
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=2161620
Reactome
R-HSA-2161620
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-2161620.2
20667974
Pubmed
2010
Structure-function analysis of human l-prostaglandin D synthase bound with fatty acid molecules
Zhou, Y
Shaw, N
Li, Y
Zhao, Y
Zhang, R
Liu, ZJ
FASEB J 24:4668-77
5.3.99.2
PGH2 is isomerised to PGD2 by HPGDS
PGH2 is isomerised to PGD2 by HPGDS
Prostaglandin D2 (PGD2) is a structural isomer of prostaglandin E2 (PGE2). There is a 9-keto and 11-hydroxy group on PGE2 with these substituents reversed on PGD2. PGD2 is formed by two evolutionarily distinct, but functionally convergent, prostaglandin D synthases: lipocalin-type prostaglandin-D synthase aka Prostaglandin-H2 D-isomerase (PTDGS) and hematopoietic prostaglandin D synthase (HPGDS). One of the main differences between these two proteins is that HPGDS requires glutathione (GSH) for catalysis while PTDGS can function without this cofactor. Here, HPGDS with GSH promotes the isomerisation of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2) (Jowsey et al. 2001, Inoue et al. 2003).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 265283
1
Reactome DB_ID: 879629
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2142683
HPGDS dimer [cytosol]
HPGDS dimer
Reactome DB_ID: 29450
2
glutathionate(1-) [ChEBI:57925]
glutathionate(1-)
glutathionate anion
glutathionate ion
glutathione
glutathionate
ChEBI
57925
Reactome DB_ID: 2142706
2
UniProt:O60760 HPGDS
HPGDS
HPGDS
PGDS
PTGDS2
GSTS
FUNCTION Bifunctional enzyme which catalyzes both the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation, and the conjugation of glutathione with a wide range of aryl halides and organic isothiocyanates. Also exhibits low glutathione-peroxidase activity towards cumene hydroperoxide.ACTIVITY REGULATION Prostaglandin PGD2 synthesis is stimulated by calcium and magnesium ions. One calcium or magnesium ion is bound between the subunits of the homodimer. The interactions with the protein are for the most part mediated via water molecules. Magnesium increases the affinity for glutathione, while calcium has no effect on the affinity for glutathione.SUBUNIT Homodimer.TISSUE SPECIFICITY Expressed in a number of megakaryocytic cell lines but not in platelets. Highly expressed in adipose tissue, macrophages and placenta. Also expressed at lower levels in lung, heart, lymph nodes, appendix, bone marrow and fetal liver.DEVELOPMENTAL STAGE Highest levels in immature megakaryocytic cells. Disappears after final differentiation to platelets.INDUCTION By 12-O-tetradecanoylphorbol-13-acetate (TPA).SIMILARITY Belongs to the GST superfamily. Sigma family.
UniProt
O60760
2
EQUAL
199
EQUAL
Reactome Database ID Release 81
2142683
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=2142683
Reactome
R-HSA-2142683
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-2142683.1
Reactome Database ID Release 81
2161729
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=2161729
Reactome Database ID Release 81
2161701
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=2161701
Reactome
R-HSA-2161701
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-2161701.3
11672424
Pubmed
2001
Mammalian class Sigma glutathione S-transferases: catalytic properties and tissue-specific expression of human and rat GSH-dependent prostaglandin D2 synthases
Jowsey, IR
Thomson, AM
Flanagan, JU
Murdock, PR
Moore, GB
Meyer, DJ
Murphy, GJ
Smith, SA
Hayes, JD
Biochem J 359:507-16
12627223
Pubmed
2003
Mechanism of metal activation of human hematopoietic prostaglandin D synthase
Inoue, T
Irikura, Daisuke
Okazaki, N
Kinugasa, S
Matsumura, H
Uodome, N
Yamamoto, M
Kumasaka, T
Miyano, M
Kai, Y
Urade, Y
Nat Struct Biol 10:291-6
PGD2 is dehydrated to PGJ2
PGD2 is dehydrated to PGJ2
Analogous to prostaglandin E2 (PGE2), dehydration of the prostaglandin D2 (PGD2) prostane ring forms prostaglandin J2 (PGJ2) (Monneret et al. 2002).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 2161634
1
Reactome DB_ID: 2142674
1
prostaglandin J2 [ChEBI:27485]
prostaglandin J2
ChEBI
27485
Reactome DB_ID: 113519
1
Reactome Database ID Release 81
2161733
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=2161733
Reactome
R-HSA-2161733
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-2161733.2
11907120
Pubmed
2002
15-Deoxy-delta 12,14-prostaglandins D2 and J2 are potent activators of human eosinophils
Monneret, G
Li, H
Vasilescu, J
Rokach, J
Powell, WS
J Immunol 168:3563-9
PGJ2 is isomerised to delta12-PGJ2
PGJ2 is isomerised to delta12-PGJ2
Delta-12-prostaglandin J2 (delta12-PGJ2) is an isomerisation product of prostaglandin J2 (PGJ2) (Monneret et al. 2002).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 2142674
1
Reactome DB_ID: 2142821
1
13,14-dihydro-Delta(12)-prostaglandin J2 [ChEBI:28130]
13,14-dihydro-Delta(12)-prostaglandin J2
ChEBI
28130
Reactome Database ID Release 81
2161563
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=2161563
Reactome
R-HSA-2161563
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-2161563.2
Delta12-PGJ2 is dehydrated to 15d-PGJ2
Delta12-PGJ2 is dehydrated to 15d-PGJ2
15-Deoxy-delta(12,14)-PDJ2 (15d-PGJ2) is a dehydration product of delta-12-prostaglandin J2 (delta12-PGJ2) (Monneret et al. 2002).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 2142821
1
Reactome DB_ID: 2142702
1
15-deoxy-Delta(12,14)-prostaglandin J2 [ChEBI:34159]
15-deoxy-Delta(12,14)-prostaglandin J2
15-Deoxy-delta-12,14-PGJ2
15-Deoxy-delta-12,14-prostaglandin J2
15-Deoxy-PGJ2
ChEBI
34159
Reactome DB_ID: 113519
1
Reactome Database ID Release 81
2161588
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=2161588
Reactome
R-HSA-2161588
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-2161588.2
PGD2 is dehydrated to 15d-PGD2
PGD2 is dehydrated to 15d-PGD2
15-Deoxy-delta 12,14-prostaglandins D2 (15d-PGD2) is a dehydrated form of prostaglandin D2 (PGD2) (Monneret et al. 2002).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 2161634
1
Reactome DB_ID: 2142817
1
15-deoxy-Delta(12,14)-prostaglandin D2 [ChEBI:63999]
15-deoxy-Delta(12,14)-prostaglandin D2
ChEBI
63999
Reactome DB_ID: 113519
1
Reactome Database ID Release 81
2161673
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=2161673
Reactome
R-HSA-2161673
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-2161673.2
1.1.1.188
PGD2 is reduced to 11-epi-PGF2a by AKRIC3
PGD2 is reduced to 11-epi-PGF2a by AKRIC3
Aldo-keto reductase family 1 member C3 (AKR1C3) aka PGFS is the enzyme involved in NADPH-dependent prostaglandin D2 11-keto reductase activity of reducing prostaglandin D2 (PGD2) to 11-epi-Prostaglandin F2alpha (11-epi-PGF2a) (Liston & Roberts 1985, Koda et al. 2004).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 70106
1
Reactome DB_ID: 29364
1
Reactome DB_ID: 879629
1
Reactome DB_ID: 2142710
1
11-epi-prostaglandin F2alpha [ChEBI:27595]
11-epi-prostaglandin F2alpha
ChEBI
27595
Reactome DB_ID: 29366
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2142714
1
EQUAL
323
EQUAL
GO
0036131
GO molecular function
Reactome Database ID Release 81
2161608
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=2161608
Reactome Database ID Release 81
2161614
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=2161614
Reactome
R-HSA-2161614
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-2161614.2
3862115
Pubmed
1985
Transformation of prostaglandin D2 to 9 alpha, 11 beta-(15S)-trihydroxyprosta-(5Z,13E)-dien-1-oic acid (9 alpha, 11 beta-prostaglandin F2): a unique biologically active prostaglandin produced enzymatically in vivo in humans
Liston, TE
Roberts LJ, 2nd
Proc Natl Acad Sci U S A 82:6030-4
15047184
Pubmed
2004
Synthesis of prostaglandin F ethanolamide by prostaglandin F synthase and identification of Bimatoprost as a potent inhibitor of the enzyme: new enzyme assay method using LC/ESI/MS
Koda, N
Tsutsui, Y
Niwa, H
Ito, S
Woodward, DF
Watanabe, K
Arch Biochem Biophys 424:128-36
1.1.1.141
PGD2/E2/F2a is oxidised to 15k-PGD2/E2/F2a by HPGD
PGD2/E2/F2a is oxidised to 15k-PGD2/E2/F2a by HPGD
15-Hydroxyprostaglandin dehydrogenase (HPGD) oxidises prostaglandins D2 (PGD2), E2 (PGE2), and F2alpha (PGF2a) to 15-keto-prostaglandin D2 (15k-PGD2), E2 (15k-PGE2), and F2alpha (15k-PGF2a) respectively (Cho et al. 2006). This reaction is inferred from rabbits (Bergholte & Okita 1986).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 29360
1
NAD(1-) [ChEBI:57540]
NAD(1-)
NAD(+)
adenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate}
NAD anion
ChEBI
57540
Converted from EntitySet in Reactome
Reactome DB_ID: 2161661
1
PGD2/E2/F2a [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
PGF2a [cytosol]
PGD2 [cytosol]
PGE2 [cytosol]
Reactome DB_ID: 70106
1
Converted from EntitySet in Reactome
Reactome DB_ID: 2161597
1
15k-PGD2,15k-PGE2,15k-PGF2a [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
15k-PGE2 [cytosol]
15k-PGF2a [cytosol]
15k-PGD2 [cytosol]
ChEBI
15547
ChEBI
28442
ChEBI
15557
Reactome DB_ID: 73473
1
NADH(2-) [ChEBI:57945]
NADH(2-)
NADH dianion
adenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate}
NADH
ChEBI
57945
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2142778
HPGD dimer [cytosol]
HPGD dimer
Reactome DB_ID: 2142677
2
UniProt:P15428 HPGD
HPGD
HPGD
SDR36C1
PGDH1
FUNCTION Catalyzes the NAD-dependent dehydrogenation (oxidation) of a broad array of hydroxylated polyunsaturated fatty acids (mainly eicosanoids and docosanoids, including prostaglandins, lipoxins and resolvins), yielding their corresponding keto (oxo) metabolites (PubMed:8086429, PubMed:10837478, PubMed:16828555, PubMed:16757471, PubMed:21916491, PubMed:25586183). Decreases the levels of the pro-proliferative prostaglandins such as prostaglandin E2 (whose activity is increased in cancer because of an increase in the expression of cyclooxygenase 2) and generates oxo-fatty acid products that can profoundly influence cell function by abrogating proinflammatory cytokine expression (PubMed:25586183, PubMed:15574495). Converts resolvins E1, D1 and D2 to their oxo products, which represents a mode of resolvin inactivation. Resolvin E1 plays important roles during the resolution phase of acute inflammation, while resolvins D1 and D2 have a unique role in obesity-induced adipose inflammation (PubMed:16757471, PubMed:22844113).SUBUNIT Homodimer.TISSUE SPECIFICITY Detected in colon epithelium (at protein level).INDUCTION Down-regulated by cortisol, dexamethasone and betamethasone. Down-regulated in colon cancer. Up-regulated by TGFB1.SIMILARITY Belongs to the short-chain dehydrogenases/reductases (SDR) family.
UniProt
P15428
1
EQUAL
266
EQUAL
Reactome Database ID Release 81
2142778
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=2142778
Reactome
R-HSA-2142778
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-2142778.1
GO
0016404
GO molecular function
Reactome Database ID Release 81
2161623
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=2161623
Reactome Database ID Release 81
2161662
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=2161662
Reactome
R-HSA-2161662
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-2161662.2
3954355
Pubmed
1986
Isolation and properties of lung 15-hydroxyprostaglandin dehydrogenase from pregnant rabbits
Bergholte, JM
Okita, RT
Arch Biochem Biophys 245:308-15
16828555
Pubmed
2006
Role of glutamine 148 of human 15-hydroxyprostaglandin dehydrogenase in catalytic oxidation of prostaglandin E2
Cho, H
Huang, L
Hamza, A
Gao, D
Zhan, CG
Tai, HH
Bioorg Med Chem 14:6486-91
1.3.1.48
15k-PGE2/F2a is reduced to dhk-PGE2/F2a by PTGR1
15k-PGE2/F2a is reduced to dhk-PGE2/F2a by PTGR1
Prostaglandin reductase 2 (PTGR2) is a 13-prostaglandin reductase which metabolises eicosanoids by catalysing NADH/NADPH-dependant double bond reduction in 15-keto-prostaglandin E2 (15k-PGE2) and F2alpha (15k-PGF2a) to produce 13,14-dihydro-15-keto-prostaglandin E2 (dhk-PGE2) and F2alpha (dhk-PGF2a) respectively (Wu et al. 2008). This has been inferred from the reaction event in mice involving prostaglandin reductase 2 (Ptgr2) (Chou et al. 2007).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 70106
1
Reactome DB_ID: 29364
1
Converted from EntitySet in Reactome
Reactome DB_ID: 2161650
1
15k-PGE2,15k-PGF2a [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
15k-PGE2 [cytosol]
15k-PGF2a [cytosol]
Reactome DB_ID: 29366
1
Converted from EntitySet in Reactome
Reactome DB_ID: 2161684
1
dhk-PGE2,dhk-PGF2a [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
dhk-PGF2a [cytosol]
dhk-PGE2 [cytosol]
ChEBI
63976
ChEBI
15550
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 8940670
UniProt:Q8N8N7 PTGR2
PTGR2
ZADH1
PTGR2
FUNCTION Functions as 15-oxo-prostaglandin 13-reductase and acts on 15-keto-PGE1, 15-keto-PGE2, 15-keto-PGE1-alpha and 15-keto-PGE2-alpha with highest activity towards 15-keto-PGE2 (PubMed:19000823). Overexpression represses transcriptional activity of PPARG and inhibits adipocyte differentiation (By similarity).SUBUNIT Monomer.TISSUE SPECIFICITY Widely expressed.SIMILARITY Belongs to the NADP-dependent oxidoreductase L4BD family.
UniProt
Q8N8N7
1
EQUAL
351
EQUAL
GO
0036132
GO molecular function
Reactome Database ID Release 81
2161566
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=2161566
Reactome Database ID Release 81
2161692
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=2161692
Reactome
R-HSA-2161692
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-2161692.2
17449869
Pubmed
2007
Identification of a novel prostaglandin reductase reveals the involvement of prostaglandin E2 catabolism in regulation of peroxisome proliferator-activated receptor gamma activation
Chou, WL
Chuang, LM
Chou, CC
Wang, AH
Lawson, JA
FitzGerald, GA
Chang, ZF
J Biol Chem 282:18162-72
19000823
Pubmed
2008
Structural basis for catalytic and inhibitory mechanisms of human prostaglandin reductase PTGR2
Wu, Yu-Hauh
Ko, Tzu-Ping
Guo, Rey-Ting
Hu, Su-Ming
Chuang, Lee-Ming
Wang, Andrew H-J
Structure 16:1714-23
5.3.99.4
PTGIS, CYP8A1 isomerise PGH2 to PGI2
PTGIS, CYP8A1 isomerise PGH2 to PGI2
Prostacyclin synthase (CYP8A1) mediates the isomerization of prostaglandin H2 to prostaglandin I2
Prostacyclin synthase (PTGIS) aka CYP8A1 mediates the isomerisation of prostaglandin H2 (PGH2) to prostaglandin I2 (PGI2) aka prostacyclin (Wada et al. 2004). This reaction is not coupled with any P450 reductase proteins nor consumes NADPH. Experiments on rats with thrombolytic models suggest endogenous MNA could be a stimulator of the COX2/PGI2 pathway and thus regulate an anti-thrombotic effect (Chlopicki et al. 2007).
Authored: Jassal, Bijay, 2008-10-01
Reviewed: Rush, MG, 2012-11-10
Edited: Jassal, Bijay, 2008-05-19
Reactome DB_ID: 30138
1
Reactome DB_ID: 31593
1
prostaglandin I2 [ChEBI:15552]
prostaglandin I2
ChEBI
15552
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 3222410
PTGIS,CYP8B1 [endoplasmic reticulum membrane]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
PTGIS [endoplasmic reticulum membrane]
UniProt
Q16647
GO
0008116
GO molecular function
Reactome Database ID Release 81
76495
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=76495
Reactome Database ID Release 81
76496
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=76496
Reactome
R-HSA-76496
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-76496.2
15115769
Pubmed
2004
Purification and characterization of recombinant human prostacyclin synthase
Wada, M
Yokoyama, C
Hatae, T
Shimonishi, M
Nakamura, M
Imai, Y
Ullrich, V
Tanabe, T
J Biochem 135:455-63
17641676
Pubmed
2007
1-Methylnicotinamide (MNA), a primary metabolite of nicotinamide, exerts anti-thrombotic activity mediated by a cyclooxygenase-2/prostacyclin pathway
Chlopicki, S
Swies, J
Mogielnicki, A
Buczko, W
Bartus, M
Lomnicka, M
Adamus, J
Gebicki, J
Br. J. Pharmacol. 152:230-9
PGI2 is hydrolysed to 6k-PGF1a
PGI2 is hydrolysed to 6k-PGF1a
The ring in prostaglandin I2 (PGI2) aka prostacyclin is highly labile and rapidly hydolyses to form the stable but biologically inactive 6-keto-prostaglandin F1alpha (6k-PGF1a) (Wada et al. 2004). PGI2 and 6k-PGF1a are often used interchangeably in the literature.
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 31593
1
Reactome DB_ID: 113519
1
Reactome DB_ID: 2142786
1
6-oxoprostaglandin F1alpha [ChEBI:28158]
6-oxoprostaglandin F1alpha
ChEBI
28158
Reactome Database ID Release 81
2161619
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=2161619
Reactome
R-HSA-2161619
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-2161619.2
5.3.99.5
TBXAS1 isomerises PGH2 to TXA2
TBXAS1 isomerises PGH2 to TXA2
Thromboxane synthase (CYP5A1) mediates the isomerization of prostaglandin H2 to thromboxane A2
Thromboxane synthase (TBXAS1) aka CYP5A1 mediates the isomerisation of prostaglandin H2 (PGH2) to thromboxane A2 (TXA2) (Miyata et al. 2001, Chevalier et al. 2001). This reaction is not coupled with any P450 reductase proteins nor consumes NADPH.
Authored: Jassal, Bijay, 2008-10-01
Reviewed: Rush, MG, 2012-11-10
Edited: Jassal, Bijay, 2008-05-19
Reactome DB_ID: 30138
1
Reactome DB_ID: 32879
1
thromboxane A2 [ChEBI:15627]
thromboxane A2
ChEBI
15627
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 65976
UniProt:P24557 TBXAS1
TBXAS1
TXAS
CYP5
TBXAS1
CYP5A1
FUNCTION Catalyzes the conversion of prostaglandin H2 (PGH2) to thromboxane A2 (TXA2), a potent inducer of blood vessel constriction and platelet aggregation (PubMed:8436233, PubMed:11297515, PubMed:9873013, PubMed:11097184, PubMed:24009185, PubMed:22735388). Cleaves also PGH2 to 12-hydroxy-heptadecatrienoicacid (12-HHT) and malondialdehyde, which is known to act as a mediator of DNA damage. 12-HHT and malondialdehyde are formed stoichiometrically in the same amounts as TXA2 (PubMed:11297515, PubMed:9873013, PubMed:22735388). Additionally, displays dehydratase activity, toward (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate (15(S)-HPETE) producing 15-KETE and 15-HETE (PubMed:17459323).PATHWAY Lipid metabolism; fatty acid metabolism.SUBUNIT Monomer.TISSUE SPECIFICITY Platelets, lung, kidney, spleen, macrophages and lung fibroblasts.DISEASE Thromboxane synthetase deficiency has been detected in some patients with a bleeding disorder due to platelet dysfunction.SIMILARITY Belongs to the cytochrome P450 family.CAUTION It is uncertain whether Met-1 is the initiator. An alternative upstream Met is found in primates, but not in other mammals.
UniProt
P24557
1
EQUAL
533
EQUAL
GO
0004796
GO molecular function
Reactome Database ID Release 81
76499
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=76499
Reactome Database ID Release 81
76500
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=76500
Reactome
R-HSA-76500
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-76500.1
11465543
Pubmed
2001
Identification of genetic variants in the human thromboxane synthase gene (CYP5A1)
Chevalier, D
Lo-Guidice, JM
Sergent, E
Allorge, D
Debuysère, H
Ferrari, N
Libersa, C
Lhermitte, M
Broly, F
Mutat Res 432:61-7
7925341
Pubmed
1994
Characterization of the human gene (TBXAS1) encoding thromboxane synthase
Miyata, A
Yokoyama, C
Ihara, H
Bandoh, S
Takeda, O
Takahashi, E
Tanabe, T
Eur J Biochem 224:273-9
TXA2 is hydrolysed to TXB2
TXA2 is hydrolysed to TXB2
Thromboxane A2 degenerates to thromboxane B2
Thromboxane A2 (TXA2) contains an unstable ether linkage that is rapidly hydrolysed under aqueous conditions to form the biologically inert thromboxane B2 (TXB2) (Wang et al. 2001, Hamberg et al. 1975), which is excreted.
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 32879
1
Reactome DB_ID: 113519
1
Reactome DB_ID: 443890
1
thromboxane B2 [ChEBI:28728]
thromboxane B2
ChEBI
28728
Reactome Database ID Release 81
443894
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=443894
Reactome
R-HSA-443894
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-443894.2
1059088
Pubmed
1975
Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides
Hamberg, M
Svensson, J
Samuelsson, B
Proc Natl Acad Sci U S A 72:2994-8
11297515
Pubmed
2001
Substrate binding is the rate-limiting step in thromboxane synthase catalysis
Wang, LH
Tsai, AL
Hsu, PY
J Biol Chem 276:14737-43
TXB2 is converted to 11dh-TXB2 by TXDH
TXB2 is converted to 11dh-TXB2 by TXDH
Thromboxane B2 (TXB2) undergoes dehydrogenation at C-11 to form 11-dehydro-thromboxane B2 (11dh-TXB2). The enzyme responsible for catalysis has been termed 11-dehydroxythromboxane B2 dehydrogenase (TXDH) (Kumlin & Granström 1986, Catella et al. 1986, Westlund et al. 1994). The human TXDH isoform has not been cloned but 11dh-TXB2 has been detected in various experiments.
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 443890
1
Reactome DB_ID: 194653
1
Reactome DB_ID: 2142828
1
11-dehydro-thromboxane B2 [ChEBI:28667]
11-dehydro-thromboxane B2
ChEBI
28667
Reactome DB_ID: 156540
1
Reactome DB_ID: 194697
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2161595
TXDH [endoplasmic reticulum lumen]
TXDH
11-dehydroxythromboxane B2 dehydrogenase
11-Hydroxythromboxane B2 reductase
GO
0036133
GO molecular function
Reactome Database ID Release 81
2161726
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=2161726
Reactome Database ID Release 81
2161732
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=2161732
Reactome
R-HSA-2161732
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-2161732.2
3823488
Pubmed
1986
Radioimmunoassay for 11-dehydro-TXB2: a method for monitoring thromboxane production in vivo
Kumlin, M
Granström, E
Prostaglandins 32:741-67
8200461
Pubmed
1994
11-Hydroxythromboxane B2 dehydrogenase is identical to cytosolic aldehyde dehydrogenase
Westlund, P
Fylling, AC
Cederlund, E
Jörnvall, H
FEBS Lett 345:99-103
3461463
Pubmed
1986
11-Dehydrothromboxane B2: a quantitative index of thromboxane A2 formation in the human circulation
Catella, F
Healy, D
Lawson, JA
FitzGerald, GA
Proc Natl Acad Sci U S A 83:5861-5
PGH2 is degraded to 12S-HHT and MDA by TBXAS1
PGH2 is degraded to 12S-HHT and MDA by TBXAS1
Thromboxane synthase (TBXAS1) aka CYP5A1 facilitates rearrangement of the PGH2 endoperoxide bridge by a complementary mechanism to prostacyclin synthase, interacting with the C-9 oxygen to promote endoperoxide bond cleavage. The C-11 oxygen radical initiates intramolecular rearrangement, resulting in either the formation of thromboxane A2 (TXA2) or 12-hydroxyheptadecatrienoic acid (12S-HHT) and malonaldehyde (MDA) (Wang et al. 2001).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 30138
1
Reactome DB_ID: 2142797
1
12S-HHTrE [ChEBI:63977]
12S-HHTrE
ChEBI
63977
Reactome DB_ID: 2161562
1
malonaldehyde [ChEBI:566274]
malonaldehyde
1,3-Propanedialdehyde
Malonodialdehyde
1,3-Propanedione
Malonic dialdehyde
MDA
Malonyldialdehyde
MDD
Malondialdehyde
1,3-Propanedial
Malonic aldehyde
ChEBI
566274
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 65976
1
EQUAL
533
EQUAL
GO
0036134
GO molecular function
Reactome Database ID Release 81
2161594
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=2161594
Reactome Database ID Release 81
2161613
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=2161613
Reactome
R-HSA-2161613
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-2161613.2
Reactome Database ID Release 81
2162123
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=2162123
Reactome
R-HSA-2162123
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-2162123.3
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
20655950
Pubmed
2011
Old and new generation lipid mediators in acute inflammation and resolution
Stables, Melanie J
Gilroy, Derek W
Prog. Lipid Res. 50:35-51
GO
0019371
GO biological process
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
ALOX5:Ca2+:Fe2+ [cytosol]
ALOX5:Ca2+:Fe2+
ALOX5 (iron, calcium cofactors)
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). Also may 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.
UniProt
P09917
2
EQUAL
674
EQUAL
Reactome DB_ID: 71067
1
iron(2+) [ChEBI:29033]
iron(2+)
FE (II) ION
Fe(2+)
Fe(II)
Ferrous ion
Fe2+
iron ion(2+)
ChEBI
29033
Reactome DB_ID: 74016
2
Reactome Database ID Release 81
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: 29370
1
ADP(3-) [ChEBI:456216]
ADP(3-)
ADP trianion
5'-O-[(phosphonatooxy)phosphinato]adenosine
ADP
ChEBI
456216
Reactome DB_ID: 265277
1
p-S272-ALOX5:Ca2+:Fe2+ [cytosol]
p-S272-ALOX5:Ca2+:Fe2+
ALOX5 (iron, calcium cofactors)
Reactome DB_ID: 265276
1
O-phospho-L-serine at 272
272
EQUAL
2
EQUAL
674
EQUAL
Reactome DB_ID: 71067
1
Reactome DB_ID: 74016
2
Reactome Database ID Release 81
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
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 81
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 81
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
RÃ¥dmark, 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
RÃ¥dmark, 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: 29768
1
Reactome DB_ID: 29368
1
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: 2318769
1
p-S272-ALOX5:Ca2+:Fe2+ [nuclear envelope]
p-S272-ALOX5:Ca2+:Fe2+
ALOX5 (iron, calcium cofactors)
Reactome DB_ID: 2318766
1
Reactome DB_ID: 2318765
1
O-phospho-L-serine at 272
272
EQUAL
2
EQUAL
674
EQUAL
Reactome DB_ID: 2318767
2
Reactome Database ID Release 81
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: 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 81
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: 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 catalyzes 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 81
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 81
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 81
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 81
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
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
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
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
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
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
meclofenamic acid [cytosol]
zileuton [cytosol]
balsalazide [cytosol]
olsalazine [cytosol]
sulfasalazine [cytosol]
Guide to Pharmacology
7219
Guide to Pharmacology
5297
Guide to Pharmacology
11569
Guide to Pharmacology
11578
Guide to Pharmacology
4840
Reactome DB_ID: 2318764
1
Reactome DB_ID: 9707188
1
ALOX5:ALOX5 inhibitors [nuclear envelope]
ALOX5:ALOX5 inhibitors
Converted from EntitySet in Reactome
Reactome DB_ID: 9707237
1
Reactome DB_ID: 2318764
1
Reactome Database ID Release 81
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 81
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
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
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
2877850
Pubmed
1986
Pharmacological and biochemical actions of sulphasalazine
Hoult, J R
Drugs 32:18-26
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
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
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
2864155
Pubmed
1985
Clinical pharmacokinetics of sulphasalazine, its metabolites and other prodrugs of 5-aminosalicylic acid
Klotz, U
Clin Pharmacokinet 10:285-302
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
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
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
15604543
Pubmed
2005
Zileuton, an oral 5-lipoxygenase inhibitor, directly reduces sebum production
Zouboulis, Ch C
Saborowski, A
Boschnakow, A
Dermatology 210:36-8
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
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
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
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2318764
Reactome Database ID Release 81
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: 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 proinflammatory 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 proinflammatory 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 DB_ID: 29426
1
zinc(2+) [ChEBI:29105]
zinc(2+)
ChEBI
29105
Reactome Database ID Release 81
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 81
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 81
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
6490615
Pubmed
1984
Leukotriene A4 hydrolase in human leukocytes. Purification and properties
RÃ¥dmark, O
Shimizu, T
Jörnvall, H
Samuelsson, B
J Biol Chem 259:12339-45
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
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
Reactome DB_ID: 70106
1
Reactome DB_ID: 29364
1
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 81
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 81
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: 70106
1
Reactome DB_ID: 29364
1
Reactome DB_ID: 266056
1
Reactome DB_ID: 29368
1
Reactome DB_ID: 2161636
1
20-hydroxy-leukotriene B4 [ChEBI:15646]
20-hydroxy-leukotriene B4
ChEBI
15646
Reactome DB_ID: 29366
1
Reactome DB_ID: 29356
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 2161611
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 81
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 81
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: 70106
1
Reactome DB_ID: 2161636
1
Reactome DB_ID: 29364
1
Reactome DB_ID: 29368
1
Reactome DB_ID: 2142740
1
20-oxoleukotriene B4 [ChEBI:63979]
20-oxoleukotriene B4
ChEBI
63979
Reactome DB_ID: 29366
1
Reactome DB_ID: 29356
2
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 2161611
GO
0097258
GO molecular function
Reactome Database ID Release 81
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 81
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: 70106
1
Reactome DB_ID: 2142740
1
Reactome DB_ID: 29364
1
Reactome DB_ID: 29368
1
Reactome DB_ID: 2161582
1
20-hydroxy-20-oxoleukotriene B4 [ChEBI:27562]
20-hydroxy-20-oxoleukotriene B4
ChEBI
27562
Reactome DB_ID: 29366
1
Reactome DB_ID: 29356
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 2161611
GO
0097259
GO molecular function
Reactome Database ID Release 81
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 81
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: 70106
1
Reactome DB_ID: 2142740
1
Reactome DB_ID: 29364
1
Reactome DB_ID: 29368
1
Reactome DB_ID: 2161582
1
Reactome DB_ID: 29366
1
Reactome DB_ID: 29356
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2161598
ALDH [cytosol]
ALDH
Aldehyde dehydrogenase
Reactome Database ID Release 81
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 81
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 81
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: 29450
1
Reactome DB_ID: 265281
1
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 81
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 81
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 81
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 81
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
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
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
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 81
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 81
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
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
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
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: 266074
1
Reactome DB_ID: 109276
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 81
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 81
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,12epi-LTB4 [cytosol]
6t-LTB4 [cytosol]
ChEBI
63982
ChEBI
63981
Reactome Database ID Release 81
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 proinflammatory 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 81
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 81
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 81
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 81
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 81
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: 29404
1
Reactome DB_ID: 2142758
1
eoxin D4 [ChEBI:63985]
eoxin D4
ChEBI
63985
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2161915
GGT [cytosol]
GGT
gamma-glutamyltransferase
GO
0097262
GO molecular function
Reactome Database ID Release 81
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 81
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: 2142758
1
Reactome DB_ID: 29356
1
Reactome DB_ID: 29424
1
Reactome DB_ID: 2142730
1
eoxin E4 [ChEBI:63986]
eoxin E4
ChEBI
63986
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2161751
DPEP [cytosol]
DPEP
Dipeptidase
GO
0097263
GO molecular function
Reactome Database ID Release 81
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 81
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 81
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
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
Synthesis of 5-eicosatetraenoic acids
Synthesis of 5-eicosatetraenoic acids
5-hydroperoxy-eicosatetraenoic acid (5-HpETE), 5-hydroxyeicosatetraenoic acid (5S-HETE) and 5-oxo-eicosatetraenoic acid (5-oxoETE) are formed after the initial step of arachidonic acid oxidation by arachidonate 5-lipoxygenase (ALOX5) (Buczynski et al. 2009, Vance & Vance 2008).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
1.11.1.9
5S-HpETE is reduced to 5S-HETE by GPX1/2/4
5S-HpETE is reduced to 5S-HETE by GPX1/2/4
Glutathione peroxidase 1 (GPX1) (Bryant et al. 1982, Sutherland et al. 2001), 2 (GPX2) (Chu et al. 1993), and 4 (Bryant et al. 1982, Sutherland et al. 2001) reduce 5-hydroperoxyeicosatetraenoic acid (5-HpETE) to 5-hydroxyeicosatetraenoic acid (5-HETE) in the presence of glutathione (GSH). This reaction is inferred from the event in rabbit involving the protein GPX1 (Chiba et al. 1999).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 29450
2
Reactome DB_ID: 266010
1
Reactome DB_ID: 2142733
1
5(S)-HETE [ChEBI:28209]
5(S)-HETE
ChEBI
28209
Reactome DB_ID: 29356
1
Reactome DB_ID: 111745
1
glutathione disulfide(2-) [ChEBI:58297]
glutathione disulfide(2-)
glutathione disulfide
(2S,2'S)-5,5'-[disulfanediylbis({(2R)-3-[(carboxylatomethyl)amino]-3-oxopropane-1,2-diyl}imino)]bis(2-azaniumyl-5-oxopentanoate)
glutathione disulfide dianion
ChEBI
58297
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 2161954
GPX1/2/4 [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
L-selenocysteine-residue-GPX4(?-197) [cytosol]
UniProt
P36969
GO
0004602
GO molecular function
Reactome Database ID Release 81
2161908
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=2161908
Reactome Database ID Release 81
2161946
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=2161946
Reactome
R-HSA-2161946
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-2161946.2
8428933
Pubmed
1993
Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GI
Chu, FF
Doroshow, JH
Esworthy, RS
J Biol Chem 268:2571-6
6816802
Pubmed
1982
Role of glutathione peroxidase and hexose monophosphate shunt in the platelet lipoxygenase pathway
Bryant, RW
Simon, TC
Bailey, JM
J Biol Chem 257:14937-43
10549853
Pubmed
1999
Cellular glutathione peroxidase as a predominant scavenger of hydroperoxyeicosatetraenoic acids in rabbit alveolar macrophages
Chiba, N
Imai, H
Narashima, K
Arai, M
Oshima, G
Kunimoto, M
Nakagawa, Y
Biol Pharm Bull 22:1047-51
11115402
Pubmed
2001
Evidence for the presence of phospholipid hydroperoxide glutathione peroxidase in human platelets: implications for its involvement in the regulatory network of the 12-lipoxygenase pathway of arachidonic acid metabolism
Sutherland, M
Shankaranarayanan, P
Schewe, T
Nigam, S
Biochem J 353:91-100
5S-HETE is oxidised to 5-oxoETE by 5-HEDH
5S-HETE is oxidised to 5-oxoETE by 5-HEDH
Current literature suggests that 5S-hydroxy-eicosatetraenoic acid (5S-HETE) itself does not appear to play a significant role in biological signalling. However, it can be further oxidised by a 5-hydroxy-eicosatetraenoic acid dehydrogenase (5-HEDH) to form the bioactive 5-oxo-eicosatetraenoic acid (5-oxoETE, also known as 5-KETE. While the gene has not yet been cloned, the biophysical properties of the human enzyme have been well characterised (Powell et al. 1992).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 2142733
1
Reactome DB_ID: 29366
1
Reactome DB_ID: 70106
1
Reactome DB_ID: 29364
1
Reactome DB_ID: 2161921
1
5-oxo-ETE [ChEBI:52449]
5-oxo-ETE
ChEBI
52449
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2161764
5-HEDH [cytosol]
5-HEDH
5-hydroxy-eicosatetraenoic acid dehydrogenase
GO
0097265
GO molecular function
Reactome Database ID Release 81
2161975
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=2161975
Reactome Database ID Release 81
2161776
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=2161776
Reactome
R-HSA-2161776
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-2161776.2
1326548
Pubmed
1992
Metabolism of 5(S)-hydroxy-6,8,11,14-eicosatetraenoic acid and other 5(S)-hydroxyeicosanoids by a specific dehydrogenase in human polymorphonuclear leukocytes
Powell, WS
Gravelle, F
Gravel, S
J Biol Chem 267:19233-41
3.1.1.81
PON1,2,3:Ca2+ dimers hydrolyse 5-HETEL to 5-HETE
PON1,2,3:Ca2+ dimers hydrolyse 5-HETEL to 5-HETE
Serum paraoxonase/arylesterases 1, 2 and 3 (PON1,2 and 3) are extracellular lactonases/lactonysing enzymes with overlapping, but also distinct substrate specificity. PONs are homodimeric proteins which bind 2 Ca2+ ions per subunit, necessary for enzyme stability and enzymatic activity. All three PONs can efficiently metabolise 5-hydroxy-eicosatetraenoic acid 1,5-lactone (5-HETEL), a product of both enzymatic and nonenzymatic oxidation of arachidonic acid and may represent one of the PONs' endogenous substrates (Draganov et al. 2005).
Authored: Jassal, Bijay, 2016-07-27
Reviewed: D'Eustachio, Peter, 2016-08-12
Edited: Jassal, Bijay, 2016-07-27
Reactome DB_ID: 109276
1
Reactome DB_ID: 8932801
1
meadowlactone [ChEBI:132873]
meadowlactone
ChEBI
132873
Reactome DB_ID: 8932804
1
5-HETE [ChEBI:60943]
5-HETE
5-hydroxy,6E,8Z,11Z,14Z-eicosatetraenoic acid
5-hydroxy-6-trans-8,11,14-cis-eicosatetraenoic acid
(6E,8Z,11Z,14Z)-5-hydroxyeicosa-6,8,11,14-tetraenoic acid
InChI=1S/C20H32O3/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-16-19(21)17-15-18-20(22)23/h6-7,9-10,12-14,16,19,21H,2-5,8,11,15,17-18H2,1H3,(H,22,23)/b7-6-,10-9-,13-12-,16-14+
5-hydroxy-6E,8Z,11Z,14Z-icosatetraenoic acid
5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid
(6E,8Z,11Z,14Z)-5-hydroxyicosa-6,8,11,14-tetraenoic acid
5-OH 6t,8c,11c,14c-20:4
C20H32O3
KGIJOOYOSFUGPC-XTDASVJISA-N
(6E,8Z,11Z,14Z)-5-hydroxy-6,8,11,14-eicosatetraenoic acid
5-hydroxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid
CCCCC\C=C/C\C=C/C\C=C/C=C/C(O)CCCC(O)=O
ChEBI
60943
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 8932645
PON1,2,3:2xCa2+ dimers [extracellular region]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
GO
0102007
GO molecular function
Reactome Database ID Release 81
8932640
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=8932640
Reactome Database ID Release 81
8932633
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=8932633
Reactome
R-HSA-8932633
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-8932633.1
15772423
Pubmed
2005
Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities
Draganov, Dragomir I
Teiber, John F
Speelman, Audrey
Osawa, Yoichi
Sunahara, Roger
La Du, Bert N
J. Lipid Res. 46:1239-47
19082953
Pubmed
2008
Paraoxonases (PON1, PON2, PON3) analyses in vitro and in vivo in relation to cardiovascular diseases
Aviram, Michael
Rosenblat, Mira
Methods Mol. Biol. 477:259-76
Reactome Database ID Release 81
2142688
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=2142688
Reactome
R-HSA-2142688
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-2142688.2
GO
0019372
GO biological process
Synthesis of 15-eicosatetraenoic acid derivatives
Synthesis of 15-eicosatetraenoic acid derivatives
The 15-eicosatetraenoic acids: 15-hydroperoxy-eicosatetraenoic acid (15-HpETE), 15-hydroxyeicosatetraenoic acid (15-HETE) and 15-oxo-eicosatetraenoic acid (15-oxoETE) are formed after the initial step of arachidonic acid oxidation by the arachidonate 15-lipoxygenases (ALOX15 and ALOX15B) (Buczynski et al. 2009, Vance & Vance 2008).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
1.13.11.33
Arachidonic acid is oxidised to 15S-HpETE by ALOX15/15B
Arachidonic acid is oxidised to 15S-HpETE by ALOX15/15B
Arachidonate 15-lipoxygenase (ALOX15) (Gulliksson et al. 2007, Kuhn et al. 1993, Izumi et al. 1991) and arachidonate 15-lipoxygenase B (ALOX15B) (Tang et al. 2002, Wecksler et al. 2008) are lipid peroxidising enzymes mainly expressed in airway epithelial cells, eosinophils, reticulocytes and in macrophages. They insert molecular oxygen at C-6 from the omega-end of arachidonic acid with formation of the unstable intermediate 15S-hydroperoxyeicosatetraenoic acid (15S-HpETE) which can be further converted, enzymatically or non-enzymatically, to 15S-hydroxyeicosatetraenoic acid (15S-HETE).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 29768
1
Reactome DB_ID: 29368
1
Reactome DB_ID: 2142718
1
15(S)-HPETE [ChEBI:15628]
15(S)-HPETE
ChEBI
15628
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 2161783
ALOX15/15B [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
GO
0050473
GO molecular function
Reactome Database ID Release 81
2161832
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=2161832
Reactome Database ID Release 81
2162002
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=2162002
Reactome
R-HSA-2162002
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-2162002.2
18570379
Pubmed
2008
Substrate specificity changes for human reticulocyte and epithelial 15-lipoxygenases reveal allosteric product regulation
Wecksler, AT
Kenyon, V
Deschamps, JD
Holman, TR
Biochemistry 47:7364-75
8334154
Pubmed
1993
Overexpression, purification and characterization of human recombinant 15-lipoxygenase
Kühn, H
Barnett, J
Grunberger, D
Baecker, P
Chow, J
Nguyen, B
Bursztyn-Pettegrew, H
Chan, H
Sigal, E
Biochim Biophys Acta 1169:80-9
17662651
Pubmed
2007
Expression of 15-lipoxygenase type-1 in human mast cells
Gulliksson, M
Brunnström, A
Johannesson, M
Backman, L
Nilsson, G
Harvima, I
Dahlén, B
Kumlin, M
Claesson, HE
Biochim Biophys Acta 1771:1156-65
11839751
Pubmed
2002
Evidence that arachidonate 15-lipoxygenase 2 is a negative cell cycle regulator in normal prostate epithelial cells
Tang, S
Bhatia, B
Maldonado, CJ
Yang, P
Newman, RA
Liu, J
Chandra, D
Traag, J
Klein, RD
Fischer, SM
Chopra, D
Shen, Jinlong
Zhau, HE
Chung, LW
Tang, DG
J Biol Chem 277:16189-201
1662607
Pubmed
1991
Purification of two forms of arachidonate 15-lipoxygenase from human leukocytes
Izumi, T
RÃ¥dmark, O
Jörnvall, H
Samuelsson, B
Eur J Biochem 202:1231-8
1.11.1.9
15S-HpETE is reduced to 15S-HETE by GPX1/2/4
15S-HpETE is reduced to 15S-HETE by GPX1/2/4
Glutathione peroxidases (GPXs) in human platelets (either GPX1, GPX2, or GPX4 are present in the cytosol) are involved in reducing 15S-hydroperoxyeicosatetraenoic acid (15S-HpETE) to 15S-hydroxyeicosatetraenoic acid (15S-HETE) (Hill et al. 1989).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 2142718
1
Reactome DB_ID: 29450
2
Reactome DB_ID: 2142707
1
15(S)-HETE [ChEBI:15558]
15(S)-HETE
ChEBI
15558
Reactome DB_ID: 29356
1
Reactome DB_ID: 111745
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 2161766
GPX1/2/4 [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
Reactome Database ID Release 81
2161937
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=2161937
Reactome Database ID Release 81
2161791
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=2161791
Reactome
R-HSA-2161791
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-2161791.2
2501828
Pubmed
1989
Role of glutathione and glutathione peroxidase in human platelet arachidonic acid metabolism
Hill, TD
White, JG
Rao, GH
Prostaglandins 38:21-32
1.1.1.232
15S-HETE is oxidised to 15-oxoETE by 15-HEDH
15S-HETE is oxidised to 15-oxoETE by 15-HEDH
A 15-hydroxy-eicosatetraenoic acid dehydrogenase (15-HEDH) oxidises 15S-hydroxyeicosatetraenoic acid (15S-HETE) to 15-oxo-eicosatetraenoic acid (15-oxoETE) (Gulliksson et al. 2007). The actual human 15-HEDH has yet to be cloned.
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 2142707
1
Converted from EntitySet in Reactome
Reactome DB_ID: 428218
1
NAD(P)+ [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
NADP+ [cytosol]
NAD+ [cytosol]
Reactome DB_ID: 2142747
1
15-oxo-ETE [ChEBI:15559]
15-oxo-ETE
ChEBI
15559
Reactome DB_ID: 70106
1
Converted from EntitySet in Reactome
Reactome DB_ID: 428206
1
NAD(P)H [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
NADPH [cytosol]
NADH [cytosol]
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2161674
15-HEDH [cytosol]
15-HEDH
15-hydroxy-eicosatetraenoic acid dehydrogenase
GO
0047034
GO molecular function
Reactome Database ID Release 81
2161741
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=2161741
Reactome Database ID Release 81
2161789
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=2161789
Reactome
R-HSA-2161789
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-2161789.2
1.13.11.33
Arachidonic acid is oxidised to 15R-HETE by Acetyl-PTGS2
Arachidonic acid is oxidised to 15R-HETE by Acetyl-PTGS2
Aspirin acetylates the cyclooxygenase, prostaglandin G/H synthase 2 (PTGS2) aka COX2. The acetylated PTGS2 triggers the formation of 15R-hydroxyeicosatetraenoic acid (15R-HETE) from arachidonic acid (Claria & Serhan 1995).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 70106
1
Reactome DB_ID: 29768
1
Reactome DB_ID: 29364
1
Reactome DB_ID: 29368
1
Reactome DB_ID: 2142738
1
15(R)-HETE [ChEBI:63989]
15(R)-HETE
ChEBI
63989
Reactome DB_ID: 29366
1
Reactome DB_ID: 29356
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2314687
Reactome Database ID Release 81
2161919
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=2161919
Reactome Database ID Release 81
2161951
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=2161951
Reactome
R-HSA-2161951
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-2161951.2
7568157
Pubmed
1995
Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions
Clà ria, J
Serhan, Charles N
Proc Natl Acad Sci U S A 92:9475-9
Reactome Database ID Release 81
2142770
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=2142770
Reactome
R-HSA-2142770
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-2142770.1
Synthesis of 12-eicosatetraenoic acid derivatives
Synthesis of 12-eicosatetraenoic acid derivatives
The 12-eicosatetraenoic acids: 12-hydroperoxy-eicosatetraenoic acid (12-HpETE), 12-hydroxyeicosatetraenoic acid (12-HETE) and 12-oxo-eicosatetraenoic acid (12-oxoETE) are formed after the initial step of arachidonic acid oxidation by the arachidonate 12 and 15 lipoxygenases (ALOX12, ALOX12B and ALOX15 respectively). This part of the pathway is bifurcated at the level of 12S-hydroperoxy-eicosatetraenoic acid (12S-HpETE), which can either be reduced to 12S-hydro-eicosatetraenoic acid (12S-HETE) or converted to hepoxilins (Buczynski et al. 2009, Vance & Vance 2008).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
1.13.11.31
Arachidonic acid is oxidised to 12R-HpETE by ALOX12B
Arachidonic acid is oxidised to 12R-HpETE by ALOX12B
The arachidonate 12-lipoxygenase, 12R-type (ALOX12B) oxidises arachidonic acid to 12R-hydroperoxy-eicosatetraenoic acid (12R-HpETE) (Boeglin et al. 1998).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 29768
1
Reactome DB_ID: 29368
1
Reactome DB_ID: 2142790
1
12(R)-HPETE [ChEBI:34145]
12(R)-HPETE
(5Z,8Z,10E,14Z)-(12R)-12-Hydroperoxyicosa-5,8,10,14-tetraenoic acid
(5Z,8Z,10E,14Z)-(12R)-12-Hydroperoxyeicosa-5,8,10,14-tetraenoic acid
ChEBI
34145
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2142822
ALOX12B:Fe2+ [cytosol]
ALOX12B:Fe2+
Reactome DB_ID: 2142832
1
UniProt:O75342 ALOX12B
ALOX12B
ALOX12B
FUNCTION Catalyzes the regio and stereo-specific incorporation of a single molecule of dioxygen into free and esterified polyunsaturated fatty acids generating lipid hydroperoxides that can be further reduced to the corresponding hydroxy species (PubMed:9837935, PubMed:9618483, PubMed:21558561). In the skin, acts upstream of ALOXE3 on the lineolate moiety of esterified omega-hydroxyacyl-sphingosine (EOS) ceramides to produce an epoxy-ketone derivative, a crucial step in the conjugation of omega-hydroxyceramide to membrane proteins (PubMed:21558561). Therefore plays a crucial role in the synthesis of corneocytes lipid envelope and the establishment of the skin barrier to water loss (PubMed:21558561). May also play a role in the regulation of the expression of airway mucins (PubMed:22441738).ACTIVITY REGULATION Increased by calcium.PATHWAY Lipid metabolism; hydroperoxy eicosatetraenoic acid biosynthesis.PATHWAY Lipid metabolism; sphingolipid metabolism.TISSUE SPECIFICITY Expressed in B-cells, hair follicles, foreskin keratinocytes and adult skin. Also expressed in psoriatic tissue.SIMILARITY Belongs to the lipoxygenase family.
UniProt
O75342
1
EQUAL
701
EQUAL
Reactome DB_ID: 71067
1
Reactome Database ID Release 81
2142822
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=2142822
Reactome
R-HSA-2142822
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-2142822.1
GO
0004052
GO molecular function
Reactome Database ID Release 81
2161752
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=2161752
Reactome Database ID Release 81
2161950
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=2161950
Reactome
R-HSA-2161950
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-2161950.2
9618483
Pubmed
1998
A 12R-lipoxygenase in human skin: mechanistic evidence, molecular cloning, and expression
Boeglin, WE
Kim, RB
Brash, AR
Proc Natl Acad Sci U S A 95:6744-9
1.11.1.9
12R-HpETE is reduced to 12R-HETE by GPX1/2/4
12R-HpETE is reduced to 12R-HETE by GPX1/2/4
Glutathione peroxidase 1 (GPX1) (Bryant et al. 1982, Sutherland et al. 2001), 2 (GPX2) (Chu et al. 1993), and 4 (Bryant et al. 1982, Sutherland et al. 2001) are involved in converting 12R-hydroperoxy-eicosatetraenoic acid (12R-HpETE) to 12R-hydro-eicosatetraenoic acid (12R-HETE).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 2142790
1
Reactome DB_ID: 29450
2
Reactome DB_ID: 2142716
1
12(R)-HETE [ChEBI:34144]
12(R)-HETE
12R-HETE
12(R)-hydroxyeicosatetraenoic acid
(5Z,8Z,10E,12R,14Z)-12-hydroxyeicosa-5,8,10,14-tetraenoic acid
(5Z,8Z,10E,14Z)-(12R)-12-Hydroxyicosa-5,8,10,14-tetraenoic acid
(5Z,8Z,10E,14Z)-(12R)-12-Hydroxyeicosa-5,8,10,14-tetraenoic acid
12(R)-hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic acid
(5Z,8Z,10E,12R,14Z)-12-hydroxy-5,8,10,14-eicosatetraenoic acid
12(R)-hydroxy-5,8,14-cis-10-trans-eicosatetraenoic acid
ChEBI
34144
Reactome DB_ID: 29356
1
Reactome DB_ID: 111745
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 2161954
Reactome Database ID Release 81
2161959
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=2161959
Reactome
R-HSA-2161959
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-2161959.2
ALOXE3 isomerises 12R-HpETE to HXA3
ALOXE3 isomerises 12R-HpETE to HXA3
Hydroperoxide isomerase (ALOXE3, e-LOX-3) is a non-heme iron-containing lipoxygenase which is atypical in that it displays a prominent hydroperoxide isomerase activity and a reduced dioxygenase activity compared to other lipoxygenases. The hydroperoxide isomerase activity catalyses the isomerisation of hydroperoxides, derived from arachidonic and linoleic acid by ALOX12B, into epoxyalcohols (Yu et al. 2003).<br>In the skin, ALOXE3 acts downstream of ALOX12B on the linoleate moiety of esterified omega-hydroxyacyl-sphingosine (EOS) ceramides to produce an epoxy-ketone derivative, a crucial step in the conjugation of omega-hydroxyceramide to membrane proteins, important for the maintenance of the skin permeability barrier and protection against water loss. Loss-of-function mutations in ALOX12B and ALOXE3 represent the second most common cause of autosomal recessive congenital ichthyosis, a hereditary disorder of keratinization (Yu et al. 2005, Wang et al. 2015). Targeted disruption of these genes in mice resulted in neonatal death due to a severely impaired permeability barrier function (Zheng et al. 2011).
Authored: Jassal, Bijay, 2016-10-11
Reviewed: D'Eustachio, Peter, 2017-01-06
Edited: Jassal, Bijay, 2016-10-11
Reactome DB_ID: 2142790
1
Reactome DB_ID: 8942209
1
hepoxilin A3 [ChEBI:36190]
hepoxilin A3
ChEBI
36190
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 8942204
UniProt:Q9BYJ1 ALOXE3
ALOXE3
ALOXE3
FUNCTION Non-heme iron-containing lipoxygenase which is atypical in that it displays a prominent hydroperoxide isomerase activity and a reduced lipoxygenases activity (PubMed:12881489, PubMed:17045234, PubMed:20921226, PubMed:20923767). The hydroperoxide isomerase activity catalyzes the isomerization of hydroperoxides, derived from arachidonic and linoleic acid by ALOX12B, into hepoxilin-type epoxyalcohols and ketones (PubMed:12881489, PubMed:17045234, PubMed:20923767). In presence of oxygen, oxygenates polyunsaturated fatty acids, including arachidonic acid, to produce fatty acid hydroperoxides (PubMed:20921226). In the skin, acts downstream of ALOX12B on the linoleate moiety of esterified omega-hydroxyacyl-sphingosine (EOS) ceramides to produce an epoxy-ketone derivative, a crucial step in the conjugation of omega-hydroxyceramide to membrane proteins (PubMed:21558561). Therefore plays a crucial role in the synthesis of corneocytes lipid envelope and the establishment of the skin barrier to water loss (PubMed:21558561). In parallel, it may have a signaling function in barrier formation through the production of hepoxilins metabolites (PubMed:21558561). Plays also a role in adipocyte differentiation through hepoxilin A3 and hepoxilin B3 production which in turn activate PPARG (By similarity). Through the production of hepoxilins in the spinal cord, it may regulate inflammatory tactile allodynia (By similarity).ACTIVITY REGULATION Lipoxygenase activity is activated by 13(S)-HPODE leading to an active free ferric enzyme (PubMed:20921226). The lipoxygenase and hydroperoxide isomerase activities are in competition and are reciprocally regulated by oxygen (PubMed:20923767). The oxygen reacts with an epoxyallylic radical intermediate leading to an epoxyallylic peroxyl radical, which, due to its limited reactivity within the enzyme active site, it dissociates and leaves the enzyme in the activated free ferric state (PubMed:20923767).PATHWAY Lipid metabolism; hydroperoxy eicosatetraenoic acid biosynthesis.PATHWAY Lipid metabolism; sphingolipid metabolism.TISSUE SPECIFICITY Predominantly expressed in skin.SIMILARITY Belongs to the lipoxygenase family.
UniProt
Q9BYJ1
1
EQUAL
711
EQUAL
GO
0051120
GO molecular function
Reactome Database ID Release 81
8942207
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=8942207
Reactome Database ID Release 81
8942208
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=8942208
Reactome
R-HSA-8942208
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-8942208.1
15629692
Pubmed
2005
Mutations associated with a congenital form of ichthyosis (NCIE) inactivate the epidermal lipoxygenases 12R-LOX and eLOX3
Yu, Zheyong
Schneider, Claus
Boeglin, William E
Brash, Alan R
Biochim. Biophys. Acta 1686:238-47
21558561
Pubmed
2011
Lipoxygenases mediate the effect of essential fatty acid in skin barrier formation: a proposed role in releasing omega-hydroxyceramide for construction of the corneocyte lipid envelope
Zheng, Yuxiang
Yin, Huiyong
Boeglin, William E
Elias, Peter M
Crumrine, Debra
Beier, David R
Brash, Alan R
J. Biol. Chem. 286:24046-56
12881489
Pubmed
2003
The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a hydroperoxide isomerase
Yu, Zheyong
Schneider, Claus
Boeglin, William E
Marnett, Lawrence J
Brash, Alan R
Proc. Natl. Acad. Sci. U.S.A. 100:9162-7
26370990
Pubmed
2015
Homozygous ALOXE3 Nonsense Variant Identified in a Patient with Non-Bullous Congenital Ichthyosiform Erythroderma Complicated by Superimposed Bullous Majocchi's Granuloma: The Consequences of Skin Barrier Dysfunction
Wang, Tao
Xu, Chenchen
Zhou, Xiping
Li, Chunjia
Zhang, Hongbing
Lian, Bill Q
Lee, Jonathan J
Shen, Jun
Liu, Yuehua
Lian, Christine Guo
Int J Mol Sci 16:21791-801
1.13.11.31
Arachidonic acid is oxidised to 12S-HpETE by ALOX12/15
Arachidonic acid is oxidised to 12S-HpETE by ALOX12/15
Arachidonate 12-lipoxygenase, 12S-type (ALOX12) (Funk et al. 1990, Izumi et al. 1990) and arachidonate 15-lipoxygenase (ALOX15) (Kuhn et al. 1993, Sigal et al. 1990) convert arachidonic acid into 12S-hydroperoxy-eicosatetraenoic acid (12S-HpETE).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 29768
1
Reactome DB_ID: 29368
1
Reactome DB_ID: 2142811
1
12(S)-HPETE [ChEBI:15626]
12(S)-HPETE
ChEBI
15626
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 2161958
ALOX12/15 [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
Reactome Database ID Release 81
2162014
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=2162014
Reactome Database ID Release 81
2161964
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=2161964
Reactome
R-HSA-2161964
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-2161964.2
2377602
Pubmed
1990
Molecular cloning, primary structure, and expression of the human platelet/erythroleukemia cell 12-lipoxygenase
Funk, CD
Furci, L
FitzGerald, GA
Proc Natl Acad Sci U S A 87:5638-42
2217179
Pubmed
1990
Cloning of the cDNA for human 12-lipoxygenase
Izumi, T
Hoshiko, S
RÃ¥dmark, O
Samuelsson, B
Proc Natl Acad Sci U S A 87:7477-81
2318885
Pubmed
1990
Expression of cloned human reticulocyte 15-lipoxygenase and immunological evidence that 15-lipoxygenases of different cell types are related
Sigal, E
Grunberger, D
Highland, E
Gross, C
Dixon, RA
Craik, CS
J Biol Chem 265:5113-20
1.11.1.9
12S-HpETE is reduced to 12S-HETE by GPX1/2/4
12S-HpETE is reduced to 12S-HETE by GPX1/2/4
Glutathione peroxidase 1 (GPX1) (Bryant et al. 1982, Sutherland et al. 2001), 2 (GPX2) (Chu et al. 1993), and 4 (Bryant et al. 1982, Sutherland et al. 2001) are involved in converting 12S-hydroperoxy-eicosatetraenoic acid (12S-HpETE) to 12S-hydro-eicosatetraenoic acid (12S-HETE). GPXs are selenoenzymes that are responsible for reducing the cellular peroxide. Cellular GPXs compete with hepoxilins A3 (HXA3) synthase for 12S-HpETE as substrate either to produce 12S-HETE or to convert to HXA3, respectively.
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 29450
2
Reactome DB_ID: 2142811
1
Reactome DB_ID: 2142678
1
12(S)-HETE [ChEBI:34146]
12(S)-HETE
(12S)-12-hydroxy-5,8,14-cis-10-trans-eicosatetraenoic acid
(5Z,8Z,10E,14Z)-(12S)-12-Hydroxyicosa-5,8,10,14-tetraenoic acid
12(S)-hydroxy-5,8,14(Z),10(E)-eicosatetraenoic acid
12(S)-hydroxyeicosatetraenoic acid
12S-HETE
12(S)-hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic acid
(5Z,8Z,10E,14Z)-(12S)-12-Hydroxyeicosa-5,8,10,14-tetraenoic acid
(5Z,8Z,10E,12S,14Z)-12-hydroxyeicosa-5,8,10,14-tetraenoic acid
ChEBI
34146
Reactome DB_ID: 29356
1
Reactome DB_ID: 111745
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 2161954
Reactome Database ID Release 81
2161999
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=2161999
Reactome
R-HSA-2161999
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-2161999.2
1.13.11.31
Arachidonic acid is converted to 12-oxoETE by ALOX12
Arachidonic acid is converted to 12-oxoETE by ALOX12
Arachidonate 12-lipoxygenase, 12S-type (ALOX12) catalyses the formation of 12-oxo-eicosatetraenoic acid (12-oxoETE) from arachidonic acid. This conversion has been observed when normal human epidermis is exposed to arachidonic acid and with the purified recombinant enzyme in vitro (Anton & Vila 2000).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 29768
1
Reactome DB_ID: 2142745
1
12-oxo-ETE [ChEBI:34151]
12-oxo-ETE
(5Z,8Z,10E,14Z)-12-Oxoicosa-5,8,10,14-tetraenoic acid
12-ketoeicosatetraenoic acid
12-OxoETE
(5Z,8Z,10E,14Z)-12-Oxoeicosa-5,8,10,14-tetraenoic acid
12-keto-ETE
12-KETE
12-oxo, 5c,8c,10t,14c-20:4
(5Z,8Z,10E,14Z)-12-oxoeicosa-5,8,10,14-tetraenoic acid
ChEBI
34151
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2142793
ALOX12:Fe2+ [cytosol]
ALOX12:Fe2+
Reactome DB_ID: 71067
1
Reactome DB_ID: 2142768
1
UniProt:P18054 ALOX12
ALOX12
12LO
LOG12
ALOX12
FUNCTION Catalyzes the regio and stereo-specific incorporation of molecular oxygen into free and esterified polyunsaturated fatty acids generating lipid hydroperoxides that can be further reduced to the corresponding hydroxy species (PubMed:17493578, PubMed:1851637, PubMed:8319693, PubMed:8500694, PubMed:18311922, PubMed:32404334). Mainly converts arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) to the specific bioactive lipid (12S)-hydroperoxyeicosatetraenoate/(12S)-HPETE (PubMed:17493578, PubMed:22984144, PubMed:24282679, PubMed:8319693, PubMed:8500694). Through the production of bioactive lipids like (12S)-HPETE it regulates different biological processes including platelet activation (PubMed:8319693, PubMed:8500694). It can also catalyze the epoxidation of double bonds of polyunsaturated fatty acids such as (14S)-hydroperoxy-docosahexaenoate/(14S)-HPDHA resulting in the formation of (13S,14S)-epoxy-DHA (PubMed:23504711). Furthermore, it 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). An additional function involves a multistep process by which it transforms leukotriene A4/LTA4 into the bioactive lipids lipoxin A4/LXA4 and lipoxin B4/LXB4, both are vasoactive and LXA4 may regulate neutrophil function via occupancy of specific recognition sites (PubMed:8250832). Can also peroxidize linoleate ((9Z,12Z)-octadecadienoate) to (13S)-hydroperoxyoctadecadienoate/ (13S-HPODE) (By similarity). Due to its role in regulating both the expression of the vascular endothelial growth factor (VEGF, an angiogenic factor involved in the survival and metastasis of solid tumors) and the expression of integrin beta-1 (known to affect tumor cell migration and proliferation), it can be regarded as protumorigenic (PubMed:9751607, PubMed:16638750, PubMed:22237009). Important for cell survival, as it may play a role not only in proliferation but also in the prevention of apoptosis in vascular smooth muscle cells (PubMed:23578768).ACTIVITY REGULATION Activated by EGF (PubMed:8912711). Arachidonic acid conversion is inhibited by (13S,14S)-epoxy-(4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoate (13S,14S-epoxy-DHA) (PubMed:23504711). Arachidonate 12-lipoxygenase activity is decreased when PH decreases from 7.4 to 6 (By similarity).PATHWAY Lipid metabolism; hydroperoxy eicosatetraenoic acid biosynthesis.TISSUE SPECIFICITY Expressed in vascular smooth muscle cells.INDUCTION Down-regulated upon starvation, by UV-irradiation and 15-lipoxygenase metabolites.SIMILARITY Belongs to the lipoxygenase family.
UniProt
P18054
2
EQUAL
663
EQUAL
Reactome Database ID Release 81
2142793
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=2142793
Reactome
R-HSA-2142793
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-2142793.1
Reactome Database ID Release 81
2161926
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=2161926
Reactome Database ID Release 81
2161948
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=2161948
Reactome
R-HSA-2161948
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-2161948.2
10692117
Pubmed
2000
Stereoselective biosynthesis of hepoxilin B3 in human epidermis
Antón, R
Vila, L
J Invest Dermatol 114:554-9
Reactome Database ID Release 81
2142712
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=2142712
Reactome
R-HSA-2142712
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-2142712.2
Synthesis of Hepoxilins (HX) and Trioxilins (TrX)
Synthesis of Hepoxilins (HX) and Trioxilins (TrX)
Hepoxilins are biologically relevant signalling molecules produced by certain arachidonate 12-lipoxygenase (ALOX12s). Hepoxilin A3 (HXA3) and B3 (HXB3) have been identified, both of which incorporate an epoxide across the C-11 and C-12 double bond, as well as an additional hydroxyl moiety. HXA3 has a C-8 hydroxyl, whereas the HXB3 hydroxyl occurs at C-10. The epoxy moiety is labile and can be hydrolyzed either by a hepoxilin specific epoxide hydrolase (HXEH) or in acidic aqueous solution to form the corresponding diol metabolites trioxilin A3 (TrXA3) and B3 (TrXB3) (Buczynski et al. 2009, Vance & Vance 2008).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Arachidonic acid is converted to HXA3/B3 by ALOX12
Arachidonic acid is converted to HXA3/B3 by ALOX12
Arachidonate 12-lipoxygenase, 12S-type (ALOX12) converts arachidonic acid to both hepoxilin A3 (HXA3) and B3 (HXB3). They both incorporate an epoxide across the C-11 and C-12 double bond, as well as an additional hydroxyl moiety with HXA3 having a C-8 hydroxyl, whereas the HXB3 hydroxyl occurs at C-10 (Sutherland et al. 2001, Nigam et al. 2004).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 29768
1
Reactome DB_ID: 29368
1
Converted from EntitySet in Reactome
Reactome DB_ID: 2162031
1
HXA3/B3 [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
HXA3 [cytosol]
HXB3 [cytosol]
ChEBI
34784
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2142793
Reactome Database ID Release 81
2161887
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=2161887
Reactome Database ID Release 81
2161794
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=2161794
Reactome
R-HSA-2161794
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-2161794.2
15123652
Pubmed
2004
The rat leukocyte-type 12-lipoxygenase exhibits an intrinsic hepoxilin A3 synthase activity
Nigam, S
Patabhiraman, S
Ciccoli, R
Ishdorj, G
Schwarz, K
Petrucev, B
Kühn, H
Haeggström, Jesper Z
J Biol Chem 279:29023-30
3.3.2.7
HXA3/B3 is hydrolysed to TrXA3/B3 by HXEH
HXA3/B3 is hydrolysed to TrXA3/B3 by HXEH
The epoxy moiety of hepoxilin A3 (HXA3) and B3 (HXB3) is labile and can be hydrolysed either by a hepoxilin specific epoxide hydrolase (HXEH) or in acidic aqueous solution to form the corresponding diol metabolites trioxilin A3 (TrXA3) and B3 (TrXB3) (Anton et al. 1995, Anton et al. 1998, Pace-Asciak et al. 1983, Pace-Asciak & Lee 1989).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 29356
1
Converted from EntitySet in Reactome
Reactome DB_ID: 2162031
1
Converted from EntitySet in Reactome
Reactome DB_ID: 2161985
1
TrXA3/B3 [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
TrXA3 [cytosol]
TrXB3 [cytosol]
ChEBI
15630
ChEBI
35032
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2161957
HXEH [cytosol]
HXEH
hepoxilin specific epoxide hydrolase
GO
0047977
GO molecular function
Reactome Database ID Release 81
2161802
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=2161802
Reactome Database ID Release 81
2161949
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=2161949
Reactome
R-HSA-2161949
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-2161949.2
6406490
Pubmed
1983
Arachidonic acid epoxides. Isolation and structure of two hydroxy epoxide intermediates in the formation of 8,11,12- and 10,11,12-trihydroxyeicosatrienoic acids
Pace-Asciak, CR
Granström, E
Samuelsson, B
J Biol Chem 258:6835-40
8829479
Pubmed
1995
Characterization of arachidonic acid metabolites through the 12-lipoxygenase pathway in human epidermis by high-performance liquid chromatography and gas chromatography/mass spectrometry
Antón, R
Abián, J
Vila, L
Rapid Commun Mass SpectromS169-82
2722835
Pubmed
1989
Purification of hepoxilin epoxide hydrolase from rat liver
Pace-Asciak, CR
Lee, WS
J Biol Chem 264:9310-3
9540966
Pubmed
1998
Occurrence of hepoxilins and trioxilins in psoriatic lesions
Antón, R
Puig, L
Esgleyes, T
de Moragas, JM
Vila, L
J Invest Dermatol 110:303-10
Reactome Database ID Release 81
2142696
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=2142696
Reactome
R-HSA-2142696
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-2142696.1
GO
0051121
GO biological process
Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE)
Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE)
Similar to the lipoxygenases, cytochrome P450 (CYP) enzymes catalyse the hydroxylation and epoxygenation of arachidonic acid. However, whereas lipoxygenases use an active non-heme iron to abstract hydrogen directly from arachidonic acid, CYPs contain a heme-iron active site that oxidizes its substrate by a different mechanism. They hydroxylate arachidonic acid between C-5 and C-15 to produce lipoxygenase-like hydroxyeicosatetraenoic acids (HETEs) and add a hydroxyl moiety to the sp3-hybridized omega-carbons to form a unique class of HETEs. The transfer of oxygen to the unstable arachidonic acid intermediate terminates the reaction by forming HETE or epoxy-eicosatrienoic acid (EETs), respectively (Capdevila et al. 2000, Buczynski et al. 2009, Vance & Vance 2008).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Arachidonic acid is hydroxylated to 16/17/18-HETE by CYP(1)
Arachidonic acid is hydroxylated to 16/17/18-HETE by CYP(1)
Cytochrome P450s 1A1 (CYP1A1), 1A2 (CYP1A2), and 1B1 (CYP1B1) convert arachidonic acid to 16-, 17-, and 18-hydroxyeicosatetraenoic acids (16-, 17-, and 18-HETEs) (Choudhary et al. 2004).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 113601
1
NADPH [ChEBI:16474]
NADPH
TPNH
ChEBI
16474
Reactome DB_ID: 140356
1
Reactome DB_ID: 156540
1
Reactome DB_ID: 113534
1
Reactome DB_ID: 113564
1
NADP(+) [ChEBI:18009]
NADP(+)
ChEBI
18009
Reactome DB_ID: 113519
1
Converted from EntitySet in Reactome
Reactome DB_ID: 2161639
1
16/17/18-HETE [endoplasmic reticulum lumen]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
18-HETE [endoplasmic reticulum lumen]
17-HETE [endoplasmic reticulum lumen]
16-HETE [endoplasmic reticulum lumen]
ChEBI
63579
ChEBI
63995
ChEBI
63994
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 2162028
CYP(1) [endoplasmic reticulum membrane]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
CYP1A2 [endoplasmic reticulum membrane]
CYP1A1 [endoplasmic reticulum membrane]
CYP1B1 [endoplasmic reticulum membrane]
UniProt
P05177
UniProt
P04798
UniProt
Q16678
GO
0004497
GO molecular function
Reactome Database ID Release 81
2161998
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=2161998
Reactome Database ID Release 81
2161795
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=2161795
Reactome
R-HSA-2161795
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-2161795.2
15258110
Pubmed
2004
Metabolism of retinoids and arachidonic acid by human and mouse cytochrome P450 1b1
Choudhary, D
Jansson, I
Stoilov, I
Sarfarazi, M
Schenkman, JB
Drug Metab Dispos 32:840-7
Arachidonic acid is hydroxylated to 19-HETE by CYP(2)
Arachidonic acid is hydroxylated to 19-HETE by CYP(2)
Several cytochrome P450s (CYPs) convert arachidonic acid to 19-hydroxyeicosatetraenoic acid (19-HETE). The CYPs and their references are as follows: CYP2C8 (Bylund et al. 1998); CYP2C9 (Bylund et al. 1998); CYP2C19 (Bylund et al. 1998); CYP4A11 (Gainer et al. 2005); CYP2U1 (Chuang et al. 2004); CYP1A1, CYP1A2, CYP1B1 (Choudhary et al. 2004).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 113601
1
Reactome DB_ID: 140356
1
Reactome DB_ID: 156540
1
Reactome DB_ID: 113534
1
Reactome DB_ID: 2142836
1
19-HETE [ChEBI:63998]
19-HETE
ChEBI
63998
Reactome DB_ID: 113564
1
Reactome DB_ID: 113519
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 2161767
CYP(2) [endoplasmic reticulum membrane]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
CYP4A11 [endoplasmic reticulum membrane]
CYP1A2 [endoplasmic reticulum membrane]
CYP2C9 [endoplasmic reticulum membrane]
CYP2C8 [endoplasmic reticulum membrane]
CYP2C19 [endoplasmic reticulum membrane]
CYP1A1 [endoplasmic reticulum membrane]
CYP1B1 [endoplasmic reticulum membrane]
CYP2U1 [endoplasmic reticulum membrane]
UniProt
Q02928
UniProt
P11712
UniProt
P10632
UniProt
P33261
UniProt
Q7Z449
Reactome Database ID Release 81
2162026
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=2162026
Reactome Database ID Release 81
2161814
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=2161814
Reactome
R-HSA-2161814
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-2161814.2
14660610
Pubmed
2004
CYP2U1, a novel human thymus- and brain-specific cytochrome P450, catalyzes omega- and (omega-1)-hydroxylation of fatty acids
Chuang, SS
Helvig, C
Taimi, M
Ramshaw, HA
Collop, AH
Amad, M
White, JA
Petkovich, M
Jones, G
Korczak, B
J Biol Chem 279:6305-14
9435160
Pubmed
1998
Cytochromes P450 with bisallylic hydroxylation activity on arachidonic and linoleic acids studied with human recombinant enzymes and with human and rat liver microsomes
Bylund, J
Kunz, T
Valmsen, K
Oliw, EH
J Pharmacol Exp Ther 284:51-60
15611369
Pubmed
2005
Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension
Gainer, JV
Bellamine, A
Dawson, EP
Womble, KE
Grant, SW
Wang, Y
Cupples, LA
Guo, CY
Demissie, S
O'Donnell, CJ
Brown, NJ
Waterman, MR
Capdevila, JH
Circulation 111:63-9
Arachidonic acid is hydroxylated to 20-HETE by CYP(3)
Arachidonic acid is hydroxylated to 20-HETE by CYP(3)
Several cytochrome P450s (CYPs) convert arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE). The CYPs and their references are as follows: CYP4A11 (Gainer et al. 2005, Powell 1998); CYP4F2 (Powell et al. 1998, Kikuta et al. 2002); CYP2U1 (Chuang et al. 2004); CYP1A1, CYP1A2, CYP1B1 (Choudhary et al. 2004).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 113601
1
Reactome DB_ID: 140356
1
Reactome DB_ID: 156540
1
Reactome DB_ID: 113534
1
Reactome DB_ID: 113564
1
Reactome DB_ID: 113519
1
Reactome DB_ID: 2142780
1
20-HETE [ChEBI:34306]
20-HETE
20-Hydroxyicosatetraenoic acid
20-Hydroxyeicosatetraenoic acid
(5Z,8Z,11Z,14Z)-20-Hydroxyicosa-5,8,11,14-tetraenoic acid
20-Hydroxy arachidonic acid
ChEBI
34306
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 2161816
CYP(3) [endoplasmic reticulum membrane]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
CYP4A11 [endoplasmic reticulum membrane]
CYP1A2 [endoplasmic reticulum membrane]
CYP4F2 [endoplasmic reticulum membrane]
CYP1A1 [endoplasmic reticulum membrane]
CYP1B1 [endoplasmic reticulum membrane]
CYP2U1 [endoplasmic reticulum membrane]
Reactome Database ID Release 81
2161836
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=2161836
Reactome Database ID Release 81
2161940
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=2161940
Reactome
R-HSA-2161940
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-2161940.2
12432928
Pubmed
2002
Prostaglandin and leukotriene omega-hydroxylases
Kikuta, Y
Kusunose, E
Kusunose, M
Prostaglandins Other Lipid Mediat 68:345-62
9618440
Pubmed
1998
Metabolism of arachidonic acid to 20-hydroxy-5,8,11, 14-eicosatetraenoic acid by P450 enzymes in human liver: involvement of CYP4F2 and CYP4A11
Powell, PK
Wolf, I
Jin, R
Lasker, JM
J Pharmacol Exp Ther 285:1327-36
Reactome Database ID Release 81
2142816
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=2142816
Reactome
R-HSA-2142816
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-2142816.1
10681399
Pubmed
2000
Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenase
Capdevila, JH
Falck, JR
Harris, RC
J Lipid Res 41:163-81
GO
0097267
GO biological process
Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET)
Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET)
The epoxidation of arachidonic acid by cytochrome P450s (CYPs) results in the formation of unique bioactive lipid mediators termed epoxyeicosatrienoic acids (EETs). Each double bond has been shown to be susceptible to oxidation, resulting in 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET. The majority of the EET biological activities are diminished by the hydrolysis to the corresponding dihydroxyeicosatrienoic acids (DHET) (Capdevila et al. 2000, Buczynski et al. 2009, Vance & Vance 2008).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Arachidonic acid is epoxidated to 5,6-EET by CYP(4)
Arachidonic acid is epoxidated to 5,6-EET by CYP(4)
Several cytochrome P450s (CYPs) convert arachidonic acid to 5,6-epoxyeicosatrienoic acid (5,6-EET). The CYPs and their references are as follows: CYP1A1, CYP1A2, CYP1B1 (Choudhary et al. 2004); CYP2J2 (Wu et al. 1996).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 70106
1
Reactome DB_ID: 29768
1
Reactome DB_ID: 29364
1
Reactome DB_ID: 29368
1
Reactome DB_ID: 2142739
1
5,6-EET [ChEBI:34450]
5,6-EET
ChEBI
34450
Reactome DB_ID: 29366
1
Reactome DB_ID: 29356
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 2161805
CYP(4) [endoplasmic reticulum membrane]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
CYP1A2 [endoplasmic reticulum membrane]
CYP2J2 [endoplasmic reticulum membrane]
CYP1A1 [endoplasmic reticulum membrane]
CYP1B1 [endoplasmic reticulum membrane]
UniProt
P51589
Reactome Database ID Release 81
2161927
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=2161927
Reactome Database ID Release 81
2161890
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=2161890
Reactome
R-HSA-2161890
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-2161890.2
8631948
Pubmed
1996
Molecular cloning and expression of CYP2J2, a human cytochrome P450 arachidonic acid epoxygenase highly expressed in heart
Wu, S
Moomaw, CR
Tomer, KB
Falck, JR
Zeldin, DC
J Biol Chem 271:3460-8
Arachidonic acid is epoxidated to 8,9/11,12/14,15-EET by CYP(5)
Arachidonic acid is epoxidated to 8,9/11,12/14,15-EET by CYP(5)
Several cytochrome P450s (CYPs) convert arachidonic acid to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (8,9-, 11,12-, 14,15-EETs). The CYPs and their references are as follows: CYP1A1, CYP1A2, CYP1B1 (Choudhary et al. 2004); CYP2C8, CYP2C9 (Rifkind et al. 1995); CYP2C19 (Bylund et al. 1998, Rifkind et al. 1995); CYP2J2 (Wu et al. 1996).
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Reactome DB_ID: 70106
1
Reactome DB_ID: 29768
1
Reactome DB_ID: 29364
1
Reactome DB_ID: 29368
1
Converted from EntitySet in Reactome
Reactome DB_ID: 2161753
1
8,9/11,12/14,15-EET [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
8,9-EET [cytosol]
11,12-EET [cytosol]
14,15-EET [cytosol]
ChEBI
34490
ChEBI
34130
ChEBI
34157
Reactome DB_ID: 29366
1
Reactome DB_ID: 29356
1
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Converted from EntitySet in Reactome
Reactome DB_ID: 2161990
CYP(5) [endoplasmic reticulum membrane]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
CYP1A2 [endoplasmic reticulum membrane]
CYP2C9 [endoplasmic reticulum membrane]
CYP2J2 [endoplasmic reticulum membrane]
CYP2C8 [endoplasmic reticulum membrane]
CYP2C19 [endoplasmic reticulum membrane]
CYP1A1 [endoplasmic reticulum membrane]
CYP1B1 [endoplasmic reticulum membrane]
Reactome Database ID Release 81
2161882
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=2161882
Reactome Database ID Release 81
2161899
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=2161899
Reactome
R-HSA-2161899
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-2161899.2
9866708
Pubmed
1998
Analysis of cytochrome P450 metabolites of arachidonic and linoleic acids by liquid chromatography-mass spectrometry with ion trap MS
Bylund, J
Ericsson, J
Oliw, EH
Anal Biochem 265:55-68
7625847
Pubmed
1995
Arachidonic acid metabolism by human cytochrome P450s 2C8, 2C9, 2E1, and 1A2: regioselective oxygenation and evidence for a role for CYP2C enzymes in arachidonic acid epoxygenation in human liver microsomes
Rifkind, AB
Lee, C
Chang, TK
Waxman, DJ
Arch Biochem Biophys 320:380-9
3.3.2.10
EET(1) is hydrolysed to DHET(1) by EPHX2
EET(1) is hydrolysed to DHET(1) by EPHX2
Epoxide hydrolase 2 (EPHX2) hydrolyses 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids ("EET(1)") to their corresponding dihydroxyeicosatrienoic acids ("DHET(1)") (Werner et al. 2002; Gomez et al. 2004). The majority of the EET biological activities are diminished by this hydrolysis.
Authored: Williams, MG, 2012-02-24
Reviewed: Rush, MG, 2012-11-10
Edited: Williams, MG, 2012-02-24
Converted from EntitySet in Reactome
Reactome DB_ID: 2161818
1
EET(1) [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
8,9-EET [cytosol]
5,6-EET [cytosol]
11,12-EET [cytosol]
14,15-EET [cytosol]
Reactome DB_ID: 29356
1
Converted from EntitySet in Reactome
Reactome DB_ID: 2161883
1
DHET(1) [cytosol]
Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity
5,6-DHET [cytosol]
(5Z,8Z,14Z)-11,12-dihydroxyicosatrienoic acid [cytosol]
(5Z,8Z,11Z)-14,15-dihydroxyicosatrienoic acid [cytosol]
(5Z,11Z,14Z)-8,9-dihydroxyicosatrienoic acid [cytosol]
ChEBI
63974
ChEBI
63969
ChEBI
63966
ChEBI
63970
PHYSIOL-LEFT-TO-RIGHT
ACTIVATION
Reactome DB_ID: 2142777
EPHX2 dimer [cytosol]
EPHX2 dimer
Reactome DB_ID: 2142819
2
UniProt:P34913 EPHX2
EPHX2
EPHX2
FUNCTION Bifunctional enzyme (PubMed:12574510). The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides (PubMed:12869654, PubMed:12574510, PubMed:22798687). Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides (By similarity). Also determines steady-state levels of physiological mediators (PubMed:12869654, PubMed:12574510, PubMed:22798687, PubMed:21217101).FUNCTION Bifunctional enzyme (PubMed:12574510). The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid and 12-phosphonooxy-octadec-9E-enoic acid (PubMed:12574510). Has phosphatase activity toward lyso-glycerophospholipids with also some lower activity toward lysolipids of sphingolipid and isoprenoid phosphates (PubMed:22217705, PubMed:22387545).ACTIVITY REGULATION Inhibited by 1-(1-acetylpiperidin-4-yl)-3-(4-(trifl uoromethoxy)phenyl)urea (TPAU), 1-cyclohexyl-3-dodecylurea (CDU), 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), 1-((3S, 5S, 7S)-adamantan-1-yl)-3-(5-(2-(2-ethoxyethoxy) ethoxy)pentyl)urea (AEPU), N-adamantyl-N[']-cyclohexyl urea (ACU), 4-(((1S, 4S)-4-(3-((3S, 5S, 7S)-adamantan-1-yl) ureido)cyclohexyl)oxy)benzoic acid (c-AUCB), 4-(((1R, 4R)-4-(3-((3S, 5S, 7S)-adamantan-1-yl)ureido)cyclohexyl)oxy)benzoic acid (t-AUCB), 4-(((1R, 4R)-4-(3-(4(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid (t-TAUCB) and to a lesser extent by 8-(3-((3S, 5S, 7S)-adamantan-1-yl)ureido) octanoic acid (AUOA). Phosphatase activity is inhibited by dodecyl-phosphate, phospholipids such as phospho-lysophosphatidic acids and fatty acids such as palmitic acid and lauric acid (PubMed:22217705, PubMed:22387545).SUBUNIT Homodimer.INDUCTION By compounds that cause peroxisome proliferation such as clofibrate, tiadenol and fenofibrate.DOMAIN The N-terminal domain has phosphatase activity. The C-terminal domain has epoxide hydrolase activity.PTM The N-terminus is blocked.PTM The covalent modification of cysteine by 15-deoxy-Delta12,14-prostaglandin-J2 is autocatalytic and reversible. It may occur as an alternative to other cysteine modifications, such as S-nitrosylation and S-palmitoylation (Probable).SIMILARITY Belongs to the AB hydrolase superfamily. Epoxide hydrolase family.
UniProt
P34913
1
EQUAL
555
EQUAL
Reactome DB_ID: 29926
2
magnesium(2+) [ChEBI:18420]
magnesium(2+)
ChEBI
18420
Reactome Database ID Release 81
2142777
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=2142777
Reactome
R-HSA-2142777
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-2142777.1
GO
0004301
GO molecular function
Reactome Database ID Release 81
2161846
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=2161846
Reactome Database ID Release 81
2161961
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=2161961
Reactome
R-HSA-2161961
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-2161961.2
12468260
Pubmed
2002
Characterization and identification of cytochrome P450 metabolites of arachidonic acid released by human peritoneal macrophages obtained from the pouch of Douglas
Werner, K
Schaefer, WR
Schweer, H
Deppert, WR
Karck, U
Zahradnik, HP
Prostaglandins Leukot Essent Fatty Acids 67:397-404
15096040
Pubmed
2004
Structure of human epoxide hydrolase reveals mechanistic inferences on bifunctional catalysis in epoxide and phosphate ester hydrolysis
Gomez, GA
Morisseau, C
Hammock, BD
Christianson, DW
Biochemistry 43:4716-23
Reactome Database ID Release 81
2142670
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=2142670
Reactome
R-HSA-2142670
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-2142670.1
GO
0019373
GO biological process
Reactome Database ID Release 81
2142753
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=2142753
Reactome
R-HSA-2142753
5
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-2142753.5
GO
0019369
GO biological process