Structural insights into the stereochemistry of the cyclooxygenase reaction

Cyclooxygenases are bifunctional enzymes that catalyse the first committed step in the synthesis of prostaglandins, thromboxanes and other eicosanoids (1-3). The two known cyclooxygenases isoforms share a high degree of amino- acid sequence similarity(1-4), structural topology(5-7) and an identical ca talytic mechanism(1-3). Cyclooxygenase enzymes catalyse two sequential reac tions in spatially distinct, but mechanistically coupled active sites(8-11) . The initial cyclooxygenase reaction converts arachidonic acid (which is a chiral) to prostaglandin G(2) (which has five chiral centres). The subseque nt peroxidase reaction reduces prostaglandin G(2) to prostaglandin H-2. Her e we report the co-crystal structures of murine apo-cyclooxygenase-2 in com plex with arachidonic acid and prostaglandin. These structures suggest the molecular basis for the stereospecificity of prostaglandin G(2) synthesis.