Tryptophan, 5-hydroxy

Serotonin or 5-hydroxytryptamine is an important biogenic amine, which is synthesized via 5-hydroxy-tryptophan from the amino acid tryptophan. The highest concentration of serotonin occurs in the wall of the intestine. About 90% of the total amount is present in enterochromaffrn cells, which are derived from the neural crest, similarly to those of the adrenal medulla. 

Following hydroxylation of tryptophan to 5-hydroxy-tryptophan by hver tyrosine hydroxylase, subsequent decarboxylation forms serotonin (5-hydroxytrypta-... 

Kulkami, A.S. Muricidal block produced by 5-hydroxy tryptophan and various drugs. Life Sci 7 125-128, 1968. 

Figure 1. Biosynthetic pathways for biogenic amines. In Drosophila and vertebrates decarboxylation of DOPA and 5-hydroxy-tryptophan is catalyzed by the same enzyme, DDC. In vertebrates this enzyme is called amino acid decarboxylase (AADC). Only vertebrates further metabolize dopamine to norepinephrine and epinephrine. TH, tryosine hydroxylase DDC, DOPA decarboxylase DBH, dopamine b-hydroxylase PNMT, phenylethanolamine N-methyltransferase. Tryp-OH tryptophan hydroxylase.

The method described above was applied to synthesize the methyl ester of Di.-/V-acetyl-5 hydroxy tryptophan [294]. 

The production of serotonin requires the absorption of the amino acid tryptophan from your food. Transport of this amino acid is influenced by the level of other amino acids in your blood that level, in turn, is also influenced by what you eat. Within the neurons of your brain, tryptophan is converted to 5-hydroxy-tryptophan by tryptophan hydroxylase, an enzyme that is usually not saturated with substrate. Therefore, if you eat less tryptophan, your brain generally produces less serotonin. Conversely, providing additional tryptophan in the diet may lead to increased production of serotonin within neurons. It is worth noting, however, that simply producing more of any neurotransmitter does not guarantee that the neuron will actually release it. If too much serotonin is produced, then the excess is simply discarded. Studies have shown that only extreme depletion or supplementation of this amino acid in the diet can influence serotonin-controlled brain processes such as mood and sleep. 

Volicer, L., Langlais, P. J., Matson, W. R., Mark, K. A., and Gamache, P. H. (1985). Serotoninergic system in dementia of the Alzheimer type. Abnormal forms of 5-hydroxy-tryptophan and serotonin in cerebrospinal fluid. Arch. Neurol. 42 1158-1161. 

The first step in the liver pathway is catalyzed by phenylalanine hydroxylase. Tetrahydrobiopterin is a cofactor. This redox cofactor is also required for the hydroxylation of tyrosine to form L-dopa (Chapter 16) and for the hydroxylation of tryptophan to form 5-hydroxy tryptophan. The structure of tetrahydrobiopterin is given in Figure 20.23. In the process of phenylalanine hydroxylation, the tetrahydrobiopterin is oxidized to dihydrobiopterin. The reduced form is then recovered via NADH and dihydrobiopterin reductase, as shown in Figure 20.23. Dihydrobiopterin, although similar in structure to folic acid, is synthesized in the human organism from GTP. 

Finally, the decarboxylation of amino acids catalyzed by several pyridoxal phosphate-dependent enzymes has been shown to proceed by a retention of configuration at the Ca atom144. The stereochemical course of the decarboxylation of 5-hydroxy tryptophan to 5-hydroxytryptamine (serotonin) catalyzed by the pyridoxal phosphate-dependent aromatic L-amino acid decarboxylase (equation 15) exemplifies such studies145. 

Another test for the biogenic amine hypothesis w ould involve precursor loading sLategies. In other w ords, compounds w hich could increase brain levels of norepinephrine and/or serotonin should demonsLate antidepressant efficacy. Results of these studies have been mixed. Several positive findings w ere reported wdth Seating depression wdth the serotonin precursors tryptophan and 5-hydroxy tryptophan (5-HT) (Shaw et al., 2001), but these w ere not consistently replicated. Less posidve results w ere reported wdth attempts to increase brain norepinephrine levels wdth precursors. 

Shaw K, Turner J, Del Mar C (2001) Tryptophan and 5-hydroxy tryptophan for depression. Cochrane Database Syst Rev CD003198. 

Hydroxy-tryptophan, 41 Hygrophanons species, 19, 22, 31, 39, 41 Hypholoma spp., 29, 96 Hypholoma coprinifacies, 29 Hypholoma cyanescens, 29, 96 Hypnosis, 115 lllnsions, 45 Imai, S., 93... 

Tryptophan is hydroxylated in a tetrahydrobiopterin-requiring reaction similar to the hydroxylation of phenylalanine. The product, 5-hydroxy-tryptophan, is decarboxylated to form serotonin. 

Tryptophan hydroxylase uses 02 and the electron donor BH4 to hydroxylate C-5 of tryptophan. The product, called 5-hyroxy-tryptophan, then undergoes a decarboxylation catalyzed by 5-hydroxy tryptophan decarboxylase, a pyridoxal phosphate-requiring enzyme. Serotonin, often referred to as 5-hydroxytryptamine, is the product of this reacdon. 

Individuals who cannot produce 5,6,7,8-tetrahydrobiopterin must be supplied with L-dopa and 5-hydroxy tryptophan, metabolic precursors to norepinephrine and serotonin. Why does supplying 5,6,7,8-tetrahydrobiopterin have no effect ... 

Simple reactions are best, but the complex conversion carried out using sequential enzymic transformations for the synthesis of labelled 5-hydroxy tryptophan, for use in neuroendocrine tumour imaging, is notable. ... 

Patients with unipolar depression are effectively treated with drugs, such as chlo-rimipramine and more recently fluoxetine, which are known to block neuronal uptake of serotonin. In addition, giving 5-hydroxy tryptophan (a precursor of serotonin) either alone or in combination with chlorimipramine seems to benefit these patients. 

I Tryptophan 5-hydroxylase 5-Hydroxy tryptophan I Aromatic L-amino acid decarboxylase 5-Hydroxytryptamine (serotonin)... 

The synthesis of serotonin from tryptophan is carried out in two steps controlled by two enzymes tryptophan hydroxylase (TPH) and aromatic L-amino acid decarboxylase (AADC). The second enzyme, A ADC, is also known as DOPA carboxylase or 5-hydroxytryptophan carboxylase when it acts specifically in 5-HT synthesis. In the first step, the TPH adds a hydroxyl chemical group (OH) to tryptophan to make 5-hydroxytryptophan, Fig (1). In the second step, AADC removes the carboxyl group (-COOH) from 5-hydroxy tryptophan to make serotonin. Fig (2). 

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