Abstract
Prostaglandin endoperoxide H synthases-1 and -2, commonly called cyclooxygenases-1 and -2 (COX-1 and -2), catalyze the committed step in prostaglandin biosynthesis-the conversion of arachidonic acid to prostaglandin endoperoxide H(2) Both COX isoforms are sequence homodimers that function as conformational heterodimers having allosteric (Eallo) and catalytic (Ecat) subunits. At least in the case of COX-2, the enzyme becomes folded into a stable Eallo/Ecat pair. Some COX inhibitors (i.e. nonsteroidal anti-inflammatory drugs and coxibs) and common fatty acids (FAs) modulate Ecat activity by binding Eallo. However, the interactions and outcomes often differ between isoforms. For example, naproxen directly and completely inhibits COX-1 by binding Ecat but indirectly and incompletely inhibits COX-2 by binding Eallo. Additionally, COX-1 is allosterically inhibited up to 50% by common FAs like palmitic acid, whereas COX-2 is allosterically activated 2-fold by palmitic acid. FA binding to Eallo also affects responses to COX inhibitors. Thus, COXs are physiologically and pharmacologically regulated by the FA tone of the milieu in which each operates-COX-1 in the endoplasmic reticulum and COX-2 in the Golgi apparatus. Cross-talk between Eallo and Ecat involves a loop in Eallo immediately downstream of Arg-120. Mutational studies suggest that allosteric modulation requires a direct interaction between the carboxyl group of allosteric effectors and Arg-120 of Eallo; however, structural studies show some allosterically active FAs positioned in COX-2 in a conformation lacking an interaction with Arg-120. Thus, many details about the biological consequences of COX allosterism and how ligand binding to Eallo modulates Ecat remain to be resolved.