Differential Sensitivity and Mechanism of Inhibition of COX-2 Oxygenation of Arachidonic Acid and 2-Arachidonoylglycerol by Ibuprofen and Mefenamic Acid

• Published in: Biochemistry (Easton) 2009-08, Vol.48 (31), p.7353-7355
• Main Authors: Prusakiewicz, Jeffery J, Duggan, Kelsey C, Rouzer, Carol A, Marnett, Lawrence J
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - metabolism; Arachidonic Acid - antagonists & inhibitors; Arachidonic Acid - metabolism; Arachidonic Acids - antagonists & inhibitors; Arachidonic Acids - metabolism; Binding, Competitive; Cyclooxygenase 2 - chemistry; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - chemistry; Endocannabinoids; Glycerides - antagonists & inhibitors; Glycerides - metabolism; Ibuprofen - chemistry; Mefenamic Acid - chemistry; Mefenamic Acid - metabolism; Mice; Oxygen - antagonists & inhibitors; Oxygen - metabolism; Protein Binding; Rapid Report
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi900999z

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.