The induction of two biosynthetic enzymes helps Escherichia coli sustain heme synthesis and activate catalase during hydrogen peroxide stress

Stefano Mancini, James A. Imlay

Research output: Contribution to journalArticlepeer-review

Abstract

Hydrogen peroxide pervades many natural environments, including the phagosomes that mediate cell-based immunity. Transcriptomic analysis showed that during protracted low-grade H2O2 stress, Escherichia coli responds by activating both the OxyR defensive regulon and the Fur iron-starvation response. OxyR induced synthesis of two members of the nine-step heme biosynthetic pathway: ferrochelatase (HemH) and an isozyme of coproporphyrinogen III oxidase (HemF). Mutations that blocked either adaptation caused the accumulation of porphyrin intermediates, inadequate activation of heme enzymes, low catalase activity, defective clearance of H2O2 and a failure to grow. Genetic analysis indicated that HemH induction is needed to compensate for iron sequestration by the mini-ferritin Dps. Dps activity protects DNA and proteins by limiting Fenton chemistry, but it interferes with the ability of HemH to acquire the iron that it needs to complete heme synthesis. HemF is a manganoprotein that displaces HemN, an iron-sulfur enzyme whose synthesis and/or stability is apparently problematic during H2O2 stress. Thus, the primary responses to H2O2, including the sequestration of iron, require compensatory adjustments in the mechanisms of iron-cofactor synthesis. The results support the growing evidence that oxidative stress is primarily an iron pathology. Among the responses of Escherichia coli to protracted hydrogen peroxide stress is the induction of two heme biosynthetic genes. These adjustments are needed to enable heme synthesis at the same time that mini-ferritins suppress DNA damage by sequestering iron.

Original languageEnglish (US)
Pages (from-to)744-763
Number of pages20
JournalMolecular Microbiology
Volume96
Issue number4
DOIs
StatePublished - May 1 2015

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

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