PTGS1

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Prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)
Pghs1.png
PDB rendering based on 1diy.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PTGS1 ; COX1; COX3; PCOX1; PES-1; PGG/HS; PGHS-1; PGHS1; PHS1; PTGHS
External IDs OMIM176805 MGI97797 HomoloGene743 IUPHAR: 1375 ChEMBL: 221 GeneCards: PTGS1 Gene
EC number 1.14.99.1
RNA expression pattern
PBB GE PTGS1 215813 s at tn.png
PBB GE PTGS1 205127 at tn.png
PBB GE PTGS1 205128 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 5742 19224
Ensembl ENSG00000095303 ENSMUSG00000047250
UniProt P23219 P22437
RefSeq (mRNA) NM_000962 NM_008969
RefSeq (protein) NP_000953 NP_032995
Location (UCSC) Chr 9:
125.13 – 125.16 Mb
Chr 2:
36.23 – 36.25 Mb
PubMed search [1] [2]
"COX-1" redirects here. COX-1 may also refer to mitochondrial cytochrome c oxidase subunit 1 (cox1).

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.[1][2]

History[edit]

Cyclooxygenase (COX) is the central enzyme in the biosynthetic pathway to prostaglandins from arachidonic acid. This protein was purified more than 20 years ago and cloned in 1988.[3][4]

Gene and isozymes[edit]

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] 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.[6]

Function[edit]

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. 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. This gene encodes COX-1, which regulates angiogenesis in endothelial cells. COX-1 is also involved in cell signaling and maintaining tissue homeostasis.

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 impotantly, 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 a Cytochrome, cytochrome P4520S1 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.[14][16]

Clinical significance[edit]

COX-1 is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin. TXA2, the major product of COX-1 in platelets, induces platelet aggregation.[17][18] Research has shown that the inhibition of COX-1 is sufficient to explain why aspirin is effective at reducing cardiac events.

See also[edit]

References[edit]

  1. ^ Yokoyama C, Tanabe T (December 1989). "Cloning of human gene encoding prostaglandin endoperoxide synthase and primary structure of the enzyme". Biochem. Biophys. Res. Commun. 165 (2): 888–94. doi:10.1016/S0006-291X(89)80049-X. PMID 2512924. 
  2. ^ 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 J. 5 (9): 2304–12. PMID 1907252. 
  3. ^ Bakhle YS (1999). "Structure of COX-1 and COX-2 enzymes and their interaction with inhibitors". Drugs Today 35 (4–5): 237–50. PMID 12973429. 
  4. ^ Sakamoto C (October 1998). "Roles of COX-1 and COX-2 in gastrointestinal pathophysiology". J. Gastroenterol. 33 (5): 618–24. doi:10.1007/s005350050147. PMID 9773924. 
  5. ^ "Entrez Gene: PTGS1 prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)". 
  6. ^ 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". Proc. Natl. Acad. Sci. U.S.A. 99 (21): 13926–31. doi:10.1073/pnas.162468699. PMC 129799. PMID 12242329. 
  7. ^ J. Lipid Res. 51:575-585, 2010
  8. ^ Prostaglandins Leukot. Essent. Fatty Acids 73:141-162, 2005
  9. ^ J. Biol. Chem. 248:5673; 1973
  10. ^ Proc. Natl. Acad. Sci. USA 71:3400; 1974
  11. ^ Prostaglandins Other Lipid Mediat. 1998 Jun;56(2-3):53-76
  12. ^ Drug Metab Dispos. 2011 Feb;39(2):180-90. doi: 10.1124/dmd.110.035121
  13. ^ Basic Res Cardiol. 2013 Jan;108(1):319. doi: 10.1007/s00395-012-0319-8
  14. ^ a b MedicineNet.com[Internet]. New York:WebMD. [updated 2003 March 3; cited 2010 February 1] Available from: http://www.medterms.com/script/main/art.asp?articlekey=7123
  15. ^ Bruton LL, Lazo JS, Parker KL. Goodman & Gilman’s: the pharmacological basis of therapeutics. 11th edition. New York: McGraw-Hill; 2006. p. 661.
  16. ^ AWS-Law.com [Internet]. Florida. [cited 2010 February 1] Available from: http://www.aws-law.com/about.asp.
  17. ^ Bruton LL, Lazo JS, Parker KL. Goodman & Gilman’s: the pharmacological basis of therapeutics. 11th edition. New York: McGraw-Hill; 2006. p. 1126.
  18. ^ Weitz Jeffrey I, "Chapter 112. Antiplatelet, Anticoagulant, and Fibrinolytic Drugs" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17e: http://www.accessmedicine.com/content.aspx?aID=2891975.

Further reading[edit]