Aromatic Amino Acids in the Brain.
Authors: M. Cansev, R. J. Wurtman
Journal: Annals of Internal Medicine (1975)

This chapter describes the aromatic L‐amino acids tryptophan and tyrosine and the effects on tyrosine metabolism of phenylalanine. Tryptophan and phenylalanine are essential amino acids and must ultimately be derived from dietary proteins; tyrosine is obtained both from dietary proteins and from the hydroxylation of phenylalanine by phenylalanine hydroxylase (PAH). The proportions of dietary tryptophan, tyrosine, and phenylalanine that enter the systemic circulation are limited by three hepatic enzymes— tryptophan dioxygenase, tyrosine aminotransferase, and phenylalanine hydroxylase—that destroy them. These enzymes all have high substrate Km’s, hence they have little effect on their amino acid substrates present in systemic blood but major, concentration‐dependent effects on the elevated concentrations, present postprandially, in portal venous blood. All of the large, neutral amino acids (LNAA)—e.g., the three aromatic amino acids; the three branched‐ chain amino acids, leucine, isoleucine, and valine—across from the brain’s capillaries into its substance through the action of a single transport molecule, LAT1. The kinetic properties of this molecule are such that it is saturated with LNAA at normal concentrations in systemic blood so that the individual LNAA compete with each other for blood–brain barrier transport. Hence the effect of any treatment on, for example, brain tryptophan, will depend not on plasma tryptophan, per se, but on the ratio of the plasma tryptophan concentration to the summed concentrations of the other, competing LNAA. Small quantities of LNAA molecules also enter the brain via choroid plexus transport into the cerebrospinal fluid. The levels of tryptophan in the brain determine the substrate‐saturation of tryptophan hydroxylase, and thus the rate at which tryptophan is converted to 5‐hydroxytryptophan and subsequently to serotonin or melatonin. Brain tyrosine levels may or may not affect the rate at which tyrosine is hydroxylated, and converted to the catecholamines dopamine and norepinephrine, depending on the firing frequency of the particular catecholaminergic neuron. If the neuron is firing with high frequency, the tyrosine hydroxylase enzyme becomes multiply phosphorylated; this markedly increases its affinity for its otherwise‐limiting cofactor (tetrahydrobiopterin) so that local tyrosine concentrations become limiting (several groups of prefrontal dopaminergic neurons normally fire unusually frequently, and are thus always susceptible to precursor control by available tyrosine levels). The abilities of the precursor amino acids, tryptophan and tyrosine, to control the rates at which neurons can produce and release their neurotransmitter products underlie a number of physiological processes, and also constitute a potential tool for amplifying or decreasing synaptic neurotransmission. List of Abbreviations: AMP, adenosine monophosphate; BBB, blood-brain barrier; BH4, tetrahydrobiopterin; CSF, cerebrospinal fluid; DOCA, deoxycorticosterone; DOPA, dihydroxyphenylalanine; DOPAC, dihydrophenylacetic acid; EMS, Eosinophilia-Myalgia syndrome; 5-HIAA, 5-hydroxyindole acetic acid; 5-HT, 5-hydroxytriptamine; 5-HTP, 5-hydroxytryptophan; HVA, homovanillic acid; IDO, indoleamine 2,3dioxygenase; INF-gamma, interferon-gamma; L-AAAD, aromatic-L-amino acid decarboxylase; L-DOPA, L-dihydroxyphenylalanine; LAT1, Large Neutral Amino Acid Transporter 1; LNAA, Large Neutral Amino Acid; MAO, monoamine oxidase; MOPEG-SO4, 3-methoxy-4-hydroxyphenylethyleneglycol-Sulphate; NAD, nicotinamide adenine dinucleotide; NEFA, nonesterified fatty acids; NMDA, N-methyl D-aspartate; PAH, phenylalanine hydroxylase; PKU, phenylketonuria; SOD, Superoxide dismutase; TAT, tyrosine aminotransferase; TDO, tryptophan dioxygenase; TH, tyrosine hydroxylase; TNF-alpha, tumor necrosis factoralpha; TPH, tryptophan hydroxylase