Amino acid depletion in the blood and brain tissue of hyperphenylalaninemic rats is abolished by the administration of additional lysine: a contribution to the understanding of the metabolic defects in phenylketonuria

The elevated phenylalanine concentration in the blood of untreated phenylketonuric children is known to be paralleled by decreased concentrations of other amino acids in the blood and brain tissue. Due to the low availability of other large, neutral amino acids in the brain, protein synthesis in, and the normal development of, the brain are disturbed. A similar effect is observed in suckling rats rendered hyperphenylalaninemic by the daily injection of phenylalanine plus alpha-methylphenylalanine, an in vivo inhibitor of the phenylalanine-hydroxylating pathway in the liver. In this study, the simultaneous injection of lysine is shown to prevent the depletion of amino acids from the blood and brain tissue, and the retardation of brain growth, in suckling hyperphenylalaninemic rats. It is suggested that both amino acids, phenylalanine and lysine, are important rate-limiting substrates for the rapid protein anabolism of developing tissues. In the presence of an excess of phenylalanine, other amino acids, and in relation to its requirement during the phase of hyperplastic growth in particular lysine, are less available from the circulation and limit phenylalanine-stimulated protein synthesis in developing tissues. The supplementation of lysine to developing hyperphenylalaninemic rats prevents the consequences of this effect, i.e., the depletion of amino acids in the blood, and therefore, in the brain tissue, and the retardation of brain growth.