TY - JOUR T1 - Asymmetric Acetylation of the Cyclooxygenase-2 Homodimer by Aspirin and Its Effects on the Oxygenation of Arachidonic, Eicosapentaenoic and Docosahexaenoic Acids JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.109.063115 SP - mol.109.063115 AU - Narayan P. Sharma AU - Liang Dong AU - Chong Yuan AU - Kathleen R. Noon AU - William L. Smith Y1 - 2010/03/01 UR - http://molpharm.aspetjournals.org/content/early/2010/03/01/mol.109.063115.abstract N2 - Prostaglandin endoperoxide H synthases (PGHSs)-1 and -2, also called cyclooxygenases (COXs), convert arachidonic acid (AA) to prostaglandin H2 (PGH2) in the committed step of prostaglandin biosynthesis. Both enzymes are homodimers, but the monomers often behave asymmetrically as conformational heterodimers during catalysis and inhibition. Here we report that aspirin maximally acetylates one monomer of human (hu) PGHS-2. The acetylated monomer of aspirin-treated huPGHS-2 forms 15-hydroperoxyeicosatetraenoic acid from AA while the non-acetylated, partner monomer forms mainly PGH2 but only at 15-20% of the rate of native huPGHS-2. These latter conclusions are based on the findings that the nonsteroidal anti-inflammatory drug diclofenac binds a single monomer of native huPGHS-2 having an unmodified Ser-530 to inhibit the enzyme and that diclofenac inhibits PGH2 but not 15-hydroperoxyeicosatraenoic acid formation by acetylated huPGHS-2. The 18R- and 17R-resolvins putatively involved in resolution of inflammation are reportedly formed via aspirin-acetylated PGHS-2 from eicosapentaenoic acid and docosahexaenoic acid, respectively, so we also characterized the oxygenation of these omega-3 fatty acids by aspirin-treated huPGHS-2. Our in vitro studies suggest that 18R- and 17R-resolvins could be formed only at low rates corresponding to less than 1% and 5%, respectively, of the rates of formation of PGH2 by native PGHS-2.The American Society for Pharmacology and Experimental Therapeutics ER -