title: Melatonin prevents myeloperoxidase heme destruction and the generation of free iron mediated by self-generated hypochlorous acid.
abstract: Myeloperoxidase (MPO) generated hypochlorous acid (HOCl) formed during catalysis is able to destroy the MPO heme moiety through a feedback mechanism, resulting in the accumulation of free iron. Here we show that the presence of melatonin (MLT) can prevent HOCl-mediated MPO heme destruction using a combination of UV-visible photometry, hydrogen peroxide (H2O2)-specific electrode, and ferrozine assay techniques. High performance liquid chromatography (HPLC) analysis showed that MPO heme protection was at the expense of MLT oxidation. The full protection of the MPO heme requires the presence of a 1:2 MLT to H2O2 ratio. Melatonin prevents HOCl-mediated MPO heme destruction through multiple pathways. These include competition with chloride, the natural co-substrate; switching the MPO activity from a two electron oxidation to a one electron pathway causing the buildup of the inactive Compound II, and its subsequent decay to MPO-Fe(III) instead of generating HOCl; binding to MPO above the heme iron, thereby preventing the access of H2O2 to the catalytic site of the enzyme; and direct scavenging of HOCl. Collectively, in addition to acting as an antioxidant and MPO inhibitor, MLT can exert its protective effect by preventing the release of free iron mediated by self-generated HOCl. Our work may establish a direct mechanistic link by which MLT exerts its antioxidant protective effect in chronic inflammatory diseases with MPO elevation.
authors.affiliation: Departments of Obstetrics and Gynecology, the C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors.forename: Faten
authors.initials: F
authors.lastname: Shaeib
authors.affiliation: Departments of Obstetrics and Gynecology, the C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors.forename: Sana N
authors.initials: SN
authors.lastname: Khan
authors.affiliation: Departments of Obstetrics and Gynecology, the C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan, United States of America; Department of Biochemistry and Genetics, Faculty of Medicine, An-Najah National University, Nablus, Palestine.
authors.forename: Iyad
authors.initials: I
authors.lastname: Ali
authors.affiliation: Departments of Obstetrics and Gynecology, the C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan, United States of America; Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors.forename: Tohid
authors.initials: T
authors.lastname: Najafi
authors.affiliation: Departments of Obstetrics and Gynecology, the C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors.forename: Dhiman
authors.initials: D
authors.lastname: Maitra
authors.affiliation: Children's Hospital of Michigan, Detroit, Michigan.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Abdulhamid
authors.affiliation: Departments of Obstetrics and Gynecology, the C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors.forename: Ghassan M
authors.initials: GM
authors.lastname: Saed
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.affiliation: Departments of Obstetrics and Gynecology, the C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan, United States of America; Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors.forename: Husam M
authors.initials: HM
authors.lastname: Abu-Soud
mesh_terms: D002384:Catalysis; D004789:Enzyme Activation; D006418:Heme / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006997:Hypochlorous Acid / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D008550:Melatonin / Q000378:metabolism*; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism*
chemical_list: D006418:Heme; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; D007501:Iron; D009195:Peroxidase; D008550:Melatonin
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