Cyclooxygenase 1 (COX-1), also known as prostaglandin-endoperoxide synthase 1 (
HUGOPTGS1), is an
enzyme that in humans is encoded by the PTGS1gene.[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 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
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.
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.
^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.
^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.
^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.
^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.
^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
Richards JA, Petrel TA, Brueggemeier RW (February 2002). "Signaling pathways regulating aromatase and cyclooxygenases in normal and malignant breast cells". The Journal of Steroid Biochemistry and Molecular Biology. 80 (2): 203–12.
doi:
10.1016/S0960-0760(01)00187-X.
PMID11897504.
S2CID12728545.
Jain S, Khuri FR, Shin DM (2004). "Prevention of head and neck cancer: current status and future prospects". Current Problems in Cancer. 28 (5): 265–86.
doi:
10.1016/j.currproblcancer.2004.05.003.
PMID15375804.
Bingham S, Beswick PJ, Blum DE, Gray NM, Chessell IP (October 2006). "The role of the cylooxygenase pathway in nociception and pain". Seminars in Cell & Developmental Biology. 17 (5): 544–54.
doi:
10.1016/j.semcdb.2006.09.001.
PMID17071117.
Takahashi Y, Ueda N, Yoshimoto T, Yamamoto S, Yokoyama C, Miyata A, Tanabe T, Fuse I, Hattori A, Shibata A (January 1992). "Immunoaffinity purification and cDNA cloning of human platelet prostaglandin endoperoxide synthase (cyclooxygenase)". Biochemical and Biophysical Research Communications. 182 (2): 433–8.
doi:
10.1016/0006-291X(92)91750-K.
PMID1734857.
Mollace V, Colasanti M, Rodino P, Lauro GM, Nistico G (August 1994). "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.
doi:
10.1006/bbrc.1994.2152.
PMID7521167.
Corasaniti MT, Melino G, Navarra M, Garaci E, Finazzi-Agrò A, Nisticò G (September 1995). "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.
doi:
10.1016/1055-8330(95)90021-7.
PMID8581564.
Hla T (January 1996). "Molecular characterization of the 5.2 KB isoform of the human cyclooxygenase-1 transcript". Prostaglandins. 51 (1): 81–5.
doi:
10.1016/0090-6980(95)00158-1.
PMID8900446.
Mahida YR, Beltinger J, Makh S, Göke M, Gray T, Podolsky DK, Hawkey CJ (December 1997). "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.
doi:
10.1152/ajpgi.1997.273.6.G1341.
PMID9435560.