6-methyltetrahydropterin and Phenylketonurias

The hph-1 mouse has low liver activity of GTP cyclohydrolase 1, the rate limiting enzyme in the biosynthesis of tetrahydrobiopterin (BH(4)). BH(4) is the cofactor for phenylalanine hydroxylase (PAH) and in the early stages of life the hph-1 mouse is hyperphenylalaninemic. At approximately 15 days after birth the blood phenylalanine levels normalize. During this period the animals provide an in vivo model which can be used to study the regulatory effects of phenylalanine on PAH, and for related pediatric metabolic disease in humans; from birth to youth. We therefore, examined; liver PAH activity using BH(4) and 6-methyltetrahydropterin (6MPH(4)) as cofactor; PAH total enzyme concentration by Western blotting using the PH8 antibody, and PAH state of phosphorylation using the PH7 antibody from 4 to 18 days after birth. The findings were compared to the wild type animals that are not hyperphenylalaninemic during this period. PAH (6MPH(4)) activity and total protein (PH8 antibody) rose steadily in the hph-1 mice. In control mice, both activity and total protein fluctuated. The degree of phosphorylation of PAH in the mutants and the state of activation (as measured by the 6MPH(4)/BH(4) activity ratio) increased as phenylalanine levels rose, and decreased when they fell. Similar patterns were not seen in the control animals. These studies provide in vivo evidence that phenylalanine concentration regulates the activity of PAH in the hph-1 mouse and that this acts via a mechanism that includes phosphorylation of the PAH molecule. The kinetic values (K(m) and V(max)) for mouse PAH are also reported.

Topics: Animals; Kinetics; Mice; Mice, Transgenic; Models, Animal; Mutation; Phenylalanine; Phenylalanine Hydroxylase; Phenylketonurias; Phosphorylation; Pterins

A patient with hyperphenylalaninemia caused by a defect in the synthesis of tetrahydrobiopterin was treated with 6-methyltetrahydropterin. This synthetic analog of the naturally occurring hydroxylation cofactor tetrahydrobiopterin, when given orally at a daily dose of 20 mg per kilogram of body weight increased depressed plasma and cerebrospinal fluid levels of norepinephrine. At a daily dose of 8 mg/kg, this pterin increased depressed cerebrospinal fluid levels of the biogenic amine metabolites dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid. At these doses of 6-methyltetrahydropterin, there was an improvement of the patient's neurological symptoms, including a pronounced decrease in eye rolling and drooling and a marked increase in muscle strength, coordination, and physical activity.

Topics: Biopterins; Blood Glucose; Child; Dose-Response Relationship, Drug; Growth Hormone; Humans; Male; Neurotransmitter Agents; Phenylalanine; Phenylketonurias; Prolactin; Pteridines; Pterins

Substantial amounts of tetrahydrobiopterin and 6-methyltetrahydropterin can be detected in CSF when these pterins are given peripherally to patients with hyperphenylalaninemia due to defective biopterin synthesis. Results of this study suggest that administration of either of these pterins in proper doses may prove to be a treatment not only for the impaired peripheral phenylalanine metabolism, but also for the neurologic disorders that are characteristic of the variant forms of hyperphenylalaninemia due to defective tetrahydrobiopterin synthesis or metabolism.

Topics: Biopterins; Brain; Child; Child, Preschool; Female; Humans; Male; Neopterin; Phenylalanine; Phenylketonurias; Pteridines; Pterins