Dopamine prevents nitration of tyrosine hydroxylase by peroxynitrite and nitrogen dioxide: is nitrotyrosine formation an early step in dopamine neuronal damage?
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.
Park
Samuel
S
Department of Psychiatry and Behavioral Neurosciences, School of Medicine, Wayne State University, 2125 Scott Hall, 540 E. Canfield, Detroit, MI 48201, USA.
Geddes
Timothy J
TJ
Javitch
Jonathan A
JA
Kuhn
Donald M
DM
D015102:3,4-Dihydroxyphenylacetic Acid / Q000494:pharmacology; D002460:Cell Line; D004295:Dihydroxyphenylalanine / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D015870:Gene Expression; D005982:Glutathione Transferase / Q000235:genetics; D049452:Green Fluorescent Proteins; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008164:Luminescent Proteins / Q000235:genetics; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins; D009566:Nitrates / Q000378:metabolism*; D009585:Nitrogen Dioxide / Q000494:pharmacology*; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins; D014443:Tyrosine / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D008164:Luminescent Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009566:Nitrates; D011993:Recombinant Fusion Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D030421:Peroxynitrous Acid; D049452:Green Fluorescent Proteins; D014443:Tyrosine; D004295:Dihydroxyphenylalanine; D014446:Tyrosine 3-Monooxygenase; D005982:Glutathione Transferase; D009585:Nitrogen Dioxide; D004298:Dopamine