Cyclooxygenase-1
Cyclooxygenase 1(COX-1), also known asprostaglandin-endoperoxide synthase 1(HUGOPTGS1), is anenzymethat in humans is encoded by thePTGS1gene.[5][6]In humans it is one of twocyclooxygenases.
History
[edit]Cyclooxygenase (COX) is the central enzyme in the biosynthetic pathway to prostaglandins fromarachidonic acid.This protein was isolated more than 40 years ago andclonedin 1988.[7][8]
Gene and isozymes
[edit]There are twoisozymesof COX encoded by distinct gene products: a constitutive COX-1 (this enzyme) and an inducibleCOX-2,which differ in their regulation of expression and tissue distribution. The expression of these two transcripts is differentially regulated by relevantcytokinesandgrowth factors.[9]This gene encodes COX-1, which regulatesangiogenesisinendothelialcells. COX-1 is also involved incell signalingand maintaining tissuehomeostasis.A splice variant of COX-1 termedCOX-3was identified in the central nervous system of dogs, but does not result in a functional protein in humans. Two smaller COX-1-derived proteins (the partial COX-1 proteins PCOX-1A and PCOX-1B) have also been discovered, but their precise roles are yet to be described.[10]
Function
[edit]Prostaglandin-endoperoxidesynthase(PTGS), also known ascyclooxygenase(COX), is the key enzyme in prostaglandin biosynthesis. It converts free arachidonic acid, released from membrane phospholipids at the sn-2 ester binding site by the enzymatic activity of phospholipase A2, to prostaglandin (PG) H2. The reaction involves both cyclooxygenase (dioxygenase) and hydroperoxidase (peroxidase) activity. The cyclooxygenase activity incorporates two oxygen molecules into arachidonic acid or alternate polyunsaturated fatty acid substrates, such aslinoleic acidandeicosapentaenoic acid.Metabolism ofarachidonic acidforms a labile intermediate peroxide,PGG2,which is reduced to the corresponding alcohol, PGH2, by the enzyme's hydroperoxidase activity.
While metabolizing arachidonic acid primarily to PGG2, COX-1 also converts this fatty acid to small amounts of a racemic mixture of15-Hydroxyicosatetraenoic acids(i.e., 15-HETEs) composed of ~22% 15(R)-HETE and ~78% 15(S)-HETEstereoisomersas well as a small amount of 11(R)-HETE.[11]The two 15-HETE stereoisomers have intrinsic biological activities but, perhaps more importantly, can be further metabolized to a major class of anti-inflammatory agents, thelipoxins.[12]In addition, PGG2 and PGH2 rearrange non-enzymatically to a mixture of12-Hydroxyheptadecatrienoic acidsviz.,1 2-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid (i.e. 12-HHT) and 12-(S)-hydroxy-5Z,8Z,10E-heptadecatrienoic acid plusMalonyldialdehyde.[13][14][15]and can be metabolized byCYP2S1to 12-HHT[16][17](see12-Hydroxyheptadecatrienoic acid). These alternate metabolites of COX-1 may contribute to its activities.
COX-1 promotes the production of the natural mucus lining that protects the inner stomach and contributes to reduced acid secretion and reduced pepsin content.[18][19]COX-1 is normally present in a variety of areas of the body, including not only the stomach but any site of inflammation.
Clinical significance
[edit]COX-1 is inhibited bynonsteroidal anti-inflammatory drugs(NSAIDs) such asaspirin.Thromboxane A2,the major product of COX-1 in platelets, induces platelet aggregation.[20][21]The inhibition of COX-1 is sufficient to explain why low doseaspirinis effective at reducing cardiac events.
See also
[edit]- Arachidonic acid
- Cyclooxygenase
- Cyclooxygenase 2
- NSAID
- Discovery and development of COX-2 selective inhibitors
- COX-2 selective inhibitor
References
[edit]- ^abcGRCh38: Ensembl release 89: ENSG00000095303–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000047250–Ensembl,May 2017
- ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^Yokoyama C, Tanabe T (December 1989). "Cloning of human gene encoding prostaglandin endoperoxide synthase and primary structure of the enzyme".Biochemical and Biophysical Research Communications.165(2): 888–94.doi:10.1016/S0006-291X(89)80049-X.PMID2512924.
- ^Funk CD, Funk LB, Kennedy ME, Pong AS, Fitzgerald GA (June 1991)."Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment".FASEB Journal.5(9): 2304–12.doi:10.1096/fasebj.5.9.1907252.PMID1907252.S2CID46147389.
- ^Bakhle YS (1999). "Structure of COX-1 and COX-2 enzymes and their interaction with inhibitors".Drugs of Today.35(4–5): 237–50.doi:10.1358/dot.1999.35.4-5.552200.PMID12973429.
- ^Sakamoto C (October 1998). "Roles of COX-1 and COX-2 in gastrointestinal pathophysiology".Journal of Gastroenterology.33(5): 618–24.doi:10.1007/s005350050147.PMID9773924.S2CID9407329.
- ^"Entrez Gene: PTGS1 prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)".
- ^Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL (October 2002)."COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression".Proceedings of the National Academy of Sciences of the United States of America.99(21): 13926–31.doi:10.1073/pnas.162468699.PMC129799.PMID12242329.
- ^Mulugeta S, Suzuki T, Hernandez NT, Griesser M, Boeglin WE, Schneider C (March 2010)."Identification and absolute configuration of dihydroxy-arachidonic acids formed by oxygenation of 5S-HETE by native and aspirin-acetylated COX-2".Journal of Lipid Research.51(3): 575–85.doi:10.1194/jlr.M001719.PMC2817587.PMID19752399.
- ^Serhan CN (2005). "Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution".Prostaglandins, Leukotrienes, and Essential Fatty Acids.73(3–4): 141–62.doi:10.1016/j.plefa.2005.05.002.PMID16005201.
- ^Wlodawer P, Samuelsson B (August 1973)."On the organization and mechanism of prostaglandin synthetase".The Journal of Biological Chemistry.248(16): 5673–8.doi:10.1016/S0021-9258(19)43558-8.PMID4723909.
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- ^John H, Cammann K, Schlegel W (June 1998). "Development and review of radioimmunoassay of 12-S-hydroxyheptadecatrienoic acid".Prostaglandins & Other Lipid Mediators.56(2–3): 53–76.doi:10.1016/s0090-6980(98)00043-4.PMID9785378.
- ^Bui P, Imaizumi S, Beedanagari SR, Reddy ST, Hankinson O (February 2011)."Human CYP2S1 metabolizes cyclooxygenase- and lipoxygenase-derived eicosanoids".Drug Metabolism and Disposition.39(2): 180–90.doi:10.1124/dmd.110.035121.PMC3033693.PMID21068195.
- ^Frömel T, Kohlstedt K, Popp R, Yin X, Awwad K, Barbosa-Sicard E, Thomas AC, Lieberz R, Mayr M, Fleming I (January 2013). "Cytochrome P4502S1: a novel monocyte/macrophage fatty acid epoxygenase in human atherosclerotic plaques".Basic Research in Cardiology.108(1): 319.doi:10.1007/s00395-012-0319-8.PMID23224081.S2CID9158244.
- ^Laine L, Takeuchi K, Tarnawski A (2008). "Gastric mucosal defense and cytoprotection: bench to bedside".Gastroenterology.135(1): 41–60.doi:10.1053/j.gastro.2008.05.030.PMID18549814.
- ^Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds. (2008).Harrison's Principles of Internal Medicine(17th ed.). New York: McGraw-Hill Medical. p.661.ISBN978-0-07-146633-2.
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Further reading
[edit]- Richards JA, Petrel TA, Brueggemeier RW (February 2002). "Signaling pathways regulating aromatase and cyclooxygenases in normal and malignant breast cells".The Journal of Steroid Biochemistry and Molecular Biology.80(2): 203–12.doi:10.1016/S0960-0760(01)00187-X.PMID11897504.S2CID12728545.
- Wu T, Wu H, Wang J, Wang J (2011)."Expression and cellular localization of cyclooxygenases and prostaglandin E synthases in the hemorrhagic brain".Journal of Neuroinflammation.8:22.doi:10.1186/1742-2094-8-22.PMC3062590.PMID21385433.
- Jain S, Khuri FR, Shin DM (2004). "Prevention of head and neck cancer: current status and future prospects".Current Problems in Cancer.28(5): 265–86.doi:10.1016/j.currproblcancer.2004.05.003.PMID15375804.
- Bingham S, Beswick PJ, Blum DE, Gray NM, Chessell IP (October 2006). "The role of the cylooxygenase pathway in nociception and pain".Seminars in Cell & Developmental Biology.17(5): 544–54.doi:10.1016/j.semcdb.2006.09.001.PMID17071117.
- Diaz A, Reginato AM, Jimenez SA (May 1992)."Alternative splicing of human prostaglandin G/H synthase mRNA and evidence of differential regulation of the resulting transcripts by transforming growth factor beta 1, interleukin 1 beta, and tumor necrosis factor alpha".The Journal of Biological Chemistry.267(15): 10816–22.doi:10.1016/S0021-9258(19)50092-8.PMID1587858.
- Takahashi Y, Ueda N, Yoshimoto T, Yamamoto S, Yokoyama C, Miyata A, Tanabe T, Fuse I, Hattori A, Shibata A (January 1992). "Immunoaffinity purification and cDNA cloning of human platelet prostaglandin endoperoxide synthase (cyclooxygenase)".Biochemical and Biophysical Research Communications.182(2): 433–8.doi:10.1016/0006-291X(92)91750-K.PMID1734857.
- Vane JR, Mitchell JA, Appleton I, Tomlinson A, Bishop-Bailey D, Croxtall J, Willoughby DA (March 1994)."Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation".Proceedings of the National Academy of Sciences of the United States of America.91(6): 2046–50.Bibcode:1994PNAS...91.2046V.doi:10.1073/pnas.91.6.2046.PMC43306.PMID7510883.
- Mollace V, Colasanti M, Rodino P, Lauro GM, Nistico G (August 1994). "HIV coating gp 120 glycoprotein-dependent prostaglandin E2 release by human cultured astrocytoma cells is regulated by nitric oxide formation".Biochemical and Biophysical Research Communications.203(1): 87–92.doi:10.1006/bbrc.1994.2152.PMID7521167.
- Inoue H, Yokoyama C, Hara S, Tone Y, Tanabe T (October 1995)."Transcriptional regulation of human prostaglandin-endoperoxide synthase-2 gene by lipopolysaccharide and phorbol ester in vascular endothelial cells. Involvement of both nuclear factor for interleukin-6 expression site and cAMP response element".The Journal of Biological Chemistry.270(42): 24965–71.doi:10.1074/jbc.270.42.24965.PMID7559624.
- Ren Y, Loose-Mitchell DS, Kulmacz RJ (February 1995). "Prostaglandin H synthase-1: evaluation of C-terminus function".Archives of Biochemistry and Biophysics.316(2): 751–7.doi:10.1006/abbi.1995.1100.PMID7864630.
- Picot D, Loll PJ, Garavito RM (January 1994). "The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1".Nature.367(6460): 243–9.Bibcode:1994Natur.367..243P.doi:10.1038/367243a0.PMID8121489.S2CID4340064.
- Kosaka T, Miyata A, Ihara H, Hara S, Sugimoto T, Takeda O, Takahashi E, Tanabe T (May 1994)."Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2".European Journal of Biochemistry.221(3): 889–97.doi:10.1111/j.1432-1033.1994.tb18804.x.PMID8181472.
- Otto JC, DeWitt DL, Smith WL (August 1993)."N-glycosylation of prostaglandin endoperoxide synthases-1 and -2 and their orientations in the endoplasmic reticulum".The Journal of Biological Chemistry.268(24): 18234–42.doi:10.1016/S0021-9258(17)46835-9.PMID8349699.
- O'Neill GP, Ford-Hutchinson AW (September 1993)."Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues".FEBS Letters.330(2): 156–60.doi:10.1016/0014-5793(93)80263-T.PMID8365485.S2CID26397839.
- Corasaniti MT, Melino G, Navarra M, Garaci E, Finazzi-Agrò A, Nisticò G (September 1995). "Death of cultured human neuroblastoma cells induced by HIV-1 gp120 is prevented by NMDA receptor antagonists and inhibitors of nitric oxide and cyclooxygenase".Neurodegeneration.4(3): 315–21.doi:10.1016/1055-8330(95)90021-7.PMID8581564.
- Ballif BA, Mincek NV, Barratt JT, Wilson ML, Simmons DL (May 1996)."Interaction of cyclooxygenases with an apoptosis- and autoimmunity-associated protein".Proceedings of the National Academy of Sciences of the United States of America.93(11): 5544–9.Bibcode:1996PNAS...93.5544B.doi:10.1073/pnas.93.11.5544.PMC39283.PMID8643612.
- Hla T (January 1996). "Molecular characterization of the 5.2 KB isoform of the human cyclooxygenase-1 transcript".Prostaglandins.51(1): 81–5.doi:10.1016/0090-6980(95)00158-1.PMID8900446.
- Mahida YR, Beltinger J, Makh S, Göke M, Gray T, Podolsky DK, Hawkey CJ (December 1997). "Adult human colonic subepithelial myofibroblasts express extracellular matrix proteins and cyclooxygenase-1 and -2".The American Journal of Physiology.273(6 Pt 1): G1341-8.doi:10.1152/ajpgi.1997.273.6.G1341.PMID9435560.
- Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN (May 1998)."Cyclooxygenase regulates angiogenesis induced by colon cancer cells".Cell.93(5): 705–16.doi:10.1016/S0092-8674(00)81433-6.PMID9630216.S2CID12704830.