Effect of α‐Methylphenylalanine and Phenylalanine on Brain Polyribosomes and Protein Synthesis

Abstract

A chronic hyperphenylalanemia was effectively produced in developing mice by daily administrations of phenylalanine (2 mg/g body wt) and a phenylalanine hydroxylase inhibitor alpha-methyl-D,L-phenylalanine (0.43 mg/g body wt). The presence of alpha-methylphenylalanine in newborn mice inhibited 65-70% of hepatic phenylalanine hydroxylase activity within 12 h. Since this maximum inhibition persisted for 24 h or longer, decreased enzyme activity was maintained by daily administrations. Whereas concentrations of phenylalanine increased approximately 40-fold in both plasma and brain following injection of alpha-methylphenylalanine and phenylalanine, plasma levels of tyrosine were not altered significantly. Concomitant with changes in phenylalanine concentrations we observed the brain polyribosomes' disaggregation, which reached a maximum 3 h after injection and persisted as long as 18 h. Polyribosomes did not become refractory to as many as 10 daily injections of alpha-methylphenylalanine and phenylalanine. In addition to polyribosome disaggregation, chronic hyperphenylalanemia reduced the rates of polypeptide chain elongation on polyribosomes isolated from brain homogenates.

Cerebral protein synthesis in a genetic mouse model of phenylketonuria

“…The radiolabeled tracer is [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]leucine, which is used in conjunction with quantitative autoradiography to achieve spatial localization of the labeled protein in the brain for the determination of rates of protein synthesis in discrete brain regions (17). The operational equation of the method is:…”

“…Studies of developing mice administered high doses of Phe have shown disaggregation of brain polyribosomes and reduced rates of polypeptide chain elongation on polyribosomes prepared from brain homogenates (9,12); both of these effects were reversed by treatment of the mice with a mixture of neutral amino acids (leucine, isoleucine, valine, threonine, tryptophan, tyrosine, methionine) (13). Direct effects of hyperphenylalaninemia on cerebral protein synthesis in vivo have, however, been more difficult to demonstrate because of the complications of making such measurements in intact animals.…”

Protein Metabolism in Phenylketonuria and Lesch-Nyhan Syndrome

“…Free amino acid concentrations have a regulatory role in protein synthesis, with decreased concentrations resulting in decreased polysomal aggregation (8). Inhibition of polysomal aggregation and decreased incorporation of labeled leucine into a wide range of tissues in the animal model of PKU have supported the proposal that decreased protein synthesis is the cause of congenital abnormalities in the offspring of mothers with PKU (2,3,9). Imbalances of a number of amino acids other than phenylalanine are present in peripheral tissues as well as brain in both mother and fetus in the animal PKU model (2), suggesting that disturbances in protein metabolism induced by high phenylalanine concentrations would be likely to be manifest throughout the body.…”

“…2 sis in animal models of PKU (1)(2)(3)(4), which has led to wide acceptance of an etiology involving impaired protein synthesis. Such a mechanism has been used in particular to explain the tissue damage that occurs in maternal PKU.…”

(S)-2-Azaniumyl-2-methyl-3-phenylpropanoate monohydrate

“…At first, it attracted attention as a substrate analogue and an inhibitor of phenylalanine hydroxylase (EC 1.14.16.1: phenylalanine 4-monooxygenase), related to phenylketonuria (PKU), a genetic disorder (Greengard et al, 1976;Binek et al, 1981). Despite the biological and pharmaceutical interest, only a few crystal structures for 2-methyl-substituted phenylalanine derivatives have been reported, for example (R)--MePheOMeÁHClÁH 2 O (QABCAX; Crisma et al, 1997), (RS)--MeTyr (DMTYRS; Gaudestad et al, 1976) or (S)--MeDOPAÁ1.5H 2 O (COSGUM; Neuman et al, 1984).…”