Non-redundant Functions of Cyclooxygenases: Oxygenation of Endocannabinoids

Lawrence J. Marnett,Carol A. Rouzer

doi:10.1074/jbc.r800005200

Abstract

The two cyclooxygenase (COX) enzymes catalyze the oxygenation of arachidonic acid to prostaglandin endoperoxides, which are the common intermediates in the biosynthesis of the bioactive lipids prostaglandins and thromboxane. COX-1 and COX-2 are approximately 60% identical in amino acid sequence, exhibit highly homologous three-dimensional structures, and appear functionally similar at the biochemical level. Recent work has uncovered a subtle functional difference between the two enzymes, namely the ability of COX-2 to efficiently utilize neutral derivatives (esters and amides) of arachidonic acid as substrates. Foremost among these neutral substrates are the endocannabinoids 2-arachidonoylglycerol and arachidonoylethanolamide. This raises the possibility that COX-2 oxygenation plays a role in a novel signaling pathway dependent on agonist-induced release of endocannabinoids and their selective oxygenation by COX-2. Among the products of COX-2 oxygenation of endocannabinoids are glyceryl prostaglandins, some of which (e.g. glyceryl prostaglandin E(2) and glyceryl prostaglandin I(2)) exhibit interesting biological activities in inflammatory, neurological, and vascular systems. These compounds are produced in intact cells stimulated with physiological agonists and have been isolated from in vivo sources. Important concepts relevant to the hypothesis of a COX-2-selective signaling pathway are presented.

Highlights

The two cyclooxygenase (COX) enzymes catalyze the oxygenation of arachidonic acid to prostaglandin endoperoxides, which are the common intermediates in the biosynthesis of the bioactive lipids prostaglandins and thromboxane
Cyclooxygenases (COX-1 and COX-2)2 catalyze the committed step in the conversion of AA to PGs, thromboxane, and PGI2 and, in so doing, trigger the biosynthesis of an important family of lipid mediators [1, 2]
COX-1 and COX-2 catalyze the oxygenation of polyunsaturated fatty acids to hydroperoxy endoperoxides at the cyclooxygenase active site and the reduction of the hydroperoxide to an alcohol at the peroxidase active site (Fig. 1) [15]

Summary

Introduction

The two cyclooxygenase (COX) enzymes catalyze the oxygenation of arachidonic acid to prostaglandin endoperoxides, which are the common intermediates in the biosynthesis of the bioactive lipids prostaglandins and thromboxane. RPMs from these animals demonstrated inducibility of COX-1 protein in response to LPS treatment but were unable to produce PGs at low concentrations of AA, as anticipated by the differences in hydroperoxide activation described above. Site-directed mutagenesis studies show that the ability of COX-2 to use neutral substrates is associated principally with its side pocket and that Arg-513 makes the major contribution to the oxidation of 2-AG and AEA [31].

Results

Conclusion