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Inactivation of human myeloperoxidase by hydrogen peroxide

Martina Paumann-Page1, Paul G Furtmüller, Stefan Hofbauer

  • 1Centre for Free Radical Research, University of Otago Christchurch, Christchurch, New Zealand; Department of Chemistry, Division of Biochemistry, BOKU - University of Natural Resources and Life Sciences, Muthgasse 18, Vienna, Austria.

Archives of Biochemistry and Biophysics
|September 17, 2013
PubMed

Insights

Hydrogen peroxide (H2O2) irreversibly inactivates human myeloperoxidase (MPO) through various mechanisms. Understanding these H2O2-induced MPO inactivation pathways is crucial for developing targeted pharmacological inhibitors.

Area of Science:

  • Biochemistry
  • Immunology
  • Enzymology

Background:

  • Human myeloperoxidase (MPO) is essential for neutrophil antimicrobial activity.
  • MPO utilizes hydrogen peroxide (H2O2) to generate reactive oxidants.
  • MPO undergoes irreversible inactivation during its function.

Purpose of the Study:

  • To elucidate the role of hydrogen peroxide (H2O2) in the inactivation of human myeloperoxidase (MPO).
  • To investigate the mechanisms of MPO inactivation by varying H2O2 concentrations.

Main Methods:

  • Treatment of MPO with low and high concentrations of H2O2 in vitro.
  • Assays to measure peroxidase activity and monitor Compound I and Compound III formation.
  • Analysis of heme group integrity, iron release, and protein structural changes.

Main Results:

  • Low H2O2 concentrations caused up to 35% loss of MPO activity, proposed via Compound I oxidation.
  • High H2O2 concentrations led to complete MPO inactivation, Compound III formation, heme destruction, and iron release.
  • Oxidation of methionine residues and decreased thermal stability were observed.
  • Proposed mechanism involves reactive oxidants generated from H2O2 and Compound III.

Conclusions:

  • Hydrogen peroxide (H2O2) acts as both an inactivator and a suicide substrate for MPO.
  • These inactivation mechanisms may occur in neutrophil phagosomes.
  • Findings can inform the design of pharmacological inhibitors targeting MPO.
Keywords:
Mechanism-based inhibitionMyeloperoxidaseNeutrophilsOxidative modificationOxidative stressSuicide inhibitor

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