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Inactivation of tyrosine hydroxylase by pterin substrates following phosphorylation by cyclic AMP-dependent protein kinase

R Roskoski , H Wilgus and KE Vrana

Department of Biochemistry and Molecular Biology, Louisiana State University Medical Center, New Orleans 70119.

We reported previously that, following phosphorylation by cyclic AMP- dependent protein kinase, tyrosine hydroxylase in rat corpus striatal extracts is inactivated in a time-dependent and apparently irreversible fashion. Removal of low molecular weight substances from these extracts by gel filtration attenuates this inactivation. We tried to determine the identity of endogenous metabolites that promote inactivation of tyrosine hydroxylase under our experimental conditions. In the present study, we report that the reducing co-substrate tetrahydrobiopterin and its analogues promoted this irreversible inactivation. The concentration that produced a 50% loss of activity (at 20 min) of the phosphorylated enzyme was 0.7 microM and that for the unphosphorylated enzyme was 420 microM. Using enzyme purified from a rat pheochromocytoma, we found that tyrosine, alpha-methyl-p-tyrosine, and a 3-iodotyrosine protected the phosphorylated enzyme against the inactivation produced by tetrahydrobiopterin. Catecholamines (dopamine, norepinephrine, epinephrine, and some of their analogues) also nullified inactivation. In contrast, the product of the reaction, dihydroxyphenylalanine, failed to attenuate the inactivation process. We performed several studies to ascertain the mechanism of inhibition by tetrahydrobiopterin. We considered the possibility that it formed reactive free radicals that produced inhibition. Free radical scavengers, however, failed to block the inhibition produced by tetrahydrobiopterin. Superoxide dismutase, catalase, and peroxidase also failed to protect tyrosine hydroxylase against inactivation. Moreover, when the experiments were performed under anaerobic conditions, the inactivation process was unaffected. These results suggest that reactive oxygenated species were not required for inactivation by tetrahydrobiopterin.

Volume 38, Issue 4, pp. 541-546, 10/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics




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F. Urano, N. Hayashi, F. Arisaka, H. Kurita, S. Murata, and H. Ichinose
Molecular mechanism for pterin-mediated inactivation of tyrosine hydroxylase: formation of insoluble aggregates of tyrosine hydroxylase.
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H. J. Choi, Y. J. Jang, H. J. Kim, and O. Hwang
Tetrahydrobiopterin Is Released from and Causes Preferential Death of Catecholaminergic Cells by Oxidative Stress
Mol. Pharmacol., September 1, 2000; 58(3): 633 - 640.
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Copyright © 1990 by the American Society for Pharmacology and Experimental Therapeutics