title: A mechanistic hypothesis for the aspirin-induced switch in lipid mediator production by cyclooxygenase-2.
abstract: Cyclooxygenase (COX) carries out stereospecific oxygen addition to arachidonic acid to generate prostaglandins, plus smaller amounts of 11- and 15-hydroxyeicosatetraenoic acids. For COX-2, the stereochemistry and relative abundance of generated products is influenced by Ser530 acetylation following aspirin treatment. The molecular bases of the high degree of stereospecificity which characterizes COX-2-catalyzed oxygenations are not yet completely understood, nor are the reasons behind the aspirin-induced shift in lipid mediator production. A mechanistic hypothesis is proposed which identifies steric shielding as the main determinant of oxygenation stereospecificity. This hypothesis is supported by a computational model which accurately reproduces experimental oxygenation patterns on both native and aspirin-inhibited COX-2.
authors.affiliation: Department of Drug Science and Technology, Via Pietro Giuria 9, 10125 Torino, Italy. paolo.tosco@unito.it
authors.forename: Paolo
authors.initials: P
authors.lastname: Tosco
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000737:chemistry / Q000378:metabolism*; D001241:Aspirin / Q000737:chemistry / Q000494:pharmacology*; D055162:Biocatalysis; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D011789:Quantum Theory; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; D001241:Aspirin; D010100:Oxygen