Melatonin prevents myeloperoxidase heme destruction and the generation of free iron mediated by self-generated hypochlorous acid.

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TitleMelatonin prevents myeloperoxidase heme destruction and the generation of free iron mediated by self-generated hypochlorous acid.
Publication TypeJournal Article
Year of Publication2015
AuthorsShaeib F, Khan SN, Ali I, Najafi T, Maitra D, Abdulhamid I, Saed GM, Pennathur S, Abu-Soud HM
JournalPLoS One
Volume10
Issue3
Paginatione0120737
Date Published2015
ISSN1932-6203
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.

DOI10.1371/journal.pone.0120737
Alternate JournalPLoS ONE
PubMed ID25835505
PubMed Central IDPMC4383586
Grant ListDK097153 / DK / NIDDK NIH HHS / United States
HL094230 / HL / NHLBI NIH HHS / United States
R01 HL066367 / HL / NHLBI NIH HHS / United States