2.0 Å structure of prostaglandin H₂ synthase-1 reconstituted with a manganese porphyrin cofactor

Prostaglandin H₂ synthase (EC 1.14.99.1) is a clinically important drug target that catalyzes two key steps in the biosynthesis of the eicosanoid hormones. The enzyme contains spatially distinct cyclooxygenase and peroxidase active sites, both of which require a heme cofactor. Substitution of ferric heme by Mn^III protoporphyrin IX greatly diminishes the peroxidase activity, but has little effect on the cyclooxygenase activity. Here, the 2.0 Å resolution crystal structure of the Mn^III form of ovine prostaglandin H₂ synthase-1 is described (R = 21.8%, R_free = 23.7%). Substitution of Mn^III for Fe^III causes no structural perturbations in the protein. However, the out-of-plane displacement of the manganese ion with respect to the porphyrin is greater than that of the iron by approximately 0.2 Å. This perturbation may help to explain the altered catalytic properties of the manganese enzyme.