Prostaglandin-endoperoxide synthase (COX) peroxidase site (COX POX site)

The peroxidase site of prostaglandin-endoperoxide synthase (COX) is a distinct catalytic domain within the bifunctional COX-1 and COX-2 enzymes, responsible for reducing prostaglandin G2 (PGG2) to prostaglandin H2 (PGH2) (UniProt P23219, P35354). This site contains a heme cofactor (protoporphyrin IX) that undergoes a redox cycle, generating a ferryl-oxo heme intermediate and a tyrosyl radical (Tyr385) necessary for the activation of the adjacent cyclooxygenase site (Smith et al., 2011, "Cyclooxygenases: structural, cellular, and molecular biology"). While most nonsteroidal anti-inflammatory drugs (NSAIDs) target the cyclooxygenase site, the peroxidase site is the primary target for the analgesic acetaminophen (paracetamol). Acetaminophen acts as a reducing cosubstrate, scavenging the oxidizing intermediates at the peroxidase site and thereby indirectly inhibiting the cyclooxygenase activity, particularly in tissues with low peroxide concentrations like the brain (Boutaud et al., 2002, "Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin biosynthesis"). This site is a key focus for developing analgesics that lack the gastrointestinal and anti-platelet side effects associated with traditional COX inhibitors.

Other names

Cyclooxygenase peroxidase sitePGH synthase peroxidase siteProstaglandin H2 synthase peroxidase domainCOX-1/COX-2 peroxidase active site

Inhibition of the peroxidase cycle by acting as a reducing cosubstrate, which reduces the heme-ferryl intermediate and prevents the formation of the tyrosyl radical required for cyclooxygenase activity.