Mechanism of Inactivation of Prostaglandin H2 Synthase 1 (PGH2S-1) by Resveratrol and its Analogs

3,4',5-Trihydroxy-trans-stilbene (resveratrol) is a natural product derived from grapes that has anti-inflammatory, anti-coagulation, and cancer chemopreventive properties. It inhibits both the cyclooxygenase (cox) and peroxidase (perox) activities of Prostaglandin H2 Synthase 1 (PGH2S-1). Resveratrol was rapidly oxidized by the perox activity, but unlike other co-reductants inactivated both enzyme activities. The irreversible loss of cox and perox activity was accompanied by the oxidation of resveratrol to yield the inactivator and had an absolute requirement for a peroxide substrate. Resveratrol represents a new class of inhibitors for PGH2S-1 that inactivate both the cox and perox activities of the enzyme, but require catalytic activation to exert their effects. Perox inhibitors are attractive because catalytic intermediates formed in the perox reaction are potent oxidants, which can generate reactive species that can damage biological macromolecules.