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.