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Cyclooxygenase-1

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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
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
"COX-1" redirects here. For mitochondrial cytochrome c oxidase subunit 1 (cox1), see MT-CO1.

Cyclooxygenase 1 (COX-1), also known as prostaglandin G/H synthase 1, prostaglandin-endoperoxide synthase 1 or prostaglandin H2 synthase 1, is an enzyme that in humans is encoded by the PTGS1 gene.[5][6] In humans it is one of two cyclooxygenases.

History

Cyclooxygenase (COX) is the central enzyme in the biosynthetic pathway to prostaglandins from arachidonic acid. This protein was isolated more than 40 years ago and cloned in 1988.[7][8]

Gene and isozymes

There are two isozymes of COX encoded by distinct gene products: a constitutive COX-1 (this enzyme) and an inducible COX-2, which differ in their regulation of expression and tissue distribution. The expression of these two transcripts is differentially regulated by relevant cytokines and growth factors.[9] This gene encodes COX-1, which regulates angiogenesis in endothelial cells. COX-1 is also involved in cell signaling and maintaining tissue homeostasis. A splice variant of COX-1 termed COX-3 was identified in the CNS 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

Prostaglandin-endoperoxide synthase (PTGS), also known as cyclooxygenase (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 as linoleic acid and eicosapentaenoic acid. Metabolism of arachidonic acid forms 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 of 15-Hydroxyicosatetraenoic acids (i.e., 15-HETEs) composed of ~22% 15(R)-HETE and ~78% 15(S)-HETE stereoisomers as 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, the lipoxins.[12] In addition, PGG2 and PGH2 rearrange non-enzymatically to a mixture of 12-Hydroxyheptadecatrienoic acids viz.,1 2-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid (i.e. 12-HHT) and 12-(S)-hydroxy-5Z,8Z,10E-heptadecatrienoic acid plus Malonyldialdehyde.[13][14][15] and can be metabolized by CYP2S1 to 12-HHT[16][17] (see 12-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

COX-1 is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin. 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 dose aspirin is effective at reducing cardiac events.

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000095303 – Ensembl, May 2017
  2. ^ a b c GRCm38: 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. PMID 2512924.
  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. PMID 1907252. S2CID 46147389.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  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. PMID 12973429.
  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. PMID 9773924. S2CID 9407329.
  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. PMC 129799. PMID 12242329.
  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. PMC 2817587. PMID 19752399.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  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. PMID 16005201.
  13. ^ Wlodawer P, Samuelsson B (August 1973). "On the organization and mechanism of prostaglandin synthetase". The Journal of Biological Chemistry. 248 (16): 5673–8. PMID 4723909.
  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. doi:10.1073/pnas.71.9.3400. PMC 433780. PMID 4215079.
  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. PMID 9785378.
  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. PMC 3033693. PMID 21068195.
  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. PMID 23224081. S2CID 9158244.
  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. PMID 18549814.
  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. ISBN 978-0-07-146633-2.
  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. ISBN 0-07-142280-3.
  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. ISBN 978-0-07-146633-2.

Further reading

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