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IC50: 76-112 μM for GTP cyclohydrolase I

6,7-Dimethyltetrahydropterin is a GTP cyclohydrolase I inhibitor.

GTP cyclohydrolase I catalyzes the formation of D-erythro-7,8-dihydroneopterin (dihydroneopterin) triphosphate and formate from GTP. Dihydroneopterin triphosphate has been identified as a critical intermediate in the biosynthesis of folic acid, pteridines in insects and amphibians, and tetrahydrobiopterin. Tetrahydrobiopterin is the obligatory cofactor for tyrosine and tryptophan hydroxylase, which are rate-limiting enzymes for biogenic amine synthesis. Tetrahydrobiopterin is the cofactor for phenylalanine hydroxylase as well, which converts Lphenylalanine to L-tyrosine.

In vitro: Previous study identified 6,7-dimethyltetrahydropterin as a noncompetitive inhibitor of GTP cyclohydrolase. However, no substrate inhibition of the enzyme was detected 1mM GTP, which is about 8-fold the Km value of the enzyme [1]. Another study found that phenylalanine hydroxylase could be inhibited by 6,7-dimethyltetrahydropterin, its cofactor. The rate of inactivation, which was irreversible, increased with the concentration of 6,7-dimethyltetrahydropterin. Moreover, 6,7-dimethyltetrahydropterin was found to be unstable when the solution was exposed to air but was stabilized by dithiothreitol the aerobic oxidation of which was significantly accelerated by 6,7-dimethyltetrahydropterin [2].

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