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Inactivation of human myeloperoxidase by hydrogen peroxide
- Paumann-Page, Martina, Furtmüller, Paul G., Hofbauer, Stefan, Paton, Louise N., Obinger, Christian, Kettle, Anthony J.
- Archives of biochemistry and biophysics 2013 v.539 no.1 pp. 51-62
- heme, humans, hydrogen peroxide, iron, methionine, myeloperoxidase, neutrophils, oxidants, oxidation, peroxidase, phagosomes, polypeptides, thermal stability
- Human myeloperoxidase (MPO) uses hydrogen peroxide generated by the oxidative burst of neutrophils to produce an array of antimicrobial oxidants. During this process MPO is irreversibly inactivated. This study focused on the unknown role of hydrogen peroxide in this process. When treated with low concentrations of H₂O₂ in the absence of reducing substrates, there was a rapid loss of up to 35% of its peroxidase activity. Inactivation is proposed to occur via oxidation reactions of Compound I with the prosthetic group or amino acid residues. At higher concentrations hydrogen peroxide acts as a suicide substrate with a rate constant of inactivation of 3.9×10⁻³s⁻¹. Treatment of MPO with high H₂O₂ concentrations resulted in complete inactivation, Compound III formation, destruction of the heme groups, release of their iron, and detachment of the small polypeptide chain of MPO. Ten of the protein’s methionine residues were oxidized and the thermal stability of the protein decreased. Inactivation by high concentrations of H₂O₂ is proposed to occur via the generation of reactive oxidants when H₂O₂ reacts with Compound III. These mechanisms of inactivation may occur inside neutrophil phagosomes when reducing substrates for MPO become limiting and could be exploited when designing pharmacological inhibitors.