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J. Biol. Chem., Vol. 283, Issue 42, 28361-28369, October 17, 2008

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Mammals Reduce Methionine-S-sulfoxide with MsrA and Are Unable to Reduce Methionine-R-sulfoxide, and This Function Can Be Restored with a Yeast Reductase^*

From the Redox Biology Center and Department of Biochemistry, University of Nebraska, Lincoln, Nebraska 68588-0664

Methionine is an essential amino acid in mammals at the junction of methylation, protein synthesis, and sulfur pathways. However, this amino acid is highly susceptible to oxidation, resulting in a mixture of methionine-S-sulfoxide and methionine-R-sulfoxide. Whether methionine is quantitatively regenerated from these compounds is unknown. Here we report that SK-Hep1 hepatocytes grew on methionine-S-sulfoxide and consumed this compound by import and methionine-S-sulfoxide reductase (MsrA)-dependent reduction, but methionine-R-sulfoxide reductases were not involved in this process, and methionine-R-sulfoxide could not be used by the cells. However, SK-Hep1 cells expressing a yeast free methionine-R-sulfoxide reductase proliferated in the presence of either sulfoxide, reduced them, and showed increased resistance to oxidative stress. Only methionine-R-sulfoxide was detected in the plasma of wild type mice, but both sulfoxides were in the plasma of MsrA knock-out mice. These results show that mammals can support methionine metabolism by reduction of methionine-S-sulfoxide, that this process is dependent on MsrA, that mammals are inherently deficient in the reduction of methionine-R-sulfoxide, and that expression of yeast free methionine-R-sulfoxide reductase can fully compensate for this deficiency.

Received for publication, July 2, 2008 , and in revised form, July 30, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant AG021518 (to V. N. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ To whom correspondence should be addressed: N151 Beadle Center, University of Nebraska, Lincoln, NE 68588. Tel.: 402-472-4948; Fax: 402-472-7842; E-mail: vgladyshev1{at}unl.edu.

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