Effects of sepiapterin and 6-acetyldihydrohomopterin on the guanosine triphosphate cyclohydrolase I of mouse, rat and the fruit-fly Drosophila.
The regulation of GTP cyclohydrolase I would lead to the regulation of tetrahydrobiopterin, an important cofactor for synthesis of neurotransmitters. In an attempt to extend a previous finding [Bellahsene, Dhondt, & Farriaux (1984) Biochem. J. 217, 59-65] that GTP cyclohydrolase I of rat liver is inhibited by subnanomolar concentrations of reduced biopterin and sepiapterin, we found that this could not be verified with the enzyme from mouse liver, fruit-fly (Drosophila) heads or, indeed, from rat liver. It was shown, however, that 12 microM-sepiapterin inhibited mouse liver GTP cyclohydrolase I. Another compound, namely 6-acetyldihydrohomopterin, was also employed in the present study to explore its effect on enzymes that lead to its synthesis in Drosophila and for effects on mammalian systems; at 2-5 microM this compound was shown to stimulate one form of mouse liver GTP cyclohydrolase I and then to inhibit at higher concentrations (40 microM). Neither sepiapterin nor 6-acetyldihydrohomopterin caused any effect on the Drosophila head enzyme. On the other hand, the sigmoid GTP concentration curve for the Drosophila enzyme may indicate a regulatory characteristic of this enzyme. Another report, on the lower level of GTP cyclohydrolase I in mutant mouse liver [McDonald, Cotton, Jennings, Ledley, Woo & Bode (1988) J. Neurochem. 50, 655-657], was confirmed and extended. Instead of having 10% activity, we find that the hph-1 mouse mutant has less than 2% activity in the liver. These studies demonstrate that micromolar levels of reduced pterins may have regulatory effects on GTP cyclohydrolase I and that a mouse mutant is available that has low enough activity to be considered as a model for human atypical phenylketonuria.
Biology Division, Oak Ridge National Laboratory, TN 37831.
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D000619:Aminohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D004330:Drosophila; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology; D051379:Mice; D008817:Mice, Mutant Strains; D011621:Pteridines / Q000494:pharmacology*; D011622:Pterins / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D001381:Azepines; D011621:Pteridines; D011622:Pterins; C032200:2-amino-4-oxo-6-acetyl-7,8-dihydro-3H,9H-pyrimidodiazepine; C016727:sepiapterin; D000619:Aminohydrolases; D006136:GTP Cyclohydrolase