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J. Biol. Chem., Vol. 280, Issue 41, 34569-34576, October 14, 2005

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Post-translational Regulation of Mercaptopyruvate Sulfurtransferase via a Low Redox Potential Cysteine-sulfenate in the Maintenance of Redox Homeostasis^*

Noriyuki Nagahara1 and Akira Katayama

From the Department of Environmental Medicine and the Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo 113-8602, Japan

3-Mercaptopyruvate sulfurtransferase (MST) (EC 2.8.1.2), a multifunctional enzyme, catalyzes a transsulfuration from mercaptopyruvate to pyruvate in the degradation process of cysteine. A stoichiometric concentration of hydrogen peroxide and of tetrathionate () inhibited rat MST (k_i = 3.3 min^–1, K_i = 120.5 µM and k_i = 2.5 min^–1, K_i = 178.6 µM, respectively). The activity was completely restored by dithiothreitol or thioredoxin with a reducing system containing thioredoxin reductase and NADPH, but glutathione did not restore the activity. On the other hand, an excess molar ratio dose of hydrogen peroxide inactivated MST. Oxidation with a stoichiometric concentration of hydrogen peroxide protected the enzyme against reaction by iodoacetate, which modifies a catalytic Cys²⁴⁷, suggesting that Cys²⁴⁷ is a target of the oxidants. A matrix-assisted laser desorption/ionization–time-of-flight mass spectrometric analysis revealed that hydrogen peroxide- and tetrathionate-inhibited MSTs were increased in molecular mass consistent with the addition of atomic oxygen and with a thiosulfate (), respectively. Treatment with dithiothreitol restored modified MST to the original mass. These findings suggested that there was no nearby cysteine with which to form a disulfide, and mild oxidation of MST resulted in formation of a sulfenate (SO^–) at Cys²⁴⁷, which exhibited exceptional stability and a lower redox potential than that of glutathione. Oxidative stress decreases MST activity so as to increase the amount of cysteine, a precursor of thioredoxin or glutathione, and furthermore, these cellular reductants restore the activity. Thus the redox state regulates MST activity at the enzymatic level, and on the other hand, MST controls redox to maintain cellular redox homeostasis.

Received for publication, May 23, 2005 , and in revised form, August 16, 2005.

^* This study was supported by the Naito Foundation. 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.

¹ To whom correspondence should be addressed: Dept. of Environmental Medicine, Nippon Medical School, 1-1-5 Sendagi Bunkyo-ku, Tokyo 113-8602, Japan. Tel.: 81-3-3822-2131; Fax: 81-3-5685-3065; E-mail: noriyuki{at}nms.ac.jp.

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