title: Salicylhydroxamic acid inhibits myeloperoxidase activity.
abstract: Salicylhydroxamic and benzohydroxamic acids were found to bind to the resting state of myeloperoxidase and inhibit ligand binding to the heme iron. An ionizable group on the enzyme with pKa = 4 affects salicylhydroxamic acid binding; binding occurs when this group is not protonated. The binding of the heme iron ligands (e.g. cyanide, nitrite, and chloride) is probably controlled by the same ionizable group. The equilibrium dissociation constant of the salicylhydroxamic acid-myeloperoxidase complex is about 2 x 10(-6) M, and the association rate constant is 7.4 x 10(6) M-1.s-1. Salicylhydroxamic acid serves as a donor to the higher oxidation state of myeloperoxidase and thereby inhibits guaiacol oxidation. Salicylhydroxamic acid was also found to bind to intestinal peroxidase and lactoperoxidase. Salicylhydroxamic acid binding to all three mammalian peroxidases was about 3 orders of magnitude stronger than benzohydroxamic acid binding. We conclude that the salicylhydroxamic and benzohydroxamic acids bind in the distal heme cavity of these peroxidases and interact with the heme ligand binding site.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4901.
authors.forename: M
authors.initials: M
authors.lastname: Ikeda-Saito
authors.forename: D A
authors.initials: DA
authors.lastname: Shelley
authors.forename: L
authors.initials: L
authors.lastname: Lu
authors.forename: K S
authors.initials: KS
authors.lastname: Booth
authors.forename: W S
authors.initials: WS
authors.lastname: Caughey
authors.forename: S
authors.initials: S
authors.lastname: Kimura
mesh_terms: D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D002417:Cattle; D006098:Granulocytes / Q000201:enzymology; D006139:Guaiacol / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D007422:Intestines / Q000201:enzymology; D007784:Lactoperoxidase / Q000037:antagonists & inhibitors; D008024:Ligands; D008892:Milk / Q000201:enzymology; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000037:antagonists & inhibitors*; D010544:Peroxidases / Q000037:antagonists & inhibitors; D012457:Salicylamides / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet; D013552:Swine
chemical_list: D008024:Ligands; D012457:Salicylamides; D006418:Heme; D006139:Guaiacol; C005703:salicylhydroxamic acid; D007784:Lactoperoxidase; D010544:Peroxidases; D009195:Peroxidase