Resveratrol (3,4', 5- trihydroxy- trans- stilbene) is a phytoalexin found in grapes that has anti- inflammatory, cardiovascular protective, and cancer chemopreventive properties. It has been shown to target prostaglandin H-2 synthase (COX)-1 and COX-2, which catalyze the first committed step in the synthesis of prostaglandins via sequential cyclooxygenase and peroxidase reactions. Resveratrol discriminates between both COX isoforms. It is a potent inhibitor of both catalytic activities of COX-1, the desired drug target for the prevention of cardiovascular disease, but only a weak inhibitor of the peroxidase activity of COX-2, the isoform target for nonsteroidal anti- inflammatory drugs. We have investigated the unique inhibitory properties of resveratrol. We find that it is a potent peroxidase- mediated mechanism-based inactivator of COX-1 only (k(inact) = 0.069 +/- 0.004 s(-1), K-i( inact) = 1.52 +/- 0.15 muM), with a calculated partition ratio of 22. Inactivation of COX-1 was time- and concentration- dependent, it had an absolute requirement for a peroxide substrate, and it was accompanied by a concomitant oxidation of resveratrol. Resveratrol-inactivated COX-1 was devoid of both the cyclooxygenase and peroxidase activities, neither of which could be restored upon gel- filtration chromatography. Inactivation of COX-1 by [H-3] resveratrol was not accompanied by stable covalent modification as evident by both SDS-PAGE and reverse phase- high performance liquid chromatography analysis. Structure activity relationships on methoxy- resveratrol analogs showed that the m-hydroquinone moiety was essential for irreversible inactivation of COX-1. We propose that resveratrol inactivates COX-1 by a hit- and- run mechanism, and offers a basis for the design of selective COX-1 inactivators that work through a mechanism- based event at the peroxidase active site.

Resveratrol is a peroxidase-mediated inactivator of COX-1 but not COX-2 - A mechanistic approach to the design of COX-1 selective agents / L. M., Szewczuk; Forti, Luca; L. A., Stivala; T. M., Penning. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - STAMPA. - 279:21(2004), pp. 22727-22737. [10.1074/jbc.M314302200]

Resveratrol is a peroxidase-mediated inactivator of COX-1 but not COX-2 - A mechanistic approach to the design of COX-1 selective agents

FORTI, Luca;
2004

Abstract

Resveratrol (3,4', 5- trihydroxy- trans- stilbene) is a phytoalexin found in grapes that has anti- inflammatory, cardiovascular protective, and cancer chemopreventive properties. It has been shown to target prostaglandin H-2 synthase (COX)-1 and COX-2, which catalyze the first committed step in the synthesis of prostaglandins via sequential cyclooxygenase and peroxidase reactions. Resveratrol discriminates between both COX isoforms. It is a potent inhibitor of both catalytic activities of COX-1, the desired drug target for the prevention of cardiovascular disease, but only a weak inhibitor of the peroxidase activity of COX-2, the isoform target for nonsteroidal anti- inflammatory drugs. We have investigated the unique inhibitory properties of resveratrol. We find that it is a potent peroxidase- mediated mechanism-based inactivator of COX-1 only (k(inact) = 0.069 +/- 0.004 s(-1), K-i( inact) = 1.52 +/- 0.15 muM), with a calculated partition ratio of 22. Inactivation of COX-1 was time- and concentration- dependent, it had an absolute requirement for a peroxide substrate, and it was accompanied by a concomitant oxidation of resveratrol. Resveratrol-inactivated COX-1 was devoid of both the cyclooxygenase and peroxidase activities, neither of which could be restored upon gel- filtration chromatography. Inactivation of COX-1 by [H-3] resveratrol was not accompanied by stable covalent modification as evident by both SDS-PAGE and reverse phase- high performance liquid chromatography analysis. Structure activity relationships on methoxy- resveratrol analogs showed that the m-hydroquinone moiety was essential for irreversible inactivation of COX-1. We propose that resveratrol inactivates COX-1 by a hit- and- run mechanism, and offers a basis for the design of selective COX-1 inactivators that work through a mechanism- based event at the peroxidase active site.
2004
279
21
22727
22737
Resveratrol is a peroxidase-mediated inactivator of COX-1 but not COX-2 - A mechanistic approach to the design of COX-1 selective agents / L. M., Szewczuk; Forti, Luca; L. A., Stivala; T. M., Penning. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - STAMPA. - 279:21(2004), pp. 22727-22737. [10.1074/jbc.M314302200]
L. M., Szewczuk; Forti, Luca; L. A., Stivala; T. M., Penning
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