PMID:12242329

Citation	Chandrasekharan, NV, Dai, H, Roos, KL, Evanson, NK, Tomsik, J, Elton, TS and Simmons, DL (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. 99:13926-31
Abstract	Two cyclooxygenase isozymes, COX-1 and -2, are known to catalyze the rate-limiting step of prostaglandin synthesis and are the targets of nonsteroidal antiinflammatory drugs. Here we describe a third distinct COX isozyme, COX-3, as well as two smaller COX-1-derived proteins (partial COX-1 or PCOX-1 proteins). COX-3 and one of the PCOX-1 proteins (PCOX-1a) are made from the COX-1 gene but retain intron 1 in their mRNAs. PCOX-1 proteins additionally contain an in-frame deletion of exons 5-8 of the COX-1 mRNA. COX-3 and PCOX mRNAs are expressed in canine cerebral cortex and in lesser amounts in other tissues analyzed. In human, COX-3 mRNA is expressed as an approximately 5.2-kb transcript and is most abundant in cerebral cortex and heart. Intron 1 is conserved in length and in sequence in mammalian COX-1 genes. This intron contains an ORF that introduces an insertion of 30-34 aa, depending on the mammalian species, into the hydrophobic signal peptide that directs COX-1 into the lumen of the endoplasmic reticulum and nuclear envelope. COX-3 and PCOX-1a are expressed efficiently in insect cells as membrane-bound proteins. The signal peptide is not cleaved from either protein and both proteins are glycosylated. COX-3, but not PCOX-1a, possesses glycosylation-dependent cyclooxygenase activity. Comparison of canine COX-3 activity with murine COX-1 and -2 demonstrates that this enzyme is selectively inhibited by analgesic/antipyretic drugs such as acetaminophen, phenacetin, antipyrine, and dipyrone, and is potently inhibited by some nonsteroidal antiinflammatory drugs. Thus, inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.
Links	PubMed PMC129799 Online version:10.1073/pnas.162468699
Keywords	Acetaminophen/pharmacology; Analgesics, Non-Narcotic/pharmacology; Animals; Aorta/enzymology; Cerebral Cortex/enzymology; Cloning, Molecular; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors/pharmacology; Dogs; Genetic Variation; Humans; Isoenzymes/genetics; Isoenzymes/metabolism; Membrane Proteins; Mice; Molecular Sequence Data; Molecular Structure; Prostaglandin-Endoperoxide Synthases/chemistry; Prostaglandin-Endoperoxide Synthases/genetics; Prostaglandin-Endoperoxide Synthases/metabolism; RNA, Messenger/genetics; RNA, Messenger/metabolism; Recombinant Proteins/chemistry; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Tissue Distribution
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