Prostaglandin endoperoxide H synthases (PGHSs), also known as cyclooxygenases (COX-1 and COX-2), catalyze the conversion of arachidonic acid and oxygen to prostaglandin H2 (PGH2), a key step in prostanoid biosynthesis. Initially, only one PGHS isozyme, COX-1, was identified, but subsequent research revealed a second isozyme, COX-2, which is induced by various stimuli and expressed in a subset of tissues. Both isozymes are homodimeric, heme-containing proteins with two catalytic sites and unique mechanisms for membrane attachment. PGHS-1 is constitutively expressed in most tissues, while PGHS-2 is inducible and expressed in specific tissues. The regulation of their expression involves multiple signal transducers and post-transcriptional mechanisms. Enzyme catalysis includes both cyclooxygenase and peroxidase activities, with the cyclooxygenase reaction requiring a hydroperoxide intermediate. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) target PGHS-1 and PGHS-2, respectively, for inhibition. PGHS-2-selective inhibitors are less ulcerogenic and more effective anti-inflammatory agents. The two isozymes likely function in separate prostanooid biosynthetic systems, with PGHS-1 generating extracellular prostanoids and PGHS-2 producing nuclear prostanoids.Prostaglandin endoperoxide H synthases (PGHSs), also known as cyclooxygenases (COX-1 and COX-2), catalyze the conversion of arachidonic acid and oxygen to prostaglandin H2 (PGH2), a key step in prostanoid biosynthesis. Initially, only one PGHS isozyme, COX-1, was identified, but subsequent research revealed a second isozyme, COX-2, which is induced by various stimuli and expressed in a subset of tissues. Both isozymes are homodimeric, heme-containing proteins with two catalytic sites and unique mechanisms for membrane attachment. PGHS-1 is constitutively expressed in most tissues, while PGHS-2 is inducible and expressed in specific tissues. The regulation of their expression involves multiple signal transducers and post-transcriptional mechanisms. Enzyme catalysis includes both cyclooxygenase and peroxidase activities, with the cyclooxygenase reaction requiring a hydroperoxide intermediate. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) target PGHS-1 and PGHS-2, respectively, for inhibition. PGHS-2-selective inhibitors are less ulcerogenic and more effective anti-inflammatory agents. The two isozymes likely function in separate prostanooid biosynthetic systems, with PGHS-1 generating extracellular prostanoids and PGHS-2 producing nuclear prostanoids.