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 - Tập 99 Số 21 - Trang 13926-13931 - 2002
N.V. Chandrasekharan1, Hu Dai2,3, Katarina Roos2,3, Nathan K. Evanson2,3, Joshua Tomsik2,3, Terry S. Elton2,3, Daniel L. Simmons2,3
1Department of Chemistry and Biochemistry, E280 Benson Science Building, Brigham Young University, Provo, UT 84602, USA.
2Communicated by John Vane, William Harvey Foundation, London, United Kingdom,
3Department of Chemistry and Biochemistry, E280 Benson Science Building, Brigham Young University, Provo, UT 84602

Tóm tắt

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 ( p artial 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 ≈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.

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Thông tin xuất bản

Proceedings of the National Academy of Sciences of the United States of America

Tập 99 Số 21

13926-13931

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