Abstract
Prostaglandin endoperoxide H synthase (PGHS) catalyzes the conversion of arachidonic acid to PGH2, the first committed step in the biosynthesis of a range of lipid mediators, termed prostaglandins (PGs) and thromboxanes.1 PGHS has both cyclooxygenase (COX) and hydroperoxidase activities.2 Aspirin and a variety of nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the COX activity of PGHS3 (Figure 1). Figure 1. The cyclooxygenase pathways of arachidonic acid metabolism. The figure depicts the constitutive pathway on the left side and the inducible pathway of arachidonic acid metabolism on the right side, generating the same lipid mediator, ie, prostaglandin E2, through a cascade of coordinate enzymatic reactions. It also illustrates the site of action of low-dose aspirin and coxibs in inhibiting selectively COX-1 and COX-2, respectively. Traditional nonsteroidal antiinflammatory drugs inhibit nonselectively both isozymes. AA indicates arachidonic acid; EP1,2,3,4, specific PGE2 receptors; LPS, lipopolysaccharide; PGE2, prostaglandin E2; PGH2, prostaglandin H2; PLA2, phospoholipase A2; PGES, PGE-synthase (c and m denote the constitutive and inducible isoforms of the enzyme, respectively). See p 1631 Before 1991, only the isoform called PGHS-1, COX-1, or the constitutive enzyme had been described. At that time, Xie et al4 and Kujubu and Herschman5 discovered mRNAs whose expression was induced in chicken and mouse fibroblasts in response to src and tumor-promoting phorbol esters, respectively, and that encoded proteins having 60% amino acid sequence identity with COX-1. Subsequent work has shown that the new protein, called PGHS-2, COX-2, or the inducible isoform, is very similar to COX-1 in structure but differs substantially from COX-1 with respect to its pattern of expression and its biology.1 In particular, COX-2 can be upregulated by cytokines, growth factors, and tumor promoters, 4,5⇓ …
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