title: Differential sensitivity and mechanism of inhibition of COX-2 oxygenation of arachidonic acid and 2-arachidonoylglycerol by ibuprofen and mefenamic acid.
abstract: Ibuprofen and mefenamic acid are weak, competitive inhibitors of cyclooxygenase-2 (COX-2) oxygenation of arachidonic acid (AA) but potent, noncompetitive inhibitors of 2-arachidonoylglycerol (2-AG) oxygenation. The slow, tight-binding inhibitor, indomethacin, is a potent inhibitor of 2-AG and AA oxygenation whereas the rapidly reversible inhibitor, 2'-des-methylindomethacin, is a potent inhibitor of 2-AG oxygenation but a poor inhibitor of AA oxygenation. These observations are consistent with a model in which inhibitors bind in one subunit of COX-2 and inhibit 2-AG binding in the other subunit of the homodimeric protein. In contrast, ibuprofen and mefenamate must bind in both subunits to inhibit AA binding.
authors: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
authors: Jeffery J
authors: JJ
authors: Prusakiewicz
authors: Kelsey C
authors: KC
authors: Duggan
authors: Carol A
authors: CA
authors: Rouzer
authors: Lawrence J
authors: LJ
authors: Marnett
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001667:Binding, Competitive; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry*; D063388:Endocannabinoids; D005989:Glycerides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007052:Ibuprofen / Q000737:chemistry*; D008528:Mefenamic Acid / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D010100:Oxygen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D052246:Cyclooxygenase 2 Inhibitors; D063388:Endocannabinoids; D005989:Glycerides; D016718:Arachidonic Acid; D008528:Mefenamic Acid; C094503:glyceryl 2-arachidonate; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D010100:Oxygen; D007052:Ibuprofen