guanosine-triphosphate and 7-8-dihydrobiopterin

Topics: Animals; Biopterins; Brain; Guanosine Triphosphate; Mixed Function Oxygenases; Pteridines; Rats; Serotonin; Tyrosine 3-Monooxygenase

Repeated intraventricular injections of 2,4-diamino-6-hydroxypyrimidine (DAO-Pyr), inhibitor of D-erythro-q-dihydroneopterin triphosphate synthetase, inhibited q-BH2 synthesis from GTP, markedly increased accumulation of 2-amino-4-hydroxy-5 (or -6)-formamido-6-triphosphoribosylaminopyrimidine (FPyd-P3) and brought about a 60% decrease in the in vivo of reduced biopterin (BH2 and BH4) pool in the brain. Nevertheless, there was no effect on the rate of hydroxylation of L-tryptophan or on the 5-hydroxytryptamine level in rat brain. These data emphasized the significance of the rate of hydrogen transfer and the limitation of the concept of "unsaturation" (i.e., the absolute amount of the carrier pterin molecule) for the synthesis of neurotransmitters in vivo.

Topics: Animals; Biopterins; Brain; Guanosine Triphosphate; Hypoxanthines; Pteridines; Pyrimidine Nucleotides; Rats; Serotonin; Tryptophan Hydroxylase

A patient with atypical phenylketonuria and normal liver dihydropteridine reductase and phenylalanine-4-hydroxylase activities excreted neopterin but not biopterin or dihydrobiopterin in urine. The oral administration of L-sepiapterin (1 mg/kg body weight) lowered serum-henylalanine from 17.1 to 1.1 mg/dl within 6 h. Comparable responses were observed after oral administration of L-erythro-7, 8-dihydrobiopterin or L-erythro-5, 6, 7, 8-tetrahydrobiopterin (each given in a dose of 2.5 mg/kg body weight). The results indicate a 7, 8-dihydrobiopterin synthetase deficiency in the patient.

Topics: Alcohol Oxidoreductases; Biopterins; Child, Preschool; Female; Guanosine Triphosphate; Humans; Phenylalanine; Phenylketonurias; Pteridines; Pterins

Three specific enzymes are involved in the cerebral synthesis of 7,8-dihydrobiopterin from GTP. These were isolated, purified, and characterized. The first enzyme, also catalyzing the rate-limiting step, is GTP-cyclohydrolase A-I or Mg2+-dependent A-II, which hydrolyze the GTP to the specific product 2-amino-6-(5-triphosphoribosyl)-amino-5-or-6-formamido-6-hydroxypyrimidine (FPyd-P3). FPyd-P3 is cyclized by a synthetase to D-erythro-7,8-dihydroneopterintriphosphate (NPTH2-P3). The new enzyme, D-erythro-7,8-dihydroneopterintriphosphate synthetase (enzyme B) is a basic protein of 9177 daltons containing three free SH groups, isoleucyl-seryl- as N- and valyl-glutamyl- as C-terminals. This enzyme of 69 amino acid residues from rat and 68 residues (one less aspartic acid) from guinea pig brain contains no hydroxyproline, methionine, or tryptophan. The enzyme from rat brain will gradually convert its product NPTH2-P3 to BH2, wherease the enzyme from guinea pig brain lacks this property. 2,4-amino-6-hydroxypyrimidine and dFPyd-P3 are effective inhibitors of this enzyme. The synthesis of BH2 from NPTH2-P3, but not from 7,8-dihydroneopterin, is catalyzed by L-erythro-7,8-dihydrobiopterin synthetase (enzyme C), which was purified to electrophoretic purity. This enzyme does not require pyridine nucleotides of Mc2+ for its catalysis.

Topics: Alcohol Oxidoreductases; Amino Acids; Aminohydrolases; Animals; Biopterins; Brain; GTP Cyclohydrolase; Guanosine Triphosphate; Guinea Pigs; Hypoxanthines; Kinetics; Magnesium; Molecular Weight; Pteridines; Rats

Topics: Animals; Biopterins; Brain; Cytosol; Guanosine Triphosphate; Humans; Microsomes; Mitochondria; Neurons; Organ Specificity; Pteridines; Rabbits; Rats; Species Specificity; Subcellular Fractions; Synaptosomes