5-Hydroxytryptamine precursors

Important products derived from amino acids include heme, purines, pyrimidines, hormones, neurotransmitters, and biologically active peptides. In addition, many proteins contain amino acids that have been modified for a specific function such as binding calcium or as intermediates that serve to stabilize proteins—generally structural proteins—by subsequent covalent cross-hnk-ing. The amino acid residues in those proteins serve as precursors for these modified residues. Small peptides or peptide-like molecules not synthesized on ribosomes fulfill specific functions in cells. Histamine plays a central role in many allergic reactions. Neurotransmitters derived from amino acids include y-aminobutyrate, 5-hydroxytryptamine (serotonin), dopamine, norepinephrine, and epinephrine. Many drugs used to treat neurologic and psychiatric conditions affect the metabolism of these neurotransmitters. 

The pathways for synthesis of the monoamine neurotransmitters are not, at least in some neurones, saturated with precursor amino acids (tyrosine for formation of noradrenaline plus dopamine tryptophan for formation of 5-hydroxytryptamine (serotonin)). Marked increases in the blood level of these amino acids can increase their concentrations in neurones which can influence the concentration of the respective neurotransmitters in some neurones in the brain. This may result in changes in behaviour. 

FIGURE 5—34. Serotonin (5-hydroxytryptamine [5HT ) is produced from enzymes after the amino acid precursor tryptophan is transported into the serotonin neuron. The tryptophan transport pump is distinct from the serotonin transporter (see Fig. 5—35). Once transported into the serotonin neuron, tryptophan is converted into 5-hydroxytryptophan (5HTP) by the enzyme tryptophan hydroxylase (TryOH) which is then converted into 5HT by the enzyme aromatic amino acid decarboxylase (AAADC). Serotonin is then stored in synaptic vesicles, where it stays until released by a neuronal impulse. 

Part of the membrane lying adjacent to the nerve terminal that contains the postsynaptic receptors. Anxiety disorder attributed to a severe, adverse life experience (e.g. threat to life) that is experienced again without the stimulus of the adverse experience. Usually used in reference to compounds which are metabolized in neurotransmitters (e.g. tryptophan is the precursor of 5-hydroxytryptamine). 

Presynaptic supply of transmitter could be affected by the dietary content of transmitter precursors. L-DOPA, the precursor of dopamine, a prominent insect CNS transmitter, occurs in several species of plants. L-5-Hydroxytryptophan, which could serve as a precursor of the indoleamine transmitter 5-hydroxytryptamine, also occurs at high levels in some plant materials. Although the consequences of altering levels of transmitters via diet are not clear, such alterations have been shown to occur with several transmitters in mammals (26) and could alter the behavior of an insect herbivore. 

N-Acetyltransferase uses acetyl-CoA to acetylate the amino moiety of arylal-kylamines. In mammalian pineal gland, this enzyme catalyzes the production of N-acetyl-5-hydroxytryptamine, which is the precursor of melatonin. It is also involved in the inactivation of monoaminergic neurotransmitters in insects. 

Purines and pyrimidines are derived largely from amino acids. The biosynthesis of these precursors of DNA, RNA, and numerous coenzymes will be discussed in detail in Chapter 25. The reactive terminus of sphingosine, an intermediate in the synthesis of sphingolipids, comes from serine. Histamine, a potent vasodilator, is derived from histidine by decarboxylation. Tyrosine is a precursor of the hormones thyroxine (tetraiodothyronine) and epinephrine and of melanin, a complex polymeric pigment. The neurotransmitter serotonin (5-hydroxytryptamine) and the nicotinamide ring of NAD + are synthesized from tryptophan. Let us now consider in more detail three particularly important biochemicals derived from amino acids. 

Tryptophan (fig. 8) is one of the twenty amino acids used by all of life on Earth to build proteins. Although plants, fungi, bacteria, and some other organisms can biosynthesize tryptophan from smaller carbon molecules, humans cannot and must ingest tryptophan as part of their diet. That is, tryptophan is one of the essential amino acids. In fungi and plants, tryptophan is the chemical precursor for the biosynthesis of tryptamines such as DMT and psilocybin. In humans and other animals, tryptophan is the precursor for the synthesis of the neurotransmitter serotonin, 5-hydroxytryptamine (5-HT fig. 9). 

Besides being fundamental constituents of proteins they are the parent substances from which powerful hormones are derived, for example, adrenaline (epinephrine), noradrenaline (norepinephrine), thyroxine and related substances, 5-hydroxytryptamine (enteramine, serotonin), and the plant hormone indoleacetic acid. Tryptophan is also the precursor of the B vitamin nicotinic acid and hence of part of the important pyridine nucleotides. All three aromatic amino acids are potential precursors of other substances having powerful physiological activity, for example, many of the alkaloids. Errors in the metabolism of the aromatic amino acids in man can give rise to sometimes serious, but fortunately comparatively rare, disorders such as alkaptonuria and phenylketonuria. The numerous metabolic pathways involved in aromatic amino acid metabolism therefore make an important as well as an interesting study. 

Table VIII gives the effects on levels of dopamine and its precursor DOPA after exposure of bulb mites in vials precoated with chlordimeform. Chlordimeform resulted in an initial increase in levels of dopamine and DOPA after 24 hours, DOPA levels still were increased, but there was a significant decrease in levels of dopamine (23). In other studies (22), it was shown that whole homogenates of bulb mites rapidly metabolized PEA, but were appreciably less active against tryptamine, 5-hydroxytryptamine, and dopamine. Moreover, no deamination of octopamine was detected (Table IX). PEA metabolism by bulb mite homogenates was inhibited...

In addition to the quantitative findings in regard to tryptophan, another early report revealed an important and unique property of tryptophan within the blood. In 1957, McMenemy et al.180 described a unique property of tryptophan — that it was the only amino acid in plasma that was largely bound to protein. This attribute, specifically the ratio of free to bound tryptophan in the blood, has much physiological significance. For example, only the small free fraction of plasma tryptophan has access to the brain. Factors that influence the equilibrium between free and bound tryptophan in the plasma have been considered to alter the availability of tryptophan to the brain, where it has special importance as a precursor of the neurotransmitter 5-hydroxytryptamine (serotonin).181183 Tryptophan differs from other amino acids in that its concentration in the plasma of rats increases (30 to 40%) after fasting, after insulin administration, or after consuming a carbohydrate meal.184... 

Autacoids are endogenous molecules with powerful pharmacologic effects but poorly defined physiologic roles. Histamine and serotonin (5-hydroxytryptamine 5-HT) are two of the most important autacoids. Both are synthesized in the body from amino acid precursors and then eliminated by amine oxidation the pathways of synthesis and metabolism are very similar to those used for catecholamine synthesis and metabolism. The ergot alkaloids are a heterogeneous group of drugs that interact with serotonin receptors, dopamine receptors, and alpha receptors. They are included in this chapter because of their effects on serotonin receptors and on smooth muscle. 

The simplest unsubstituted indole and its methyl derivative, scatol, were found in some Lepiota and Tricholoma species. The probable biogenetic precursor of all indole metabolites is the amino acid tryptophan, widely distributed in fungi, or its derivative tryptamine, found in some species of Coprinus, Inocybe, Panaeolus, Sacrodon, and Boletus (7). Investigation of a strong biological activity characteristic of an animal hormone function revealed the presence 5-hydroxytryptamine (serotonin), which was found in large amounts in some Panaeolus and Amanita species. 

The latter possibility was reconsidered more recently by Stijve (755, 765). According to his observations, psilocybin in Psilocybe semilance-ata ind in five Inocybe species was accompanied by its precursor baeo-cystine, which may indicate that during biosynthesis phosphorylation precedes methylation in conformity with the sequence tryptophan tryptamine — 4-hydroxytryptamine norbaeocystine baeocystine ... 

Tryptophan is a precursor of serotonin (5-hydroxytryptamine) and the authors point out that the symptoms resemble the serotonin syndrome, which occurs when serotonin levels are increased. They warn against the concurrent use of tryptophan with fluoxetine or other serotonin reuptake inhibitors. This caution is echoed by most of the manufacturers of the SSRIs the UK manufacturer of paroxetine additionally mentions oxitriptan [L-5-hydroxytryptophan]... 

Serotonin S-hydroxytryptamine, M, 176.2, a plant and animal hormone. It is produced by hydroxylation of L-tryptophan to 5-hydroxytryptophan, followed by decarboxylation. The synthesis occurs in the central nervous system, lung, spleen and argentaffine light cells of the intestinal mucosa. S. is stored in thrombocytes and mast cells of the blood. It acts as a Neuro-transmitter (see), stimulates peristalsis of the intestine, and causes a dose-dependent constriction of smooth muscle. It stimulates the release from arterial endothelium of a dilator substance which counteracts its primary constricting effect [T.M. Cocks X A. Angus Nature 305 (1983) 627-630]. S. is a precursor of the hormone Melatonin (see). It is inactivated and degraded by monoamine oxidases and aldehyde oxidases to 5-hydroxy-indoleacetic acid. 

In blood platelets approximately 60% of the ADP + ATP is contained in granules together with serotonin (5-hydroxytryptamine). These adenine nucleotides are relatively inert metabolically, as incubation of platelets with radioactive precursors does not lead to their labeling, whereas non-particulate nucleotides readily become highly labeled (see references 28, 29). 

Hydroxytryptamine, in contrast to its biochemical precursor 5-hydroxytryp-tophane, does not pass the blood-brain barrier, or only with difficulty. Oates et found an increased production of phenylethylamine in patients... 

Tryptophan is metabolized by several different pathways (Fig. 1) each yielding biologically important substances such as tryptamine and in particular serotonin (5-hydroxytryptamine), which seems to be involved in certain mental disorders. Indole-3-acetic acid is a plant growth hormone its precursor is tryptamine or indole-3-pyruvic acid. In humans, the microorganisms of the large intestine can further degrade indole-3-acetic acid to yield indole, skatole (3-methyl-indole) and other substances. 

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