Figure 3

Production of prostaglandins by COXs. (a) The two reactions performed by cyclooxygenases: the conversion of arachidonic acid to prostaglandin G₂ by the cyclooxygenase activity and the conversion of prostaglandin G₂ to prostaglandin H₂ by the peroxidase activity. (b) The cell-specific synthases that are involved in the conversion of prostaglandin H₂ to the five principal prostaglandins. (c) The reaction mechanism of COX-1. (1) First, a ferryl-oxo (FeIV) protoporphyrin radical in the heme in the peroxidase active site is produced when endogenous oxidant(s) oxidizes ferric heme (FeIII) to ferryl-oxo (FeIV) protoporphyrin radical through a two-electron oxidation. (2) The Tyr384 residue in the cyclooxygenase active site is activated, through a single-electron reduction reaction with the FeIV protoporphyrin radical, to produce a tyrosyl radical. In the first step of the oxygenation process (3), the 13-pro(S) hydrogen of arachidonic acid in the COX site is abstracted by the tyrosyl radical to produce the arachidonyl radical. (4) This is followed by the reaction of the arachidonyl radical with two molecules of oxygen, to yield prostaglandin G₂. (5) Prostaglandin G₂ then diffuses (dotted line) to the peroxidase active site and is reduced to prostaglandin H₂ by the peroxidase activity (1). AA, arachidonic acid; EnR, an endogenous reductant; Fe⁺⁺⁺, ferric heme; Fe=O ⁺⁺⁺⁺, Ferryl-oxo FeIV porphyrin radical; Tyr-OH, active site tyrosine; Tyr-O, tyrosyl radical.