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Originally published In Press as doi:10.1074/jbc.M209042200 on October 9, 2002

J. Biol. Chem., Vol. 277, Issue 50, 48295-48302, December 13, 2002
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Dopamine Biosynthesis Is Regulated by S-Glutathionylation
POTENTIAL MECHANISM OF TYROSINE HYDROXYLASE INHIBITION DURING OXIDATIVE STRESS*,

Chad R. BorgesDagger , Timothy Geddes§, J. Throck WatsonDagger , and Donald M. Kuhn§||**

From the Dagger  Department of Biochemistry, Michigan State University, East Lansing, Michigan 48824, the § Department of Psychiatry and Behavioral Neurosciences and the || Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, and the  John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan 48201

Tyrosine hydroxylase (TH), the initial and rate-limiting enzyme in the biosynthesis of the neurotransmitter dopamine, is inhibited by the sulfhydryl oxidant diamide in a concentration-dependent manner. The inhibitory effect of diamide on TH catalytic activity is enhanced significantly by GSH. Treatment of TH with diamide in the presence of [35S]GSH results in the incorporation of 35S into the enzyme. The effect of diamide-GSH on TH activity is prevented by dithiothreitol (DTT), as is the binding of [35S]GSH, indicating the formation of a disulfide linkage between GSH and TH protein cysteinyls. Loss of TH catalytic activity caused by diamide-GSH is partially recovered by DTT and glutaredoxin, whereas the disulfide linkage of GSH with TH is completely reversed by both. Treatment of intact PC12 cells with diamide results in a concentration-dependent inhibition of TH activity. Incubation of cells with [35S]cysteine, to label cellular GSH prior to diamide treatment, followed by immunoprecipitation of TH shows that the loss of TH catalytic activity is associated with a DTT-reversible incorporation of [35S]GSH into the enzyme. A combination of matrix-assisted laser desorption/ionization/mass spectrometry and liquid chromatography/tandem mass spectrometry was used to identify the sites of S-glutathionylation in TH. Six cysteines (177, 249, 263, 329, 330, and 380) of the seven cysteine residues in TH were confirmed as substrates for modification. Only Cys-311 was not S-glutathionylated. These results establish that TH activity is influenced in a reversible manner by S-glutathionylation and suggest that cellular GSH may regulate dopamine biosynthesis under conditions of oxidative stress or drug-induced toxicity.

* This work was supported by NIDA, National Institutes of Health Grant DA10756 and by a Veterans Affairs Merit Award.The costs of publication of this article were defrayed in part by the payment of page charges. The 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 a table showing assignment of all peaks from LC/MS/MS analysis and a figure showing the amino acid sequence of rat tyrosine hydroxylase.

** To whom correspondence should be addressed: Dept. of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 2125 Scott Hall, 540 E. Canfield, Detroit, MI 48201. Tel.: 313-577-9737; Fax: 313-577-9737; E-mail: donald.kuhn@wayne.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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