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J. Biol. Chem., Vol. 278, Issue 31, 28736-28742, August 1, 2003

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Dopamine Prevents Nitration of Tyrosine Hydroxylase by Peroxynitrite and Nitrogen Dioxide

IS NITROTYROSINE FORMATION AN EARLY STEP IN DOPAMINE NEURONAL DAMAGE?^*

Samuel Park , Timothy J. Geddes  , Jonathan A. Javitch ¶ and Donald M. Kuhn   || **

From the Department of Psychiatry and Behavioral Neurosciences, 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, and the ^¶Center for Molecular Recognition and Departments of Pharmacology and Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York 10032

Peroxynitrite and nitrogen dioxide (NO₂) are reactive nitrogen species that have been implicated as causal factors in neurodegenerative conditions. Peroxynitrite-induced nitration of tyrosine residues in tyrosine hydroxylase (TH) may even be one of the earliest biochemical events associated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced damage to dopamine neurons. Exposure of TH to peroxynitrite or NO₂ results in nitration of tyrosine residues and modification of cysteines in the enzyme as well as inactivation of catalytic activity. Dopamine (DA), its precursor 3,4-dihydroxyphenylalanine, and metabolite 3,4-dihydroxyphenylacetic acid completely block the nitrating effects of peroxynitrite and NO₂ on TH but do not relieve the enzyme from inhibition. o-Quinones formed in the reaction of catechols with either peroxynitrite or NO₂ react with cysteine residues in TH and inhibit catalytic function. Using direct, real-time evaluation of tyrosine nitration with a green fluorescent protein-TH fusion protein stably expressed in intact cells (also stably expressing the human DA transporter), DA was also found to prevent NO₂-induced nitration while leaving TH activity inhibited. These results show that peroxynitrite and NO₂ react with DA to form quinones at the expense of tyrosine nitration. Endogenous DA may therefore play an important role in determining how DA neurons are affected by reactive nitrogen species by shifting the balance of their effects away from tyrosine nitration and toward o-quinone formation.

Received for publication, April 25, 2003 , and in revised form, May 22, 2003.

^* This work was supported by National Institute on Drug Abuse Grants DA06067 (to S. U. P.), DA107856 (to D. M. K.), DA14692 (to D. M. K.), DA11495 (to J. A. J.), by National Institute of Mental Health Grant MH57324 (to J. A. J.), and by a Veterans Affairs Merit Award (to D. M. K.). 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.

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

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