Investigations on experimental hyperphenylalaninemia in rats have revealed that the incorporation of sulfate into sulfatides of brain (including myelin) is decreased and that the turnover of part of the myelin of the central nervous system is dramatically increased. It has been demonstrated that this decreased incorporation of sulfate is due to inhibition of the PAPS forming system of brain. This system is different from that of liver in that it can be inhibited by phenylalanine, some of its metabolites and other amino acids at concentrations occurring in untreated patients with inborn errors affecting the metabolism of these amino acids. It is furthermore known that specifically cerebroside sulfatide when bound to myelin basic protein protects this protein from proteolytic attack. The ATP-sulfurylase and APS-kinase from liver and brain will be purified. The effect of phenylalanine, phenylalanine metabolites and other amino acids on the sulfate activating system (ATP-sulfurylase and APS-kinase) will be investigated as an explanation for the decreased synthesis of sulfatides in brain of hyperphenylalaninemic rats which in turn could explain the increased turnover of myelin in this condition. The effects of phenylalanine, phenylalanine metabolites and other amino acids on the kinetics of the sulfate activating system will be studied as well as the effects of these compounds on the level of activity of ATP-sulfurylase and APS kinase, through interference with the biosynthesis of these enzymes. The in vivo incorporation of sulfatides into myelin and into myelin subfractions will be measured to determine whether newly synthesized sulfatide is incorporated into myelin to the same degree as newly synthesized protein in the hyperphenylalaninemic condition as compared to the same parameters in control rats.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Biochemistry Study Section (BIO)
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Medical College of Georgia (MCG)
Schools of Medicine
United States
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Hommes, F A (1991) On the mechanism of permanent brain dysfunction in hyperphenylalaninemia. Biochem Med Metab Biol 46:277-87
Hommes, F A; Lee, J S (1990) The control of 5-hydroxytryptamine and dopamine synthesis in the brain: a theoretical approach. J Inherit Metab Dis 13:37-57
Hommes, F A (1989) The role of the blood-brain barrier in the aetiology of permanent brain dysfunction in hyperphenylalaninaemia. J Inherit Metab Dis 12:41-6
Matsuo, K; Hommes, F A (1988) The development of the muscarinic acetylcholine receptor in normal and hyperphenylalaninemic rat cerebrum. Neurochem Res 13:867-70
Matsuo, K; Hommes, F (1987) Regional distribution of the phenylalanine-sensitive ATP-sulphurylase in brain. J Inherit Metab Dis 10:62-5
Matsuo, K; Moss, L; Hommes, F (1987) Development of adenosine 5'-triphosphate sulfurylase and adenosine phosphosulfate kinase in rat cerebrum and liver. Dev Neurosci 9:128-32
Hommes, F A; Moss, L; Touchton, J (1987) Purification and some properties of liver adenylylsulfate kinase. Biochim Biophys Acta 924:270-5
Hommes, F A; Moss, L (1986) The assay of ATP-sulfurylase. Anal Biochem 154:100-3