A conserved motif liganding the [4Fe–4S] cluster in [4Fe–4S] fumarases prevents irreversible inactivation of the enzyme during hydrogen peroxide stress

Zheng Lu, James A. Imlay

Research output: Contribution to journalArticle

Abstract

Organisms have evolved two different classes of the ubiquitous enzyme fumarase: the [4Fe–4S] cluster-containing class I enzymes are oxidant-sensitive, whereas the class II enzymes are iron-free and therefore oxidant-resistant. When hydrogen peroxide (H2O2) attacks the most-studied [4Fe–4S] fumarases, only the cluster is damaged, and thus the cell can rapidly repair the enzyme. However, this study shows that when elevated levels of H2O2 oxidized the class I fumarase of the obligate anaerobe Bacteroides thetaiotaomicron (Bt-Fum), a hydroxyl-like radical species was produced that caused irreversible covalent damage to the polypeptide. Unlike the fumarase of oxygen-tolerant bacteria, Bt-Fum lacks a key cysteine residue in the typical “CXnCX2C″ motif that ligands [4Fe–4S] clusters. Consequently H2O2 can access and oxidize an iron atom other than the catalytic one in its cluster. Phylogenetic analysis showed that certain clades of bacteria may have evolved the full “CXnCX2C″ motif to shield the [4Fe–4S] cluster of fumarase. This effect was reproduced by the construction of a chimeric enzyme. These data demonstrate the irreversible oxidation of Fe–S cluster enzymes and may recapitulate evolutionary steps that occurred when microorganisms originally confronted oxidizing environments. It is also suggested that, if H2O2 is generated within the colon as a consequence of inflammation or the action of lactic acid bacteria, the inactivation of fumarase could potentially impair the central fermentation pathway of Bacteroides species and contribute to gut dysbiosis.

Original languageEnglish (US)
Article number101296
JournalRedox Biology
Volume26
DOIs
StatePublished - Sep 2019

Keywords

  • 4Fe–4S] fumarase
  • Bacteroides
  • Hydrogen peroxide
  • Irreversible damage

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

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