Regulation of 5-hydroxytryptamine Synthesis

There is a great deal of evidence that changes of precursor availability, within the range of normal physiological variation, can affect the synthesis of n e w transmitters in the brain.The transmitter amine 5-hydroxytryptamine (serotonin; 5-HT) is derived from tryptophan, and it has been shown that changes in blood tryptophan levels are reflected in changes in brain 5-HT synthesis.Since the blood tryptophan level is affected by the diet, it seems likely that food intake can affect 5-H T synthesis in the brain.The first step in 5-HT synthesis is the hydroxylation of tryptophan to 5hydroxytryptophan, catalysed by tryptophan hydroxylase (L-tryptophan m o n e oxygenase; EC I .14.I 6.4).This is followed by decarboxylation to the biologicallyactive amine, catalysed by aromatic amino acid decarboxylase (L-aromatic amino acid carboxy-lyase; EC 4.1.1.28).In the central nervous system, 5-HT is stored in pre-synaptic vesicles before release as a neurotransmitter; thereafter it can either be taken up by the presynaptic neuron (where it may either be re-utilized or catabolized) or be catabolized in the post-synaptic neuron.The catabolism of 5-HT is again a twostep process; the first reaction is catalysed by monoamine oxidase (monoamine:oxygen oxidoreductase (deaminating); EC 1.4.3.4) and yields 5-hydroxyindoleacetaldehyde as a transient intermediate, which is then oxidized to 5-hydroxyindoleacetic acid (5-HIAA), a reaction catalysed by aldehyde dehydrogenase (aldehyde:NAD oxidoreductase, EC 1.2.1.3).5-HIM is cleared from the central nervous system and is excreted in the urine.Control of the amount of 5-HT in the central nervous system could conceivably occur by change in the rate of either synthesis or oxidative catabolism.Control of monoamine oxidase is not generally thought to be a physiological mechanism of 5- H T regulation, although inhibition of the enzyme is frequently used clinically to increase brain amine levels (including 5-HT) in the treatment of psychological depression.Aromatic amino acid decarboxylase is pyridoxal phosphate dependent, but appears to be relatively resistant to the effects of vitamin B, deficiency.Neither the total activity of the enzyme nor apo-enzyme:holoenzyme is altered in the brain or liver of animals severely-vitamin B,-deficient (Bayoumi & Bender, unpublished observations).The enzyme has a low Michaelis constant (K,) for 5hydroxytryptophan (approximately 40 C(M, Bender & Coulson, 1972) and a relatively high activity in the brain.On these grounds it would appear unlikely that