Arachidonic Acid Oxygenation by COX-1 and COX-2

Abstract

Prostaglandins were discovered in human semen in 1930, but their low concentrations and instability precluded identification for nearly 30 years (for a brief historical review, see Ref. 1). Once they were identified, it was clear they arose from polyunsaturated fatty acids by a complex series of reactions involving oxygenation, cyclization, and the generation of five chiral centers from an achiral substrate. The mechanism of prostaglandin biosynthesis was outlined in 1967 by Hamberg and Samuelsson (2), and the basic tenets have been confirmed in subsequent studies. The key step in their proposed mechanism was the formation of bicyclic peroxides (endoperoxides) as the initial products of polyunsaturated fatty acid oxygenation (Fig. 1). The term cyclooxygenase (COX) 1, 2 was coined to describe the enzyme that carried out this complex chemical transformation, and its role was confirmed by the isolation of prostaglandin endoperoxides in 1973 (3, 4).In addition to catalyzing a fascinating metabolic transformation, COX is an enormously important pharmacological target. Vane reported in 1971 (5) that non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin formation and demonstrated that their relative inhibitory potency in vitro correlates to their antiinflammatory activity in vivo. This not only explained the beneficial activity of NSAIDs but also their side effects such as gastrointestinal toxicity and bleeding because prostaglandins and related molecules (i.e. thromboxane) are involved in a very broad range of physiological and pathophysiological responses. The importance of these molecules as autocrine and paracrine mediators has been confirmed recently by the phenotypes of mice bearing targeted deletions in COX genes or prostaglandin receptor genes.The discovery of a second gene (COX-2) coding for cyclooxygenase and the demonstration that its protein product is distributed differently from the originally discovered enzyme (COX-1) raised the possibility that some of the beneficial effects of NSAIDs may be separable from their side effects by development of isoform-selective inhibitors (6 -9). This hypothesis has been dramatically validated by the demonstration that selective COX-2 inhibitors are anti-inflammatory and analgesic but lack the gastric toxicity associated with all currently available NSAIDs (10, 11). Cyclooxygenase CatalysisSubstantial evidence supports the hypothesis that COX oxygenates arachidonic acid by a free radical mechanism (Fig. 1). Thus, COX appears to have co-opted the process that gives rise to isoprostanes to generate prostaglandins. The major differences between COX-catalyzed and spontaneous oxidation of arachidonic acid are the increased rate and high degree of stereochemical control of the enzymatic reaction (1 of 64 possible isomers predominates). Thus, the overall role of COX is rather simple: stereospecifically remove the 13-pro-S-hydrogen and control the stereochemistry of oxygenation. How does it do this?Oxidizing Agent-A protein tyrosyl radical appears to be the oxidiz...

Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat

“…The production of pro-inflammatory prostanoids is an injurious mechanism associated to the COX-2 enzymatic activity and this process is associated with the generation of highly reactive oxygen species, which have potent deleterious effects on cells [42]. We found that delayed treatment of rats with nimesulide completely abolished the marked increase in PGE 2 seen in the ischemic cortex 24 h after stroke.…”

Structural and Functional Basis of Cyclooxygenase Inhibition

“…10,[24][25][26] This review will focus on the structural and functional basis of the inhibition of COX enzymes by nonselective and COX-2 selective inhibitors. It will integrate kinetic, mechanistic, and structural information to illustrate not only the range of molecules with COX inhibitory activity but also the diversity of mechanisms by which they act.…”

Redundancy in the Signaling Pathways and Promoter Elements Regulating Cyclooxygenase-2 Gene Expression in Endotoxin-treated Macrophage/Monocytic Cells

“…process, phospholipase A 2 catalyzes the release of arachidonic acid from membrane phospholipids, while COX catalyzes the conversion of arachidonic acid into PGs (2,3). There are two isoforms of COX, COX-1 and COX-2, the product of two different genes.…”