1. Department of Microbiology, Cornell University, Ithaca, New York 14853, USA

Correspondence to: John D. Helmann¹ Correspondence and requests for materials should be addressed to J.D.H. (Email: jdh9@cornell.edu).

Abstract

The sensing of reactive oxygen species is essential for cellular responses to oxidative stress¹. The sensing of peroxides is typically mediated by redox-active cysteines in sensors such as the bacterial OxyR, OhrR, and Hsp33 proteins^{2, 3}. Bacillus subtilis PerR is the prototype for a widespread family of metal-dependent peroxide sensors that regulate inducible peroxide-defence genes⁴. Here we show that PerR senses peroxides by metal-catalysed oxidation. PerR contains two metal-binding sites: a structural Zn²⁺ site and a regulatory divalent metal ion site that preferentially binds Fe²⁺ or Mn²⁺ (ref. 5). Protein oxidation, catalysed by a bound ferrous ion, leads to the rapid and direct incorporation of one oxygen atom into histidine 37 (H37) or H91, two of the residues that coordinate the bound Fe²⁺. This mechanism accounts for the ability of PerR to sense low levels of hydrogen peroxide in vivo. The reduction of hydrogen peroxide by metal ions to generate highly reactive hydroxyl radicals underlies the genotoxic effects of peroxides¹, and has been shown to contribute to enzyme inactivation, but has not previously been shown to provide a regulatory mechanism for peroxide sensing.

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