TP or not TP: primary mediators in a close runoff?

Aspirin has emerged as a remarkably safe, inexpensive, and effective drug for the secondary prevention of the complications of atherosclerotic disease. It acts by inhibiting the enzyme prostaglandin (PG) G/H synthase, actually a bifunctional protein that sequentially catalyzes the conversion of arachidonic acid to the highly reactive endoperoxide intermediates PGG2 and PGH2 via its cyclooxygenase (COX) and peroxidase functions. This enzyme, colloquially termed COX, has been crystallized1 and the mechanism of action of aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) elucidated.2–4 The catalytic site is buried deep within the core of the enzyme and is accessed by the substrate via a hydrophobic tunnel. Aspirin irreversibly acetylates a serine residue at position 529 in the human enzyme,5 close to but not at the catalytic site, though still blocking access to it by the arachidonic acid substrate. NSAIDs, by contrast, act reversibly as competitive inhibitors at the catalytic site. Indeed, transient occupancy of that site after dosing with an NSAID may mask the serine from the effects of a subsequent dose of aspirin.6