COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression

• N. V. Chandrasekharan

  Department of Chemistry and Biochemistry, E280 Benson Science Building, Brigham Young University, Provo, UT 84602

• Hu Dai

  Department of Chemistry and Biochemistry, E280 Benson Science Building, Brigham Young University, Provo, UT 84602

• K. Lamar Turepu Roos

  Department of Chemistry and Biochemistry, E280 Benson Science Building, Brigham Young University, Provo, UT 84602

• Nathan K. Evanson

  Department of Chemistry and Biochemistry, E280 Benson Science Building, Brigham Young University, Provo, UT 84602

• Joshua Tomsik

  Department of Chemistry and Biochemistry, E280 Benson Science Building, Brigham Young University, Provo, UT 84602

• Terry S. Elton

  Department of Chemistry and Biochemistry, E280 Benson Science Building, Brigham Young University, Provo, UT 84602

• Daniel L. Simmons

  Department of Chemistry and Biochemistry, E280 Benson Science Building, Brigham Young University, Provo, UT 84602

抄録

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.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 99 (21), 13926-13931, 2002-09-19

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1361137043614701568
• NII論文ID: 80015645137
• DOI: 10.1073/pnas.162468699
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.162468699
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