Dopamine, in the presence of tyrosinase, covalently modifies and inactivates tyrosine hydroxylase.
Dopamine has been implicated as a potential mediating factor in a variety of neurodegenerative disorders. Dopamine can be oxidized to form a reactive dopamine quinone that can covalently modify cellular macromolecules including protein and DNA. This oxidation can be enhanced through various enzymes including tyrosinase and/or prostaglandin H synthase. One of the potential targets in brain for dopamine quinone damage is tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis. The present studies demonstrated that dopamine quinone, the formation of which was enhanced through the activity of the melanin biosynthetic enzyme, tyrosinase, covalently modified and inactivated tyrosine hydroxylase. Dihydroxyphenylalanine (DOPA; the catechol-containing precursor of dopamine) also inactivated tyrosine hydroxylase under these conditions. Catecholamine-mediated inactivation occurred with both purified tyrosine hydroxylase as well as enzyme present in crude pheochromocytoma homogenates. Inactivation was associated with covalent incorporation of radiolabelled dopamine into the enzyme as assessed by immunoprecipitation, size exclusion chromatography, and denaturing sodium dodecylsulfate (SDS)-polyacrylamide gel electrophoresis. Furthermore, the covalent modification and inactivation of tyrosine hydroxylase was blocked by antioxidant compounds (dithiothreitol, reduced glutathione, or NADH). In addition to kinetic feedback inhibition and the formation of an inhibitory dopamine/Fe+3 complex, these findings suggest that a third mechanism exists by which dopamine (or DOPA) can inhibit tyrosine hydroxylase, adding further complexity to the regulation of catecholamine biosynthesis.
Xu
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Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1083, USA.
Stokes
A H
AH
Roskoski
R
R
Vrana
K E
KE
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002850:Chromatography, Gel; D004295:Dihydroxyphenylalanine / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D005246:Feedback; D005978:Glutathione / Q000494:pharmacology; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D009243:NAD / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016716:PC12 Cells / Q000201:enzymology; D010300:Parkinson Disease / Q000378:metabolism; D010940:Plant Proteins / Q000378:metabolism; D011233:Precipitin Tests; D051381:Rats; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000975:Antioxidants; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010940:Plant Proteins; D009243:NAD; C104705:dopamine quinone; D004295:Dihydroxyphenylalanine; D014446:Tyrosine 3-Monooxygenase; D014442:Monophenol Monooxygenase; D005978:Glutathione; D004229:Dithiothreitol; D004298:Dopamine