5- Hydroxytryptophan, from tryptophan

Mitoma, C., Weissbach, H. and Udenfriend, S., Formation of 5-hydroxytryptophan from tryptophan by Chromobacterium violaceum. Nature 175, 994 (1955). 

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. 

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. 

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. 

Fig. 6.12. Chromatography of 3H-labelled extracted products following incubation of homogenates of Hymenolepis diminuta in [3H]tryptophan 5HT, 5-hydroxytryptamine 5HTP, 5-hydroxytryptophan TRY, tryptophan or, origin fr, solvent front. The data were obtained by subtracting the radioactivity in boiled homogenates (blanks) from that in unboiled homogenates. Radiolabelled tryptophan was metabolised in the latter to [3H]5HTP and [3H]5HT. (After Ribeiro Webb, 1983a.)...

Ribeiro, P. Webb, R. A. (1983a). The synthesis of 5-hydroxytryptamine from tryptophan and 5-hydroxytryptophan in the cestode Hymenolepis diminuta. International Journal for Parasitology, 13 101-6. 

Histamine is synthesized from the amino acid histidine by simple decarboxylation catalysed by histidine decarboxylase. Serotonin is synthesized primarily in platelets, the gastro-intestinal (GI) tract and the brain from the indolyl amino acid tryptophan tryptophan —> 5-hydroxytryptophan [via tryptophan hydroxylase + tetrahydrobiopterin] —> 5-hydroxy-tryptamine (serotonin) [via 5-hydroxytryptophan decarboxylase]. 

Serotonin or 5-hydroxytryptamine (5-HT), a monoamine, is widely distributed in many cells of the body and about 1-2% of the entire serotonin body content is found in the CNS. Serotonin is synthesized by the enzyme amino acid decarboxylase from 5-hydroxytryptophan (which is derived from tryptophan via tryptophan hydroxylase). The rate-limiting step is the production of 5-hydroxytryptophan by tryptophan hydroxylase. Serotonin is removed from the synapse by a high-affinity serotonin uptake site that is capable of transporting serotonin in either direction, depending on the concentration. 

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. 

Catecholamines are synthesized from the amino acid tyrosine, and serotonin from tryptophan as shown in Figure 29-2. The rate-limiting step in catecholamine biosynthesis involves conversion of tyrosine to 3,4-dihydroxyphenylalanine (L-dopa) by the enzyme, tyrosine hydroxylase. A related enzyme, tryptophan hydroxylase, catalyzes conversion of tryptophan to 5-hydroxytryptophan in the first step of serotonin synthesis. 

The other physiologically important monoamine is 5-hydroxytryptamine (serotonin or 5-HT). It is formed from tryptophan via 5-hydroxytryptophan (5-HTP) Figure 5.2). The nature and properties of tryptophan-5-hydroxy-lase is still obscure, though the hydroxylation of tryptophan in vivo has been demonstrated. There is no clear evidence that this conversion occurs in brain tissue. The decarboxylation of 5-HTP, however, takes place in brain and the decarboxylating enzyme is found in all cerebral areas which contain 5-hydroxytryptamine. 5-HTP decarboxylase is closely related to, if not identical with, DOPA decarboxylase - and agents which inhibit dopan ine formation similarly inhibit the production of 5-hydroxytryptamine. There... 

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). 

Brain cells take up tryptophan, which is then converted to 5-hydroxytryptophan by tryptophan hydroxylase, an enzyme whose activity is similar to that of phenylalanine hydroxylase. Aromatic amino acid decarboxylase then catalyzes the formation of the potent neurotransmitter 5-hydroxytryptamine, also called serotonin. In the blood, tryptophan is bound to serum albumin, with an affinity such that about 10% of the tryptophan is freely diffusable. The rate of tryptophan uptake by brain cells depends on the concentration of free tryptophan. In these cells, tryptophan concentration is normally well below that of the Km for tryptophan hydroxylase. Aspirin and other drugs displace tryptophan from albumin, thereby increasing the concentration of free tryptophan. 

Little is known about factors which limit the production of amines. The metabolic reaction which limits the biosynthesis of dopamine and serotonin is believed not to be the decarboxylation of their biochemical precursors dopa and 5-hydroxytryptophane by the ubiquitous decarboxylase, but to be the hydroxylation of the parent compounds tyrosine, and tryptophane. 140-3,189) Under comparable experimental conditions the production of serotonin from 5-hydroxytryptophane took place 30-40 times faster than from tryptophane,and the production of dopamine and noradrenaline respectively from labelled dopa was 70-100 times faster than from labelled tyrosine. In the biosynthesis of noradrenaline, the hydroxylation of dopamine, catalysed by dopamine-j -oxidase, takes place fairly slowly and is considered to be a rate-limiting reaction. ... 

Numerous investigations under varied experimental conditions make it almost certain that serotonin is synthesized from tryptophane and 5-hydroxytryptophane in animals and in man/ 137-9, i4i, 142, 160,... 

With 1-hydroxytryptophan derivatives, similar substituent effects are observed (99H2815). In order to realize better yields of 5-substituted tryptophans, car-boxy and amino groups are transformed to ester and/or amide groups, choosing the 1-methoxy moiety as a leaving group. As a result, ( )-Ab-acetyl-5-chlorotryptophan methyl ester (219, 52%) is obtained together with 220 (7%) from ( )-218 by the reaction with aqueous HCl (Scheme 32). ( )-5-Bromo-Ab-methoxycarbonyltryptophan methylamide (222, 50%) becomes readily available... 

The product of the hydroxylation of tryptophan, 5-hydroxytryptophan, is rapidly decarboxylated to 5-HT by a specific decarboxylase enzyme. This is generally thought to be a soluble enzyme which suggests that 5-HT is synthesised in the cytoplasm, before it is taken up into the storage vesicles. If this is the case, then considerable losses might be incurred from its metabolism by monoamine oxidase before it reaches the storage vesicles. Indeed, this could explain why 5-HT turnover seems to greatly exceed its rate of release. 

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 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). 

Whilst the term biogenic amine strictly encompasses all amines of biological origin, for the purpose of this article it will be employed to refer to the catecholamine (dopamine, noradrenaline) and serotonin group of neurotransmitters. These neurotransmitters are generated from the amino acid precursors tyrosine and tryptophan, respectively, via the action of the tetrahydrobiopterin (BH4)-dependent tyrosine and tryptophan hydroxylases. Hydroxylation of the amino acid substrates leads to formation of 3,4-dihydroxy-l-phenylalanine ( -dopa) and 5-hydroxytryptophan, which are then decarboxylated via the pyridoxalphosphate-dependent aromatic amino acid decarboxylase (AADC) to yield dopamine and serotonin [4]. In noradrenergic neurones, dopamine is further metabolised to noradrenaline through the action of dopamine-jS-hydroxylase [1]. 

Melatonin is synthesized from the amino acid tryptophan by several enzymes located inside cells in the pineal gland. As seen in Figure 4.3, tryptophan is first converted to 5-hydroxytryptophan... 

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. 

One of the best characterized physiological functions of (6R)-tetrahydrobio-pterin (BH4, 43) is the action as a cofactor for aromatic amino acid hydroxylases (Scheme 28). There are three types of aromatic amino acid hydroxylases phenylalanine hydroxylase [PAH phenylalanine monooxygenase (EC 1.14.16.1)], tyrosine hydroxylase [TH tyrosine monooxygenase (EC 1.14.16.2)] and tryptophan hydroxylase [TPH tryptophan monooxygenase (EC 1.14.16.4)]. PAH converts L-phenylalanine (125) to L-tyrosine (126), a reaction important for the catabolism of excess phenylalanine taken from the diet. TH and TPH catalyze the first step in the biosyntheses of catecholamines and serotonin, respectively. Catecholamines, i.e., dopamine, noradrenaline and adrenaline, and serotonin, are important neurotransmitters and hormones. TH hydroxylates L-tyrosine (126) to form l-DOPA (3,4-dihydroxyphenylalanine, 127), and TPH catalyzes the hydroxylation of L-tryptophan (128) to 5-hydroxytryptophan (129). The hydroxylated products, 127 and 129, are decarboxylated by the action of aromatic amino acid decarboxylase to dopamine (130) and serotonin (131), respectively. 

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