title: Rapid reactions of peroxynitrite with heme-thiolate proteins as the basis for protection of prostacyclin synthase from inactivation by nitration.
abstract: Prostacyclin (PGI(2)) synthase is a heme-thiolate (P450) protein which reacts with low levels of peroxynitrite (PN) under tyrosine nitration and inactivation. Studying heme proteins as models, we have found the heme-thiolate protein NADH-NO reductase (P450(NOR)) to be highly efficient in decomposing PN under concomitant nitration of phenol. The present study investigates two other P450 proteins, P450(BM-3) and chloroperoxidase, in order to test for the specific role of the thiolate ligand in the reaction with PN. A comparison with horseradish peroxidase and microperoxidase gives evidence of kinetic differences that classify heme-thiolate proteins, but not other heme proteins, as effective inhibitors of PGI(2) synthase nitration and inactivation. P450(BM-3) with PN catalyzes phenol nitration and nitration of its own tyrosine below 10 microM PN, whereas chloroperoxidase and P450(NOR) at such concentrations also nitrate phenol but not enzyme-bound tyrosine residues. We conclude that heme-thiolate proteins in general exhibit high reactivity with PN and turnover, probably due to the special electronic structure of the presumed thiolate-ferryl intermediate.
authors.affiliation: Faculty of Biology, University of Konstanz, Konstanz, 78457, Germany.
authors.forename: M H
authors.initials: MH
authors.lastname: Zou
authors.forename: A
authors.initials: A
authors.lastname: Daiber
authors.forename: J A
authors.initials: JA
authors.lastname: Peterson
authors.forename: H
authors.initials: H
authors.lastname: Shoun
authors.forename: V
authors.initials: V
authors.lastname: Ullrich
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006420:Hemeproteins / Q000378:metabolism*; D006735:Horseradish Peroxidase / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007700:Kinetics; D008954:Models, Biological; D009566:Nitrates / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D006420:Hemeproteins; D009566:Nitrates; C039642:peroxynitric acid; D014443:Tyrosine; D003577:Cytochrome P-450 Enzyme System; D006735:Horseradish Peroxidase; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase