Hypochlorous acid and myeloperoxidase‐catalyzed oxidation of iron‐slfur clusters in bacterial respiratory dehydrogenases

Abstract

Hypochlorous acid and related oxidants derived from myeloperoxidase‐catalyzed reactions contribute to the microbicidal activities of phagocytosing nuetrophils and monocytes. Microbial ironsulfur (Fe/S) clusters have been suggested as general targets of myeloperoxidase‐derived oxiations, but no susceptible Fe/S site has yet been identified. In this study, the effects of HOCl and myeloperoxidase‐catalyzed peroxidation of chloride ion upon EPR‐detectable Fe/S clusters in Escherichia coli and Pseudomonas aeruginosa were examined. Increasing amounts of oxidant produced progressive loss of signal amplitudes from the S‐1 and S‐3 Fe/S clusters of succinate: ubiquinone oxidoreductase in respiring membrane fragments. These changes were compared to loss of microbial viability, succinate uptake rates, succinate dehydrogenase activity and succinate‐dependent respiration. The amounts of oxidant required to destroy Fe/S clusters exceeded the amounts required to kill organisms or inhibit respiratory function by fators of four or five. Power saturation characteristics of the S‐1 signal indicated tht the S‐2 signal was also resistant to modification, even in highly oxidized membranes. Loss of succinate‐dependent respiration was closely associated with HOCl and myeloperoxidase‐mediated microbicidal activity against P. aeruginosa and was also an early event in the oxidant‐mediated metabolic dysfunctiosn fo E. coli. However, these effects were not caused by the destruction of the Fe/S clusters within the succinat: ubiquinone oxidoreductase. Rather, the major respiration‐inhibiting lesion(s) appeared to reside at points in the respiratory chain between the Fe/S clusters and the ubiquinone reductase site. Copyright © 1991, Wiley Blackwell. All rights reserved