☆ 4.8 Article

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

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2013)

Journal

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Volume 135, Issue 28, Pages 10404-10410

Publisher

AMER CHEMICAL SOC

DOI: 10.1021/ja402870k

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Categories

Chemistry, Multidisciplinary

Funding

Chemical Computing Group (Montreal, Quebec, Canada)
COSMOlogic (Leverkusen, Germany)

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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.

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