Chapter 11: The Peroxidase and Cyclooxygenase Activity of Prostaglandin H Synthase
Published:26 Oct 2015
Cyclooxygenase (COX) is a homodimeric enzyme that catalyzes the oxygenation of arachidonic acid (AA) in the committed step of prostaglandin (PG) biosynthesis. Two isoforms of COX exist: COX-1, a housekeeping enzyme that maintains homeostatic PG synthesis, and COX-2, an inducible form involved in inflammatory and mitogenic processes. COX-2 can also oxygenate the endocannabinoids, 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (AEA) to their respective PG glyceryl ester and ethanolamide derivatives, respectively. PG biosynthesis occurs through COX's two distinct, interdependent peroxidase and cyclooxygenase activities. Hydroperoxides play a multifaceted role in COX catalysis by acting as substrates for the peroxidase reaction, initiators or activators for the cyclooxygenase reaction, and inactivators of enzymatic activity. Thus, regulation of peroxide levels, primarily by glutathione peroxidase, suppresses PG biosynthesis, while peroxides generated during the cyclooxygenase reaction impose an upper limit on PG production through enzyme inactivation. Within this context, functional differences between the COX isoforms with regard to their peroxide-dependent activation allow differential control of PG biosynthesis, even when both enzymes are present in the same intracellular compartment. Furthermore, substrate-specific differences in sensitivity to peroxide tone may play a role in determining the relative rate of oxygenation of AA versus the endocannabinoids.