Structure of COX-1 and COX-2 enzymes and their interaction with inhibitors

Cyclooxygenase (COX) is the central enzyme in the biosynthetic pathway to prostaglandins (PGs) from arachidonic acid (AA). This protein was purified more than 20 years ago and cloned in 1988. A few years later another protein with COX activity was identified and called COX-2. Although the isoforms of COX are derived from different genes of different size and give rise to distinct mRNA sequences, the proteins are highly homologous in sequence and in three-dimensional structure. They also contain the same two catalytic sites, a peroxidase and a COX site, use the same substrate, AA, and form the same product. The detailed structures of the active COX sites in the isoforms are almost identical. Nevertheless, there are very important biological differences between COX-1 and COX-2. The latter is a highly inducible protein, absent from most tissues in normal conditions but increasing rapidly in response to inflammatory stimuli such as bacterial endotoxin, cytokines, or growth factors. Furthermore, there are differences in substrate binding and, particularly, in inhibitor binding sites that allow the isoforms to be inhibited differentially. This difference is therapeutically significant and selective inhibitors of COX-2 exhibit antiinflammatory potency without the gastric and renal toxicities of the aspirin-like drugs. Selective COX-2 inhibitors may also have important effects on cell growth, development, or survival, reflecting the location of COX-2 on the nuclear membrane of cells. Although much is known of the structure of the isoforms, all the questions have not yet been answered. The new therapeutic possibilities offered by selective inhibitors of COX-2 will encourage a continuing and more detailed analysis of the structures and functions of these closely related proteins.