Superoxide poisons mononuclear iron enzymes by causing mismetallation

Mianzhi Gu, James A. Imlay

Research output: Contribution to journalArticle

Abstract

Summary: Superoxide (O2-) is a primary agent of intracellular oxidative stress. Genetic studies in many organisms have confirmed that excess O2- disrupts metabolism, but to date only a small family of [4Fe-4S] dehydratases have been identified as direct targets. This investigation reveals that in Escherichia coliO2- also poisons a broader cohort of non-redox enzymes that employ ferrous iron atoms as catalytic cofactors. These enzymes were inactivated by O2- both in vitro and in vivo. Although the enzymes are known targets of hydrogen peroxide, the outcome with O2- differs substantially. When purified enzymes were damaged by O2- in vitro, activity could be completely restored by iron addition, indicating that the O2- treatment generated an apoprotein without damaging the protein polypeptide. Superoxide stress inside cells caused the progressive mismetallation of these enzymes with zinc, which confers little activity. When O2- stress was terminated, cells gradually restored activity by extracting zinc from the proteins. The overloading of cells with zinc caused mismetallation even without O2- stress. These results support a model in which O2- repeatedly excises iron from these enzymes, allowing zinc to compete with iron for remetallation of their apoprotein forms. This action substantially expands the physiological imprint of O2- stress.

Original languageEnglish (US)
Pages (from-to)123-134
Number of pages12
JournalMolecular Microbiology
Volume89
Issue number1
DOIs
StatePublished - Jul 1 2013

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

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