Defects of tetrahydrobiopterin synthesis and their possible relationship to a disorder of purine metabolism (the Lesch-Nyhan syndrome).

The metabolic pathways of pterin de novo synthesis, interconversion and salvage which lead to the tetrahydrobiopterin cofactor of phenylalanine 4-monooxygenase, tyrosine 2-monooxygenase and tryptophan 5-monooxygenase are reviewed and data on the enzymes which catalyze the individual steps are presented. Analogies drawn between the inborn errors of tetrahydrobiopterin production and the Lesch-Nyhan syndrome, in which purine salvage is deficient, are used as a basis for the hypothesis that the neurological manifestations of the Lesch-Nyhan syndrome are due to neurotransmitter imbalance which stems from an imbalance of the aromatic amino acid monooxygenase activities which are themselves due to impaired pterin biosynthesis. The latter arises because, in the absence of the hypoxanthine phosphoribosyltransferase catalyzed purine salvage pathway, the supply of GTP for the GTP cyclohydrolase reaction, which is the first reaction on the pterin de novo synthesis pathway, is reduced. It is proposed that the different aromatic amino acid monooxygenases are differentially affected by this constrained pterin production. The activities of those most directly related to the quantal production of the cerebral neurotransmitters dopamine, norepinephrine and 5-hydroxytryptamine are affected whereas liver phenylalanine 4-monooxygenase activity is not overtly impaired. The results of different lines of research which support this concept are cited, as is direct evidence for a selective reduction of dopamine production in the basal ganglia of patients with the Lesch-Nyhan syndrome. It is proposed that lack of GMP for functions, other than its role in pterin de novo synthesis, accounts for the features of the Lesch-Nyhan syndrome which do not occur when only tetrahydrobiopterin production is deficient as in the inborn errors of tetrahydrobiopterin synthesis.