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The Journal of Neuroscience, December 1, 1999, 19(23):10289-10294
Peroxynitrite Inactivation of Tyrosine Hydroxylase: Mediation by
Sulfhydryl Oxidation, not Tyrosine Nitration
Donald M.
Kuhn1, 2,
Cheryl W.
Aretha1, and
Timothy J.
Geddes1
1 Department of Psychiatry and Behavioral Neurosciences
and 2 Center for Molecular Medicine and Genetics, Wayne
State University School of Medicine, Detroit, Michigan 48201
Tyrosine hydroxylase (TH) is the initial and rate-limiting enzyme
in the biosynthesis of dopamine (DA). TH activity is significantly diminished in Parkinson's disease (PD) and by the neurotoxic
amphetamines, thereby accentuating the reductions in DA associated with
these conditions. Reactive oxygen and nitrogen species have been
implicated in the damage to DA neurons seen in PD and in reaction to
amphetamine drugs of abuse, so we investigated the hypothesis that
peroxynitrite (ONOO ) could interfere with TH
catalytic function. ONOO caused a
concentration-dependent inactivation of TH. The inactivation was
associated with tyrosine nitration (maximum of four tyrosine residues
nitrated per TH monomer) and extensive sulfhydryl oxidation. Tetranitromethane, which causes sulfhydryl oxidation at pH 6 and 8 but
which nitrates tyrosines only at pH 8, inactivated TH equally at either
pH. Bicarbonate protected TH from ONOO-induced
inactivation and sulfhydryl oxidation but increased significantly tyrosine nitration. PNU-101033 blocked
ONOO-induced tyrosine nitration in TH but could
not prevent enzyme inactivation or sulfhydryl oxidation. Together,
these results indicate that the inactivation of TH by
ONOO is mediated by sulfhydryl oxidation. The
coincident nitration of tyrosine residues appears to exert little
influence over TH catalytic function.
Key words:
peroxynitrite; tyrosine hydroxylase; tyrosine nitration; sulfhydryl oxidation; dopamine; Parkinson's disease; neurotoxic
amphetamines
Copyright © 1999 Society for Neuroscience 0270-6474/99/192310289-06$05.00/0
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