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.
