5-Hydroxytryptamine catabolism

Serotonin is an indolamine neurotransmitter, derived from the amino acid L-tryptophan. Tryptophan is converted to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase. 5-HTP is converted to 5-hydroxytryptamine (serotonin, 5-HT) by aromatic amino acid decarboxylase. In the pineal gland, 5-HT may be further converted to /V-acetyl serotonin by 5-HT /V-acetyltransferase and then to melatonin by 5-hyroxyindole-O-methyltransferase. 5-HT is catabolized by monoamine oxidase, and the primary end metabolite is 5-hydroxyindoleacetic acid (5-HIAA). 

Apart from the relatively small amounts that are required for synthesis of the neurotransmitter serotonin (5-hydroxytryptamine), and for net new protein synthesis, essentially the whole of the dietary intake of tryptophan is metabolized by way of the oxidative pathway shown in Figures 8.4 and 9.4, which provides both a mechanism for total catabolism by way of acetyl coenzyme A and a pathway for synthesis of the nicotinamide nucleotide coenzymes (Section 8.3). 

There is a great deal of evidence that deficiency of serotonin (5-hydroxytryptamine) is a factor in depressive illness, and many antidepressant drugs act to decrease its catabolism or enhance its interaction with receptors. A key enzyme involved in the synthesis of serotonin (and the catecholamines) is aromatic amino acid decarboxylase, which is pyridoxal phosphate-dependent. Therefore, it has been suggested that vitamin Be deficiency may result in reduced formation of the neurotransmitters and thus be a factor in the etiology of depression. Conversely, it has been suggested that supplements of vitamin Be may increase aromatic amino acid decarboxylase activity, and increase amine synthesis and have a mood-elevating or antidepressant effect. There is little evidence that vitamin Be deficiency affects the activity of aromatic amino acid decarboxylase. In patients with kidney failure, undergoing renal dialysis, the brain concentration of pyridoxal phosphate falls to about 50% of normal, with no effect on serotonin, catecholamines, or their metabolites (Perry etal., 1985). 

MDMA (3.4-methylenedioxymethylamphetamjne EA 1475 XTC Ecstasy E ) has amphetamine-like actions, and induces release of, and is a (re-) uptake inhibitor of 5-hydroxytryptamine. Also, it is a monoamine-oxidase INHIBITOR (MAOI, type A), slowing catabolism of 5-HT. It is a PSYCHOTROPIC AGENT and drug of abuse. 

A number of routes by which 5-hydroxytryptamine may be broken down or otherwise inactivated have been established . The most important involves monoamine oxidase, which converts 5-hydroxytryptamine into 5-hydroxyindoleacetaldehyde II). Catabolism is completed by an aldehyde dehydrogenase which forms 5-hydroxyindoleacetic acid III), the principal urinary metabolite of 5-hydroxytryptamine. Like noradrenaline, 5-hydroxy-tryptamine can also be conjugated with glucuronic and sulphuric acids. 

Tyrosine is either used for the biosynthesis of proteins, thyroxine, epinephrine, or melanin, or catabo-lized to yield fumaryl acetoacetate. The biosynthesis of proteins and thyroxine is discussed elsewhere this discussion is restricted to epinephrine and melanin synthesis and tyrosine catabolism. Dopa 3,4-dihydroxy-phenylalanine is an intermediate common to epinephrine and melanin. To yield epinephrine, dopa is first decarboxylated by an enzyme called dopa decarboxylase. This enzyme is present in several mammalian tissues, including the adrenal medulla, where the reaction yields hydroxytryptamine chloride. From this... 

Hydroxytryptamine is deaminated oxidatively to 5-hydroxyindole acetic acid. In addition, 5-hydroxytryptamine is catabolized in substantially smaller amounts by reduction to the corresponding alcohol, 5-hydroxytryptophol, (1868-70) is excreted in the free form and combined as the glucuronide or sulphate. 7V-Methylation of 5-hydroxytryptamine gives iV-methylsero-tonin, which can be methylated further to 7V, -dimethylserotonin (= bufotenine). The iV-methylation is catalysed by a relatively unspecific iV-methyltransferase. By acetylation of 5-hydroxytryptamine 7V-acetyl-serotonin is produced, which is an intermediary product in the course of the melatonin synthesis (= 5-methoxy-AT-acetylserotonin). The production of 5-methoxytryptamine, which we were able to demonstrate in normal human blood and urine, seems to occur fairly easily by deacetylation of melatonin, whereas a direct 0-methylation of serotonin to 5-methoxy-tryptamine, at least in vitro, takes place to a substantially smaller extent. ... 

Normally in man about 98% of 5-hydroxytryptamine is catabolized by oxidative deamination and only 2% by reduction to 5-hydroxytryptophol/ Intake of ethyl alcohol raises the excretion of 5-hydroxytryptophol to about 50%/ ... 

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