Cyclooxygenase-1 Explained

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

• Arachidonic acid
• Cyclooxygenase
• Cyclooxygenase 2
• NSAID
• Discovery and development of COX-2 selective inhibitors
• COX-2 selective inhibitor

Further reading

• Richards JA, Petrel TA, Brueggemeier RW . Signaling pathways regulating aromatase and cyclooxygenases in normal and malignant breast cells . The Journal of Steroid Biochemistry and Molecular Biology . 80 . 2 . 203–12 . February 2002 . 11897504 . 10.1016/S0960-0760(01)00187-X . 12728545 .
• Wu T, Wu H, Wang J, Wang J . Expression and cellular localization of cyclooxygenases and prostaglandin E synthases in the hemorrhagic brain . Journal of Neuroinflammation . 8 . 22 . 2011 . 21385433 . 3062590 . 10.1186/1742-2094-8-22 . free .
• Jain S, Khuri FR, Shin DM . Prevention of head and neck cancer: current status and future prospects . Current Problems in Cancer . 28 . 5 . 265–86 . 2004 . 15375804 . 10.1016/j.currproblcancer.2004.05.003 .
• Bingham S, Beswick PJ, Blum DE, Gray NM, Chessell IP . The role of the cylooxygenase pathway in nociception and pain . Seminars in Cell & Developmental Biology . 17 . 5 . 544–54 . October 2006 . 17071117 . 10.1016/j.semcdb.2006.09.001 .
• Diaz A, Reginato AM, Jimenez SA . 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 . May 1992 . 10.1016/S0021-9258(19)50092-8 . 1587858 . free .
• Takahashi Y, Ueda N, Yoshimoto T, Yamamoto S, Yokoyama C, Miyata A, Tanabe T, Fuse I, Hattori A, Shibata A . Immunoaffinity purification and cDNA cloning of human platelet prostaglandin endoperoxide synthase (cyclooxygenase) . Biochemical and Biophysical Research Communications . 182 . 2 . 433–8 . January 1992 . 1734857 . 10.1016/0006-291X(92)91750-K .
• Vane JR, Mitchell JA, Appleton I, Tomlinson A, Bishop-Bailey D, Croxtall J, Willoughby DA . 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 . March 1994 . 7510883 . 43306 . 10.1073/pnas.91.6.2046 . 1994PNAS...91.2046V . free .
• Mollace V, Colasanti M, Rodino P, Lauro GM, Nistico G . 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 . August 1994 . 7521167 . 10.1006/bbrc.1994.2152 .
• Inoue H, Yokoyama C, Hara S, Tone Y, Tanabe T . 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 . October 1995 . 7559624 . 10.1074/jbc.270.42.24965 . free .
• Ren Y, Loose-Mitchell DS, Kulmacz RJ . Prostaglandin H synthase-1: evaluation of C-terminus function . Archives of Biochemistry and Biophysics . 316 . 2 . 751–7 . February 1995 . 7864630 . 10.1006/abbi.1995.1100 .
• Picot D, Loll PJ, Garavito RM . The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1 . Nature . 367 . 6460 . 243–9 . January 1994 . 8121489 . 10.1038/367243a0 . 1994Natur.367..243P . 4340064 .
• Kosaka T, Miyata A, Ihara H, Hara S, Sugimoto T, Takeda O, Takahashi E, Tanabe T . Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2 . European Journal of Biochemistry . 221 . 3 . 889–97 . May 1994 . 8181472 . 10.1111/j.1432-1033.1994.tb18804.x . free .
• Otto JC, DeWitt DL, Smith WL . 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 . August 1993 . 10.1016/S0021-9258(17)46835-9 . 8349699 . free .
• O'Neill GP, Ford-Hutchinson AW . Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues . FEBS Letters . 330 . 2 . 156–60 . September 1993 . 8365485 . 10.1016/0014-5793(93)80263-T . 26397839 . free .
• Corasaniti MT, Melino G, Navarra M, Garaci E, Finazzi-Agrò A, Nisticò G . 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 . September 1995 . 8581564 . 10.1016/1055-8330(95)90021-7 .
• Ballif BA, Mincek NV, Barratt JT, Wilson ML, Simmons DL . 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 . May 1996 . 8643612 . 39283 . 10.1073/pnas.93.11.5544 . 1996PNAS...93.5544B . free .
• Hla T . Molecular characterization of the 5.2 KB isoform of the human cyclooxygenase-1 transcript . Prostaglandins . 51 . 1 . 81–5 . January 1996 . 8900446 . 10.1016/0090-6980(95)00158-1 .
• Mahida YR, Beltinger J, Makh S, Göke M, Gray T, Podolsky DK, Hawkey CJ . 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 . December 1997 . 9435560 . 10.1152/ajpgi.1997.273.6.G1341.
• Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN . Cyclooxygenase regulates angiogenesis induced by colon cancer cells . Cell . 93 . 5 . 705–16 . May 1998 . 9630216 . 10.1016/S0092-8674(00)81433-6 . 12704830 . free .

Notes and References

1. Yokoyama C, Tanabe T . 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 . 2512924 . 10.1016/S0006-291X(89)80049-X .
2. Funk CD, Funk LB, Kennedy ME, Pong AS, Fitzgerald GA . Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment . FASEB Journal . 5 . 9 . 2304–12 . June 1991 . 1907252 . 10.1096/fasebj.5.9.1907252. free . 46147389 .
3. Bakhle YS . Structure of COX-1 and COX-2 enzymes and their interaction with inhibitors . Drugs of Today . 35 . 4–5 . 237–50 . 1999 . 12973429 . 10.1358/dot.1999.35.4-5.552200.
4. Sakamoto C . Roles of COX-1 and COX-2 in gastrointestinal pathophysiology . Journal of Gastroenterology . 33 . 5 . 618–24 . October 1998 . 9773924 . 10.1007/s005350050147 . 9407329 .
5. Web site: 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 . 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 . 12242329 . 129799 . 10.1073/pnas.162468699 . free .
7. Mulugeta S, Suzuki T, Hernandez NT, Griesser M, Boeglin WE, Schneider C . 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 . 19752399 . 2817587 . 10.1194/jlr.M001719 . free .
8. Serhan CN . 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 . 16005201 . 10.1016/j.plefa.2005.05.002 .
9. Wlodawer P, Samuelsson B . On the organization and mechanism of prostaglandin synthetase . The Journal of Biological Chemistry . 248 . 16 . 5673–8 . August 1973 . 10.1016/S0021-9258(19)43558-8 . 4723909 . free .
10. Hamberg M, Samuelsson B . 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 . 4215079 . 433780 . 10.1073/pnas.71.9.3400. 1974PNAS...71.3400H . free .
11. John H, Cammann K, Schlegel W . Development and review of radioimmunoassay of 12-S-hydroxyheptadecatrienoic acid . Prostaglandins & Other Lipid Mediators . 56 . 2–3 . 53–76 . June 1998 . 9785378 . 10.1016/s0090-6980(98)00043-4.
12. Bui P, Imaizumi S, Beedanagari SR, Reddy ST, Hankinson O . Human CYP2S1 metabolizes cyclooxygenase- and lipoxygenase-derived eicosanoids . Drug Metabolism and Disposition . 39 . 2 . 180–90 . February 2011 . 21068195 . 3033693 . 10.1124/dmd.110.035121 .
13. Frömel T, Kohlstedt K, Popp R, Yin X, Awwad K, Barbosa-Sicard E, Thomas AC, Lieberz R, Mayr M, Fleming I . Cytochrome P4502S1: a novel monocyte/macrophage fatty acid epoxygenase in human atherosclerotic plaques . Basic Research in Cardiology . 108 . 1 . 319 . January 2013 . 23224081 . 10.1007/s00395-012-0319-8 . 9158244 .
14. Laine L, Takeuchi K, Tarnawski A . Gastric mucosal defense and cytoprotection: bench to bedside . Gastroenterology . 135 . 1 . 41–60 . 2008 . 18549814 . 10.1053/j.gastro.2008.05.030 .
15. Book: Fauci . Anthony S. . Eugene . Braunwald . Dennis L. . Kasper . Stephen L. . Hauser . Dan L. . Longo . J. Larry . Jameson . Joseph . Loscalzo . vanc . Harrison's Principles of Internal Medicine . limited . 2008 . McGraw-Hill Medical . New York . 978-0-07-146633-2. 17th . 661 .
16. Book: Parker . Keith L. . Brunton . Laurence L. . Lazo . John S. . vanc . Goodman & Gilman's The Pharmacological Basis of Therapeutics . 2005 . McGraw-Hill Medical Publishing Division . New York . 0-07-142280-3 . 1126 . 11th .
17. Book: Weitz, Jeffrey I . Fauci . Anthony S. . Eugene . Braunwald . Dennis L. . Kasper . Stephen L. . Hauser . Dan L. . Longo . J. Larry . Jameson . Joseph . Loscalzo . vanc . Harrison's Principles of Internal Medicine . 2008 . McGraw-Hill Medical . New York . 978-0-07-146633-2. 17th . Chapter 112. Antiplatelet, Anticoagulant, and Fibrinolytic Drugs .