American Chemical Society
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A Mechanistic Hypothesis for the Aspirin-Induced Switch in Lipid Mediator Production by Cyclooxygenase‑2

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journal contribution
posted on 2013-07-17, 00:00 authored by Paolo Tosco
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.