Prostaglandin-endoperoxide synthase 2 (COX-2) peroxidase site (COX-2 peroxidase site)

Prostaglandin-endoperoxide synthase 2 (COX-2) is a bifunctional enzyme responsible for the rate-limiting step in prostaglandin synthesis, converting arachidonic acid into prostaglandin H2 (PGH2). The enzyme possesses two spatially distinct but functionally coupled active sites: the cyclooxygenase site and the peroxidase site. The peroxidase site catalyzes the two-electron reduction of prostaglandin G2 (PGG2) to PGH2 and is vital for the activation of the cyclooxygenase site by generating a tyrosyl radical (Tyr-385) via a heme-dependent redox reaction (UniProt P35354). COX-2 is typically induced by inflammatory stimuli, cytokines, and growth factors, making it a central player in pain, fever, and inflammatory diseases. While most conventional NSAIDs target the cyclooxygenase channel, certain compounds like acetaminophen are thought to exert their effects by reducing the peroxide tone or directly inhibiting the peroxidase activity, particularly in environments with low peroxide concentrations (Boutaud et al., 2002, PNAS). Targeting the peroxidase site offers a distinct pharmacological strategy for modulating the pro-inflammatory and pro-pyretic effects of COX-2 while potentially avoiding some side effects of traditional COX inhibitors.

Other names

PTGS2 peroxidase siteCyclooxygenase-2 peroxidase siteCOX-2 POX siteProstaglandin G/H synthase 2 peroxidase site

The peroxidase site reduces prostaglandin G2 (PGG2) to prostaglandin H2 (PGH2) using a heme cofactor. Drugs like acetaminophen are thought to inhibit this site by acting as a reducing cosubstrate or by lowering the peroxide tone, which prevents the formation of the tyrosyl radical necessary for cyclooxygenase activity (Boutaud et al., 2002, PNAS; Smith et al., 2011, Annu Rev Biochem).