5-Hydroxytryptamine metabolism

The many investigations which have examined inter alia, the effect on 5-hydroxytryptamine metabolism of convulsant and anticonvulsant drugs, of electroshock and insulin coma, have yielded results which though interesting throw little light on the physiological function of 5-hydroxytrypt-amine . 

Goble, A. J., Hay, D. R. and Sandler, M., 5-Hydroxytryptamine metabolism in acquired heart disease associated with argentaffin carcinoma. Lancet, 1955, p. 1016. 

Blomstrand E, Perrett D, Parry-Billings M, Newsholme EA. Effect of sustained exercise on plasma amino acid concentrations and on 5-hydroxytryptamine metabolism in six different brain regions in the rat. Acta Physiol Scand 1989 136 473 181. Blomstrand E. Amino acids and central fatigue. Amino Acids 2001 20 25-34. Fernstrom JD, Fernstrom MH. Exercise, serum free tryptophan, and central fatigue. J Nutr 2006 136 553S-559S. 

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. 

A number of genetic diseases that result in defects of tryptophan metabolism are associated with the development of pellagra despite an apparently adequate intake of both tryptophan and niacin. Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan, resulting in large losses due to intestinal malabsorption and failure of the renal resorption mechanism. In carcinoid syndrome there is metastasis of a primary liver tumor of enterochromaffin cells which synthesize 5-hydroxy-tryptamine. Overproduction of 5-hydroxytryptamine may account for as much as 60% of the body s tryptophan metabolism, causing pellagra because of the diversion away from NAD synthesis. 

Bakhit, C. Morgan, M.E. Peat, M.A. and Gibb. J.W. Long-term effects of methamphetamine on the synthesis and metabolism of 5-hydroxytryptamine in various regions of the rat brain. Neuropharmacology 20 1135-1140, 1981. 

Rosecrans, J. A., Lovell, R. A., and Freedman, D. X. (1967) Effects of lysergic acid diethylamide on the metabolism ofbrain 5-hydroxytryptamine. Biochem. Pharmacol., 16 2011-2021. 

Tryptophan possesses a complex heterocyclic side chain known as indole. It is the metabolic precnrsor to serotonin (5-hydroxytryptamine 5-HT), an important nenrotransmitter. 

Certain foods can trigger a migraine attack by effects on neurotransmitter release or metabolism in the brain. For example, a number of foods contain tryptamine which is known to cause release of other amines (dopamine, noradrenaline and 5-hydroxytryptamine) from both nerve terminals and platelets. This release could initiate the sequence of events that results in the migraine attack. Elimination of such foods from the diet can decrease the number of headaches. Compounds that discourage platelet aggregation (e.g. aspirin) may prevent such attacks. 

Figure 2.18. The major pathway leading to the synthesis and metabolism of 5-hydroxytryptamine (5-HT). Metabolism of tryptophan to tryptamine is a minor pathway which may be of functional importance following administration of a monoamine oxidase (MAO) inhibitor. Tryptamine is a trace amine. L-Aromatic amino acid decarboxylase is also known to decarboxylate dopa and therefore the term "L-aromatic amino acid decarboxylase" refers to both "dopa decarboxylase"...

Some rather important indole derivatives influence our everyday lives. One of the most common ones is tryptophan, an indole-containing amino acid found in proteins (see Section 13.1). Only three of the protein amino acids are aromatic, the other two, phenylalanine and tyrosine being simple benzene systems (see Section 13.1). None of these aromatic amino acids is synthesized by animals and they must be obtained in the diet. Despite this, tryptophan is surprisingly central to animal metabolism. It is modified in the body by decarboxylation (see Box 15.3) and then hydroxylation to 5-hydroxytryptamine (5-HT, serotonin), which acts as a neurotransmitter in the central nervous system. 

Serotonin (5-hydroxytryptamine, or 5HT) is present in the brain as well as in the periphery. In humans, about 90% of the total serotonin in the body is in enterochro-maffin cells in the gastrointestinal tract the remaining 10% occurs primarily in the platelets and brain. The physiological significance of the vast amounts of serotonin constantly synthesized and metabolized in the periphery still remains an enigma. Brain serotonin has been implicated as a potential neurotransmitter in the mediation of a wide variety of phenomena (see Actions). 

In Section 1.3, the general effects of fluorine substitution on drug activity and selectivity have been treated. As seen frequently with other enzymatic reactions, introduction of fluorine can have dramatic effects on the properties of substrates and inhibitors of MAOs [26]. For example, preliminary studies indicated that fluorination of 5-hydroxytryptamine in the 6- or the 4,6-positions (3,4) causes this predominantly MAO A substrate to be metabolized significantly by platelet MAO B [27]. Although no direct evidence was obtained, this may be caused by increased lipophilicity introduced by fluorine substitution. 

Sizer AR, Long SK, Roberts MHT A modulatory function of 5-hydroxytryptamine in the central nervous system, in Serotonin, CNS Receptors and Brain Function (Advances in the Biosciences, Vol 85). Edited by Bradley PB, Handley SL, Cooper SJ, et al. Oxford, England, Pergamon, 1992, pp 135-146 Skett P Biochemical basis of sex differences in drug metabolism. Pharmacol TTier 38 269-304, 1988... 

The hereditary absence of phenylalanine hydroxylase, which is found principally in the liver, is the cause of the biochemical defect phenylketonuria (Chapter 25, Section B).430 4308 Especially important in the metabolism of the brain are tyrosine hydroxylase, which converts tyrosine to 3,4-dihydroxyphenylalanine, the rate-limiting step in biosynthesis of the catecholamines (Chapter 25), and tryptophan hydroxylase, which catalyzes formation of 5-hydroxytryptophan, the first step in synthesis of the neurotransmitter 5-hydroxytryptamine (Chapter 25). All three of the pterin-dependent hydroxylases are under complex regulatory control.431 432 For example, tyrosine hydroxylase is acted on by at least four kinases with phosphorylation occurring at several sites.431 433 4338 The kinases are responsive to nerve growth factor and epidermal growth factor,434 cAMP,435 Ca2+ + calmodulin, and Ca2+ + phospholipid (protein kinase C).436 The hydroxylase is inhibited by its endproducts, the catecholamines,435 and its activity is also affected by the availability of tetrahydrobiopterin.436... 

Ribeiro, P. and Webb, R.A. (1 984) The occurrence, synthesis and metabolism of 5-hydroxytryptamine and 5-hydroxytryptophan in the cestode Hymenolepis diminuta. Comparative Biochemistry and Physiology C 79, 159-164. 

Hydroxytryptamine (serotonin, 5HT) is metabolized according to the following scheme ... 

North RA (2002) Molecular Physiology of P2X Receptors. Physiol Rev 82 1013-67 Ohta K, Araki N, Shibata M, Komatsumoto S, Shimazu K, Fukuuchi Y (1994) Presynaptic ionotropic glutamate receptors modulate in vivo release and metabolism of striatal dopamine, noradrenaline, and 5-hydroxytryptamine involvement of both NMDA and AMPA/kainate sub-... 

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). 

Toumois C, Mutel V, Manivet P, Launay JM, Kellermann O. Cross-talk between 5-hydroxytryptamine receptors in a serotonergic cell line. Involvement of arachi-donic acid metabolism. J Biol Chem 1998 273 17,498—17,503. 

Effects of 5-hydroxytryptamine on carbohydrate metabolism in Hymenolepis diminuta (Cestoda). Canadian Journal of Physiology and Pharmacology, 61 137—43. 

Amino acid decarboxylations are involved in the synthesis of several metabolically important amines, e.g., 5-hydroxytryptamine (serotonin) from tryptophan, histamine from histidine, and y-aminohutyric acid (GABA) from glutamate. 

---