Superoxide modulates the activity of myeloperoxidase and optimizes the production of hypochlorous acid.
Myeloperoxidase catalyses the conversion of H2O2 and Cl- to hypochlorous acid (HOCl). It also reacts with O2- to form the oxy adduct (compound III). To determine how O2- affects the formation of HOCl, chlorination of monochlorodimedon by myeloperoxidase was investigated using xanthine oxidase and hypoxanthine as a source of O2- and H2O2. Myeloperoxidase was mostly converted to compound III, and H2O2 was essential for chlorination. At pH 5.4, superoxide dismutase (SOD) enhanced chlorination and prevented formation of compound III. However, at pH 7.8, SOD inhibited chlorination and promoted formation of the ferrous peroxide adduct (compound II) instead of compound III. We present spectral evidence for a direct reaction between compound III and H2O2 to form compound II, and for the reduction of compound II by O2- to regenerate native myeloperoxidase. These reactions enable compound III and compound II to participate in the chlorination reaction. Myeloperoxidase catalytically inhibited O2- -dependent reduction of Nitro Blue Tetrazolium. This inhibition is explained by myeloperoxidase undergoing a cycle of reactions with O2-, H2O2 and O2-, with compounds III and II as intermediates, i.e., by myeloperoxidase acting as a combined SOD/catalase enzyme. By preventing the accumulation of inactive compound II, O2- enhances the activity of myeloperoxidase. We propose that, under physiological conditions, this optimizes the production of HOCl and may potentiate oxidant damage by stimulated neutrophils.
Kettle
A J
AJ
Department of Pathology, Christchurch School of Medicine, Christchurch Hospital, New Zealand.
Winterbourn
C C
CC
D003512:Cyclohexanones / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006997:Hypochlorous Acid / Q000378:metabolism*; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013053:Spectrophotometry; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000494:pharmacology*; D014527:Uric Acid / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000378:metabolism
D003512:Cyclohexanones; D003574:Cytochrome c Group; D013481:Superoxides; D014527:Uric Acid; D006997:Hypochlorous Acid; C006991:chlorodimedone; D006861:Hydrogen Peroxide; D009195:Peroxidase; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase