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Cyclooxygenase-1

From Wikipedia, the free encyclopedia
"COX-1" redirects here. For mitochondrial cytochrome c oxidase subunit 1 (cox1), seeMT-CO1.
PTGS1
Identifiers
AliasesPTGS1,COX1, COX3, PCOX1, PES-1, PGG/HS, PGHS-1, PGHS1, PHS1, PTGHS, prostaglandin-endoperoxide synthase 1
External IDsOMIM:176805;MGI:97797;HomoloGene:743;GeneCards:PTGS1;OMA:PTGS1 - orthologs
EC number1.14.99.1
Orthologs
SpeciesHumanMouse
Entrez

5742

19224

Ensembl

ENSG00000095303

ENSMUSG00000047250

UniProt

P23219

P22437

RefSeq (mRNA)

NM_008969

RefSeq (protein)

NP_032995

Location (UCSC)Chr 9: 122.37 – 122.4 MbChr 2: 36.12 – 36.14 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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

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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

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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

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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

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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

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References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000095303–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000047250–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^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.
  6. ^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.
  7. ^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.
  8. ^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.
  9. ^"Entrez Gene: PTGS1 prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)".
  10. ^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.
  11. ^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.
  12. ^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.
  13. ^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.
  14. ^Hamberg M, Samuelsson B (September 1974)."Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets".Proceedings of the National Academy of Sciences of the United States of America.71(9): 3400–4.Bibcode:1974PNAS...71.3400H.doi:10.1073/pnas.71.9.3400.PMC433780.PMID4215079.
  15. ^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.
  16. ^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.
  17. ^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.
  18. ^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.
  19. ^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.
  20. ^Parker KL, Brunton LL, Lazo JS (2005).Goodman & Gilman's The Pharmacological Basis of Therapeutics(11th ed.). New York: McGraw-Hill Medical Publishing Division. p. 1126.ISBN0-07-142280-3.
  21. ^Weitz JI (2008). "Chapter 112. Antiplatelet, Anticoagulant, and Fibrinolytic Drugs". In Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J (eds.).Harrison's Principles of Internal Medicine(17th ed.). New York: McGraw-Hill Medical.ISBN978-0-07-146633-2.

Further reading

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