N. Toshiharu, Mizutani Kimiko, Nagatsu Ikuko
Jul 15, 1972
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Journal
Biochemical Pharmacology
Abstract
Abstract The relationship between the structure and the cofactor or inhibitor activity of various synthetic 5, 6, 7, 8-tetrahydropteridines (including tetrahydrobiopterin, the possible natural cofactor) on bovine adrenal tyrosine hydroxylase, has been studied. 5,8-Unsubstituted tetrahydropterins (2-amino-4-hydroxy-5, 6, 7, 8-tetrahydropteridines) had the cofactor activity, among which tetrahydrobiopterin had the lowest Km value and the highest Vmax value. Norepinephrine inhibited tyrosine hydroxylase in competition with tetrahydrobiopterin or other tetrahydropterin cofactors. 8-Unsubstituted 2-amino-4-hydroxytetrahydropteridines with an alkyl group and the N—5 position inhibited the activity of the enzyme in competition with 6, 7-dimethyltetrahydropterin, their 2-hydroxy analogues did not inhibit the enzyme. Substitution of the tetrahydropterins at the N—8 position by an alkyl group abolished their inhibitor activities. 5-Methyl-6, 7-diphenyltetrahydropterin was the most potent inhibitor. The possibility that the cofactor or inhibitor activities which have been measured are not due to the tetrahydropteridines but due to the corresponding dihydropteridines is ruled out from the facts that 7, 8-dihydropterins had no cofactor activity and that the 5-alkyltetrahydropterins were stable during the incubation in the assay system including mercaptoethanol. However, 7,8-dihydropterins inhibited the activity in competition with 6, 7-dimethyltetrahydropterin as a cofactor.