The transport of the eight
amino acids (
phenylalanine,
tyrosine,
tryptophan,
valine,
leucine,
isoleucine,
histidine and
methionine) using the large neutral
amino acid transporter of the blood-brain barrier (BBB) has been calculated using published kinetic data. The fate of the
amino acids has been followed from blood to interstitial space, to cell and through metabolism which included, for
tyrosine and
tryptophan, the
hydroxylases. The system was analysed in terms of flux control coefficients. Since the summation theorem did not hold, the system clearly behaved as a non-homogeneous system. At physiological levels of these eight
amino acids, the largest contribution to the control of the flux of
tyrosine is given by the
hydroxylase step, followed by the diffusional component of the transport across the BBB. For
tryptophan it is the
hydroxylase step, followed by the carrier-mediated transport across the BBB. For the other
amino acids it is the metabolism, followed by the diffusional component of the BBB transport. These parameters for
tyrosine and
tryptophan were determined at increased levels of blood
phenylalanine,
tyrosine or
histidine. The flux through
tryptophan hydroxylase can be affected by high blood levels of
tyrosine and
histidine to values also observed in
hyperphenylalaninaemia. Since hypertyrosinaemia (type II) and hyperhistidinaemia are not associated with
mental retardation, it is concluded that interference with transport across the BBB of
tyrosine and
tryptophan, as well as the flux through
tryptophan hydroxylase leading to the synthesis of
5-hydroxytryptamine, do not contribute to the cause of permanent brain dysfunction in
hyperphenylalaninaemia. It can be calculated that addition of
tyrosine to the diet to raise the blood
tyrosine level in
phenylketonuria patients may have a beneficial effect for the synthesis of
neurotransmitters derived from
tyrosine.