Hydroxytryptophan to Serotonin

The first evidence for 5HTP as an intermediate in serotonin formation was the demonstration of potent 5HTP decarboxylase activity in tissues. This enzyme was purified from guinea pig and hog kidney and shown to be separable from 3,4-dihydroxyphenylalanine(dopa) decarboxylase. By procedures involving differential heat inactivation, salt fractionation, and adsorption on alumina it was possible to change the ratio of dopa decarboxylase to 5HTP decarboxylase by as much as twentyfold (Clark el al., 1954). 

5HTP is not (Clark et al., 1954). Other factors which argue for two separate enzymes are (1) tremendously different pH optima, 6.9 for dopa and 8.1 for 5HTP (2) tremendously different substrate enzyme affinities and (3) marked differences in their abilities to dissociate from the coenzyme, pyri-doxal phosphate. 

In addition to pyridoxal phosphate it has been reported that 5HTP decarboxylase also seems to require a metal. This metal requirement stems from the finding that chelating agents such as ethylenediamine tetraacetate inhibit activity (Beiler and Martin, 1954). Inhibition by chelating agents has been confirmed in the reviewer s laboratory. 

Inhibition of 5HTP decarboxylase has been suggested as the mechanism of action of one-hydrazinophthalazine (Perry et al., 1955 von Schuler and Meier, 1955), a potent hypotensive agent. However, no supporting evidence is given for this action in the article. Studies in the author s laboratory have corroborated this report and indicate that 1-hydrazinophthalazine can 

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Decarboxylation of L-3,4-dihydroxyphenylalanine to dopamine, and of 5-hydroxytryptophan to serotonin, is catalyzed by aromatic L-amino acid decarboxylase. A single enzyme may be responsible for both activities. This assay permits simultaneous determination of both activities. 

Conversion of L-dopa to dopamine and of 5-hydroxytryptophan to serotonin are both catalyzed by... 

Abnormal indole derivatives in the urine and low levels of serotonin (a product of tryptophan metabolism) in blood and brain point to a defect in tryptophan metabolism in PKU. 5-Hydroxytryptophan decarboxylase, which catalyzes the conversion of 5-hydroxytryptophan to serotonin, is inhibited in vitro by some of the metabolites of phenylalanine. Phenylalanine hydroxylase is similar to the enzyme that catalyzes the hydroxylation of tryptophan to 5-hydroxytryptophan, a precursor of serotonin. In vitro, phenylalanine is also found to inhibit the hydroxylation of tryptophan. The mental defects associated with PKU may be caused by decreased production of serotonin. High phenylalanine levels may disturb the transport of amino... 

Early experiments that attempted to increase serotonin function were necessarily restricted to drug treatments that caused a generalized effect throughout the brain and presumably were influencing all serotonin receptors. Using this approach, the systemic administration of 5-hydroxytryptophan, to in-... 

The postsynaptic physiological effects of serotonin are varied and widespread. The administration of serotonin leads to powerful smooth-muscle effects in the cardiovascular and gastrointestinal systems. Vasodilation and hypotension may result, partly through central effects, if the serotonin concentration in the CNS is increased by administration of the serotonin precursor 5-hydroxytryptophan. Unlike serotonin, this precursor can cross the blood-brain barrier. Intestinal mobility is also influenced by serotonin. 

Serotonin, also called 5-hydroxytryptamine, is synthesized and stored at several sites in the body (Figure 21.18). By far the largest amount of serotonin is found in cells of the intestinal mucosa. Smaller amounts occur in platelets and in the central nervous system. Serotonin is synthesized from tryptophan, which is hydroxy-lated in a reaction analogous to that catalyzed by phenylalanine hydroxylase. The product, 5-hydroxytryptophan, is decarboxylated to serotonin. Serotonin has multiple physiologic roles, including pain perception, affective disorders, and regulation of sleep, temperature, and blood pressure. 

Aromatic L-amino acid decarboxylase catalyzes the decarboxylation of l-5-hydroxytryptophan (l-5-HTP) to serotonin (5-HT). In the assay, l-5-HTP was used as the substrate and the formation of 5-HT was measured. 

In view of the hypoglycemic and insulinase-inhibitory action of l-tryptophan, it seemed pertinent to Mirsky to study the effect of various metabolic products of tryptophan on the blood sugar of normal and diabetic rats (M9), A statistically significant hypoglycemic response was produced after oral administration of anthranilic acid, niacin, indole-3-acetic acid, 5-hydroxytryptophan, and serotonin. A hypoglycemic fol-... 

The synthesis of 5-HT from tryptophan in serotonergic neurons occurs in two steps. First, the enzyme tryptophan hydroxylase catalyzes the conversion of tryptophan to 5-hydroxytryptophan (5-HTP). Then, the enzyme aromatic amino acid decarboxylase catalyzes the conversion of 5-FlTP to serotonin. 

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 atom. The stereochemical course of the decarboxylation of 5-hydroxytryptophan to 5-hydroxytryptamine (serotonin) catalyzed by the pyridoxal phosphate-dependent aromatic L-amino acid decarboxylase (equation 15) exemplifies such studies. ... 

The enzyme AADC is involved in different metabolic pathways synthesizing two important neurotransmitters dopamine and serotonin [24]. AADC decarboxylates L-dihydroxy-phenylalanine to form dopamine and 5-hydroxytryptophan to produce serotonin. Tryptophan decarboxylase activity is detected in many brain neurons and non-nervous tissue cells. 

Hartnup disease, an autosomal recessive trait that interferes with the absorption of tryptophan, and carcinoid syndrome in which the amino acid is preferentially oxidized to 5-hydroxytryptophan and serotonin. Prolonged treatment with the drug isoniazid, which competes with pyridoxal 5 -phosphate (a vitamin Be-derived coenzyme required in the tryptophan-to-niacin pathway), also reduces the conversion of tryptophan to niacin. Oral contraceptives that contain high doses of estrogen increase tryptophan conversion efficiency (Braidman and Rose 1971). 

An intermediate in the conversion of tryptophan to 5-hydroxy tryptamine (serotonin). In some cases of carcinoid syndrome it i excreted in large amounts in the urine, even though the 5 hydroxyindoleacetic acid excretion may be normal. This i thought to be because the cells lack the decarboxylase whicl converts 5-hydroxytryptophan to 5-hydroxytryptamine. 

In contrast, substrates having other struetural types of side ehain at the 3 position dimerize under aeidie eonditions, and never produee the 5-substituted produets. These faets seem to support the 1-Hydroxyindole Hypotheses, whieh elaim the formation of serotonin from 1-hydroxytryptophan and/or -tryptamine in the aeidie eompartment within eukaryotie eells. 

The precursor for the synthesis of 5-HT is the amino acid L-tryptophan, which is obtained from dietary protein (Fig. 2.2A). L-tryptophan is converted to 5-hydroxytryptophan (5-HTP) in serotonin neurons by the enzyme tryptophan... 

Serotonin is synthesized from tryptophan in two steps. Tryptophan is hydroxylated by tryptophan hydroxylase, and 5-hydroxytryptophan is decarboxylated to give serotonin. Most serotonin in the body is found in the enterochromaffin cells of the intestinal tract and the pineal gland. Platelets take up and store serotonin but do not synthesize it. 

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). 

Several amino acids are broken down by de-carbo qflation. This reaction gives rise to what are known as biogenic amines, which have various functions. Some of them are components of biomolecules, such as ethanolamine in phospholipids (see p. 50). Cysteamine and T-alanine are components of coenzyme A (see p.l2) and of pantetheine (see pp. 108, 168). Other amines function as signaling substances. An important neurotransmitter derived from glutamate is y-aminobutyrate (GABA, see p.356). The transmitter dopamine is also a precursor for the catecholamines epinephrine and norepinephrine (see p.352). The biogenic amine serotonin, a substance that has many effects, is synthesized from tryptophan via the intermediate 5-hydroxytryptophan. 

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