Oxidative damage in microbial cells occurs during exposure to the toxic metal chromium, but it is not certain whether such oxidation accounts for the toxicity of Cr. Here, a Saccharomyces cerevisiae sod1Delta mutant (defective for the Cu,Zn-superoxide dismutase) was found to be hypersensitive to Cr(VI) toxicity under aerobic conditions, but this phenotype was suppressed under anaerobic conditions. Studies with cells expressing a Sod1p variant (Sod1(H46C)) showed that the superoxide dismutase activity rather than the metal-binding function of Sod1p was required for Cr resistance. To help identify the macromolecular target(s) of Cr-dependent oxidative damage, cells deficient for the reduction of phospholipid hydroperoxides (gpx3Delta and gpx1Delta/gpx2Delta/gpx3Delta) and for the repair of DNA oxidation (ogg1Delta and rad30Delta/ogg1Delta) were tested, but were found not to be Cr-sensitive. In contrast, S. cerevisiae msraDelta (mxr1Delta) and msrbDelta (ycl033cDelta) mutants defective for peptide methionine sulfoxide reductase (MSR) activity exhibited a Cr sensitivity phenotype, and cells overexpressing these enzymes were Cr-resistant. Overexpression of MSRs also suppressed the Cr sensitivity of sod1Delta cells. The inference that protein oxidation is a primary mechanism of Cr toxicity was corroborated by an observed approximately 20-fold increase in the cellular levels of protein carbonyls within 30 min of Cr exposure. Carbonylation was not distributed evenly among the expressed proteins of the cells; certain glycolytic enzymes and heat-shock proteins were specifically targeted by Cr-dependent oxidative damage. This study establishes an oxidative mode of Cr toxicity in S. cerevisiae, which primarily involves oxidative damage to cellular proteins.

• PMID: 15942001
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• PubMed
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Journal Article | Research Support, N.I.H., Extramural | Research Support, U.S. Gov't, P.H.S.

Authors

Sumner ER, Shanmuganathan A, Sideri TC, Willetts SA, Houghton JE, Avery SV

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