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.