title: COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression.
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.
authors.affiliation: Department of Chemistry and Biochemistry, E280 Benson Science Building, Brigham Young University, Provo, UT 84602, USA.
authors.forename: N V
authors.initials: NV
authors.lastname: Chandrasekharan
authors.forename: Hu
authors.initials: H
authors.lastname: Dai
authors.forename: K Lamar Turepu
authors.initials: KL
authors.lastname: Roos
authors.forename: Nathan K
authors.initials: NK
authors.lastname: Evanson
authors.forename: Joshua
authors.initials: J
authors.lastname: Tomsik
authors.forename: Terry S
authors.initials: TS
authors.lastname: Elton
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Simmons
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000201:enzymology; D002540:Cerebral Cortex / Q000201:enzymology; D003001:Cloning, Molecular; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004285:Dogs; D014644:Genetic Variation; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D018712:Analgesics, Non-Narcotic; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000082:Acetaminophen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; C466421:cyclooxygenase-3