Journal of Inherited Metabolic Disease

, Volume 6, Issue 1, pp 32–35 | Cite as

Inhibition byl-phenylalanine of tryptophan transport by synaptosomal plasma membrane vesicles: Implications in the pathogenesis of phenylketonuria

  • E. Herrero
  • M. C. Aragon
  • C. Gimenez
  • F. Valdivieso


Phenylalanine is accumulated in the genetically linked deficiency phenylketonuria. The effect ofl-phenylalanine on the transport of tryptophan was studied using membrane vesicles from rat-brain synaptosomes. Phenylalanine at similar concentrations to those found in phenylketonuric patients competitively inhibits tryptophan uptake, with aKi of the same order as theKm for tryptophan. This inhibition could be responsible for the depletion of serotonin found in phenylketonuria.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aragon, M. C., Gimenez, C., Mayor, Jr. F., Marvizon, J. G. and Valdivieso, F. Tyrosine transport by membrane vesicles isolated from rat brain.Biochim. Biophys. Acta 646 (1981) 465–470PubMedGoogle Scholar
  2. Aragón, M. C., Gimenez, C. and Valdivieso, F. Inhibition by phenylalanine of tyrosine transport by synaptosomal plasma membrane vesicles: implications in the pathogenesis of phenylketonuria.J. Neurochem. 39 (1982) 1185–1187PubMedGoogle Scholar
  3. Barbosa, E., Joanny, P. and Carriol, J. Accumulation active du tryptophane dans le cortex cérébral isolé du rat.C. R. Soc. Biol. (París) 164 (1970) 345–350Google Scholar
  4. Blasberg, R. G. and Lajtha, A. Substrate specificity on steady-state amino acid transport in mouse brain slices.Arch. Biochem. 112 (1965) 361–377CrossRefGoogle Scholar
  5. Blau, K. Phenylalanine hydroxylase deficiency: Biochemical, physiological, and clinical aspects of phenylketonuria and related phenylalaninemias. In Youdim, M. B. H. (ed)Aromatic Amino Acid Hydroxylases and Mental Disease, Wiley, New York, NY (1979), pp. 77–139Google Scholar
  6. Fernston, J. W. and Wurtzman, R. J. Brain serotonin content: physiological dependence on plasma tryptophan levels.Science 173 (1974) 149–152Google Scholar
  7. Grahame-Smith, D. G. and Parfitt, A. G. Tryptophan transport across the synaptosomal membrane.J. Neurochem. 17 (1970) 1339–1352PubMedGoogle Scholar
  8. Grahame-Smith, D. G. Studies in vivo on the relationship between brain tryptophan, brain 5-HT synthesis, and hyperactivity in rats treated with a monoamine oxidative inhibitor andl-tryptophan.J. Neurochem. 18 (1971) 1053–1066PubMedGoogle Scholar
  9. Guroff, G. and Udenfriend, S. Studies on aromatic amino acid uptake by rat brainin vivo.J. Biol. Chem. 237 (1962) 803–806PubMedGoogle Scholar
  10. Hedqvist, P. and Stjarne, L. The relative role of recapture and of ‘de novo’ synthesis for the maintenance of neurotransmitter homeostasis in noradrenergic nerves.Acta Physiol. Scand. 76 (1969) 270–276PubMedCrossRefGoogle Scholar
  11. Johnston, G. A. R. and Iversen, L. L. Glycine uptake in rat central nervous systems slices and homogenates: Evidence for different uptake systems in spinal cord and cerebral cortex.J. Neurochem. 18 (1971) 1951–1961PubMedGoogle Scholar
  12. Kanner, B. I. Active transport of α-aminobutyric acid by membrane vesicles isolated from rat brain.Biochemistry 17 (1978) 1207–1211CrossRefPubMedGoogle Scholar
  13. Kanner, B. I. and Sharon, I. Active transport ofl-proline by membrane vesicles isolated from rat brain.Biochim. Biophys. Acta 600 (1980) 185–194PubMedGoogle Scholar
  14. Korpi, E. R. Tryptophan and phenylalanine transport in rat cerebral cortex slices as influenced by sodium ions.Neurochem. Res. 5 (1980) 415–431CrossRefPubMedGoogle Scholar
  15. Kuhar, M. J. and Zarbin, M. A. Synaptosomal transport: A chloride dependence for choline, GABA, glycine, and several other compounds.J. Neurochem. 31 (1978) 251–256PubMedGoogle Scholar
  16. Laakso, M. L. and Oja, S. S. Transport of tryptophan and tyrosine in rat brain slices in the presence of lithium.Neurochem. Res. 4 (1979) 411–423CrossRefPubMedGoogle Scholar
  17. Lädhesmäki, P. and Hannus, M.-L. Effect of aromatic acids on the influx of aromatic amino acids in rat brain slices.Exp. Brain. Res. 30 (1977) 539–548Google Scholar
  18. Lajtha, A. Amino acid transport in the brainin vivo andin vitro. In Wolstenholme, G. E. W. and Fitzsimons, D. W. (eds.)Aromatic Amino Acids in the Brain, Elsevier, Amsterdam, 1974, pp. 25–41Google Scholar
  19. Logan, W. J. and Snyder, S. H. High affinity uptake systems for glycine, glutamic and aspartic acids in synaptosomes of rat central nervous tissues.Brain. Res. 42 (1972) 413–431CrossRefPubMedGoogle Scholar
  20. Mandell, A. J. and Knapp, S. Regulation of serotonin biosynthesis in brain: role of the high affinity uptake of tryptophan into serotonergic neurons.Fed. Proc., Fed. Am. Soc. Exp. Biol. 36 (1977) 2142–2148Google Scholar
  21. Marvizón, J. G., Mayor, Jr. F., Argón, M. C., Gimenez, C., and Valdivieso, F.l-Aspartate transport into plasma membrane vesicles derived from rat brain synaptosomes.J. Neurochem. 37 (1981) 1401–1406PubMedGoogle Scholar
  22. Mayor, Jr. F., Marvizón, J. G., Aragon, M. C., Giménez, C. and Valdivieso, F. Glycine transport into plasma membrane vesicles derived from rat brain synaptosomes.Biochem. J. 198 (1981) 535–541PubMedGoogle Scholar
  23. McKean, C. H., Boggs, D. E. and Peterson, N. A. The influence of high phenylalanine and tyrosine on the concentration of essential amino acids in brain.J. Neurochem. 15 (1968) 235–241PubMedGoogle Scholar
  24. McKean, C. H. The effects of high phenylalanine concentration on serotonin and catecholamine metabolism in the human brain.Brain Res. 47 (1972) 469–476CrossRefPubMedGoogle Scholar
  25. Neame, K. D. Phenylalanine as inhibitor of transport of amino-acids in brain.Nature (London) 192 (1961) 173–174PubMedGoogle Scholar
  26. Pratt, O. E. The transport of metabolizable substances into the living brain. In Levi, G., Battistin, L. and Lajtha, A. (eds.)Transport Phenomena in the Nervous System: Physiological and Pathological Aspects. Advances in Experimental Medicine and Biology. Plenum Press, New York, 1976, pp 55–75Google Scholar
  27. Pratt, O. E. The needs of the brain for amino acids and how they are transported across the blood-brain barrier. In Belton, N. R. and Toothill, C. (eds.)Transport and Inherited Disease. MTP Press, Lancaster, 1981, pp. 87–122Google Scholar
  28. Resch, K., Imm, W., Ferber, E., Wallach, D. F. M. and Fisher, H. Quantitative determination of soluble and membrane proteins through their native fluorescence.Naturwissenschaften 58 (1971) 220CrossRefPubMedGoogle Scholar
  29. Sershen, H. and Lajtha, A. Inhibition pattern of analogs indicates the presence of ten or more transport systems for amino acids in brain cells.J. Neurochem. 32 (1979) 719–726PubMedGoogle Scholar
  30. Tyfield, L. A. and Holton, J. B. The effect of high concentrations of histidine on the level of other amino acids in plasma and brain of the mature rat.J. Neurochem. 26 (1976) 101–105PubMedGoogle Scholar
  31. Vahvelainen, M.-L. and Oja, S. S. Kinetic analysis of phenylalanine-induced inhibition in the saturable influx of tyrosine, tryptophan, leucine and histidine into brain cortex slices from adult and 7-day-old rats.J. Neurochem. 24 (1975) 885–892PubMedGoogle Scholar
  32. Vorhees, C. V., Butcher, R. E. and Berry, H. K. Progress in experimental phenylketonuria: a critical review.Neurosci. Biobehav. Rev. 5 (1981) 177–190CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM and MTP Press Limited 1983

Authors and Affiliations

  • E. Herrero
    • 1
  • M. C. Aragon
    • 1
  • C. Gimenez
    • 1
  • F. Valdivieso
    • 1
  1. 1.Departamento de Bioquímica y Biología Molecular, Centro de Biología Molecular, Facultad de CienciasUniversidad Autónoma de MadridMadrid-34Spain

Personalised recommendations