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Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5402-7. doi: 10.1073/pnas.1100410108. Epub 2011 Mar 14.

Iron enzyme ribulose-5-phosphate 3-epimerase in Escherichia coli is rapidly damaged by hydrogen peroxide but can be protected by manganese.

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  • 1Department of Microbiology, University of Illinois, Urbana, IL 61801, USA.


H(2)O(2) is commonly generated in biological habitats by environmental chemistry and by cellular immune responses. H(2)O(2) penetrates cells, disrupts metabolism, and blocks growth; it therefore is of interest to identify the major cellular molecules that H(2)O(2) damages and the strategies by which cells protect themselves from it. We used a strain of Escherichia coli that lacks catalases and peroxidases to impose protracted low-grade H(2)O(2) stress. Physiological analysis indicated that the pentose-phosphate pathway, in particular, was poisoned by submicromolar intracellular H(2)O(2). Assays determined that ribulose-5-phosphate 3-epimerase (Rpe) was specifically inactivated. In vitro studies demonstrated that Rpe employs a ferrous iron atom as a solvent-exposed cofactor and that H(2)O(2) rapidly oxidizes this metal in a Fenton reaction. The oxidized iron is released immediately, causing a loss of activity. Most Rpe proteins could be reactivated by remetallation; however, a small fraction of proteins were irreversibly damaged by each oxidation cycle, and so repeated cycles of oxidation and remetallation progressively led to permanent inactivation of the entire Rpe pool. Manganese import and iron sequestration are key elements of the H(2)O(2) stress response, and we found that manganese can activate Rpe in vitro in place of iron, converting the enzyme to a form that is unaffected by H(2)O(2). Indeed, the provision of manganese to H(2)O(2)-stressed cells protected Rpe and enabled the pentose-phosphate pathway to retain function. These data indicate that mononuclear iron enzymes can be primary targets of H(2)O(2) stress and that cells adapt by shifting from iron- to manganese-centered metabolism.

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