Kinetic mechanism of the bifunctional enzyme prostaglandin-H-synthase. Effect of electron donors on the cyclooxygenase reaction
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Prostaglandin-H-synthase (PGHS, EC 188.8.131.52) catalyzes the first committed step in biosynthesis of all prostaglandins, thromboxanes, and prostacyclins by converting arachidonic acid to prostaglandin H2 (PGH2). PGHS exhibits two enzymatic activities: cyclooxygenase activity converting arachidonic acid to prostaglandin G2 (PGG2) and peroxidase activity reducing the hydroperoxide PGG2 to the corresponding alcohol, PGH2. Despite the many investigations of the kinetics of PGHS, many features such as the absence of competition and mutual activation between the cyclooxygenase and peroxidase activities cannot be explained in terms of existing schemes. In this work we have studied the influence of different electron donors (N,N,N′,N′-tetramethyl-p-phenylenediamine, L-epinephrine, 2,2′-azinobis(3-ethylbenzthiazoline-6-sulfonic acid), potassium ferrocyanide) on the PGHS activities. The proposed scheme describes independent but interconnected cyclooxygenase and peroxidase activities of PGHS. It also explains the experimental data obtained in the present work and known from the literature.
Key wordsprostaglandin-H-synthase bifunctional enzyme cyclooxygenase activity kinetic mechanism inhibition naproxen TMPD
general formula for alcohols
general formula for peroxides
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