Biology:Cyclooxygenase-1

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Cyclooxygenase 1 (COX-1), also known as prostaglandin-endoperoxide synthase 1 (HUGO PTGS1), is an enzyme that in humans is encoded by the PTGS1 gene.[1][2] 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.[3][4]

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.[5] 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 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.[6]

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.[7] 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.[8] 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.[9][10][11] and can be metabolized by CYP2S1 to 12-HHT[12][13] (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.[14][15] 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.[16][17] The inhibition of COX-1 is sufficient to explain why low dose aspirin is effective at reducing cardiac events.

See also

References

  1. ↑ "Cloning of human gene encoding prostaglandin endoperoxide synthase and primary structure of the enzyme". Biochemical and Biophysical Research Communications 165 (2): 888–94. December 1989. doi:10.1016/S0006-291X(89)80049-X. PMID 2512924. 
  2. ↑ "Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment". FASEB Journal 5 (9): 2304–12. June 1991. doi:10.1096/fasebj.5.9.1907252. PMID 1907252. 
  3. ↑ "Structure of COX-1 and COX-2 enzymes and their interaction with inhibitors". Drugs of Today 35 (4–5): 237–50. 1999. doi:10.1358/dot.1999.35.4-5.552200. PMID 12973429. 
  4. ↑ "Roles of COX-1 and COX-2 in gastrointestinal pathophysiology". Journal of Gastroenterology 33 (5): 618–24. October 1998. doi:10.1007/s005350050147. PMID 9773924. 
  5. ↑ "Entrez Gene: PTGS1 prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5742. 
  6. ↑ "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. October 2002. doi:10.1073/pnas.162468699. PMID 12242329. 
  7. ↑ "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. March 2010. doi:10.1194/jlr.M001719. PMID 19752399. 
  8. ↑ "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. 2005. doi:10.1016/j.plefa.2005.05.002. PMID 16005201. 
  9. ↑ "On the organization and mechanism of prostaglandin synthetase". The Journal of Biological Chemistry 248 (16): 5673–8. August 1973. doi:10.1016/S0021-9258(19)43558-8. PMID 4723909. 
  10. ↑ "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. September 1974. doi:10.1073/pnas.71.9.3400. PMID 4215079. Bibcode: 1974PNAS...71.3400H. 
  11. ↑ "Development and review of radioimmunoassay of 12-S-hydroxyheptadecatrienoic acid". Prostaglandins & Other Lipid Mediators 56 (2–3): 53–76. June 1998. doi:10.1016/s0090-6980(98)00043-4. PMID 9785378. 
  12. ↑ "Human CYP2S1 metabolizes cyclooxygenase- and lipoxygenase-derived eicosanoids". Drug Metabolism and Disposition 39 (2): 180–90. February 2011. doi:10.1124/dmd.110.035121. PMID 21068195. 
  13. ↑ "Cytochrome P4502S1: a novel monocyte/macrophage fatty acid epoxygenase in human atherosclerotic plaques". Basic Research in Cardiology 108 (1): 319. January 2013. doi:10.1007/s00395-012-0319-8. PMID 23224081. 
  14. ↑ "Gastric mucosal defense and cytoprotection: bench to bedside". Gastroenterology 135 (1): 41–60. 2008. doi:10.1053/j.gastro.2008.05.030. PMID 18549814. 
  15. ↑ Harrison's Principles of Internal Medicine (17th ed.). New York: McGraw-Hill Medical. 2008. p. 661. ISBN 978-0-07-146633-2. https://archive.org/details/harrisonsprincip00asfa. 
  16. ↑ Parker, Keith L.; Brunton, Laurence L.; Lazo, John S. (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. 
  17. ↑ Weitz, Jeffrey I (2008). "Chapter 112. Antiplatelet, Anticoagulant, and Fibrinolytic Drugs". 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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