The control of 5‐hydroxytryptamine and dopamine synthesis in the brain: A theoretical approach

Abstract

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.

Blood‐brain barrier transport of amino acids in healthy controls and in patients with phenylketonuria

“…Theoretical calculations of brain amino acid fluxes in PKU, based on estimated plasma amino acid concentration and on experimentally determined Vma x and K m values, have previously been carried out (Hommes 1989;Hommes and Lee 1990a). In those studies it was concluded that effects at the BBB could not provide an entire explanation for the aetiology of brain damage, since similar Completion effects take place in histidinaemia and tyrosinaemia, type II, where brain dysfunction does not develop to the same extent.…”

Large Neutral Amino Acid Supplementation Exerts Its Effect through Three Synergistic Mechanisms: Proof of Principle in Phenylketonuria Mice

“…High brain Phe concentrations have been found to be neurotoxic and to affect brain metabolism [ 10 – 14 ], while reduced brain availability of non-Phe LNAA has been related to impaired cerebral protein synthesis [ 6 , 15 ]. In addition, impaired cerebral monoaminergic neurotransmitter synthesis may result from outcompeted brain uptake of their amino acid precursors tyrosine and tryptophan [ 16 ], and/or from an inhibitory effect of high brain Phe concentrations on tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) [ 17 ].…”

The effect of plasma valine, isoleucine and leucine on the control of the flux through tyrosine‐ and tryptophan‐hydroxylase in the brain

“…Recent calculations on the control of tyrosine hydroxylase and tryptophan hydroxylase in brain have shown that the supply of substrates for these enzymes as well as the flux through these enzymes is largely controlled by the phenylalanine level and that the transport across the BBB does not contribute to the cause of permanent brain dysfunction in PKU (Hommes, 1989;Hommes and Lee, 1990). These calculations raised the question as to whether increased plasma concentrations of VIL could modify the flux through the hydroxylases or lower the brain phenylalanine levels to therapeutically acceptable levels.…”