Serotonin, tryptophan metabolism

As shown in Figure 8.2, NAD(P) can be synthesized from the tryptophan metaboUte quinolinic acid. The oxidative pathway of tryptophan metabolism is shown in Figure 8.4. Under normal conditions, almost aU of the dietary intake of tryptophan, apart from the small amount that is used for net new protein synthesis, is metabolized by this pathway, and hence is potentially available for NAD synthesis. About 1% of tryptophan metabolism is by way of 5-hydroxylation and decarboxylation to 5-hydroxytryptarnine (serotonin), which is excreted mainly as 5-hydroxyindoleacetic acid. 

Carcinoid is a tumor of the enterochromaffin cells that normally synthesize 5-hydroxytrytophan and 5-hydroxytryptamine. The carcinoid syndrome is seen when there are significant metastases of the primary tumor in the liver. It is characterized by increased gastrointestinal motility and diarrhea, as well as by regular periodic flushing. These symptoms can be attributed to systemic release of large amounts of serotonin and can be controlled with inhibitors of tryptophan hydroxylase, such as p-chlorophenylalanine. The synthesis of 5-hydroxytryptamine in advanced carcinoid syndrome may be so great that as much as 60% of the body s tryptophan metabolism proceeds by this pathway, compared with about 1% under normal conditions. A significant number of... 

Figure 8.4. Pathways of tryptophan metabolism. Tryptophan dioxygenase, EC 1.13.11.11 formylkynurenine formamidase, EC 3.5.1.9 kynurenine hydroxylase, EC 1.14.13.9 kynttreninase, EC 3.7.1.3 3-hydroxyanthranilate oxidase, EC 1.10.3.5 picolinate carboxylase, EC 4.1.1.45 kynurenine oxoglutarate aminotransferase, EC 2.6.1.7 kynurenine glyoxylate aminotransferase, 2.6.1.63 tryptophan hydroxylase, EC 1.14.16.4 and 5-hydroxytryptophan decarboxylase, EC 4.1.1.26. Relative molecular masses (Mr) tryptophan, 204.2 serotonin, 176.2 kynurenine, 208.2 3-hydroxykynurenine, 223.2 kynurenic acid, 189.2 xanthurenic acid, 205.2 and quinolinic add 167.1. CoA, coenzyme A...

Finally, it was found (B7) that the excretion of 5-hydroxyindoleacetic acid, which is taken as an index of tryptophan metabolism by the serotonin pathway, is affected by the administration of tryptophan neither in normal nor in schizophrenic subjects. 

In Hartnup disease tryptophan absorption is impaired and in malignant carcinoid syndrome tryptophan metabolism is altered resulting in excess serotonin synthesis. 

Some women suffer from mental deprc.ssion when taking estrogen-containing oral contraceptives, and this depression could be due to another malfunction in tryptophan metabolism, leading to S-hydroxytryptamine (serotonin). Some evidence indicates that the decarboxylation of S-hydroxytrypto-phan is inhibited (in vitro) by estfogen conjugates competing with pyridoxal phosphate for the decarboxylase apoenzyme. 

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... 

In mice fed a tryptophan-deficient diet ad libitum for 1 week, Jones et al.31 reported on tissue serotonin synthesis rates, systemic tryptophan metabolism, and its response to steroid or cycloheximide treatment. In the experimental mice, brain serotonin synthesis was decreased while duodenal serotonin synthesis was increased following a tryptophan load. Liver total protein was depressed in experimental mice but increased following a tryptophan load. Blood tryptophan (total and free) and albumin were decreased in experimental mice, but ratios of albumin-bound tryptophan were increased. Enzyme kinetic studies indicated that, in experimental mice, brain tryptophan-5-hydroxylase had a reduced Vmax but the enzyme response to tryptophan or hydrocortisone injection was increased. However, hepatic tryptophan-2,3-dioxygenase response to tryptophan or hydrocortisone injection was blunted in experimental mice. 

Tryptophan is the most extensively studied amino acid in relation to alcohol and alcoholism. This is probably because it is the precursor of serotonin. Serotonin levels as altered by ethanol could have a role in disturbances in mood, clinical features of alcohol dependence, and alcohol withdrawal states. The control of alcohol consumption itself by serotonin has been considered.96 Accounts of the effects of ethanol on tryptophan and serotonin metabolism have been reviewed.9798 This section limits itself to selected aspects of ethanol and tryptophan metabolism in experimental animals and in humans. How these changes may secondarily affect serotonin metabolism is mentioned. 

In the rat, the most often studied animal species, whose tryptophan metabolism resembles closely that of humans, acute ethanol administration, as described earlier, induces a biphasic effect on serum tryptophan levels, an initial increase followed by a later inhibition. Similarly, acute ethanol administration exerts a biphasic effect on brain serotonin synthesis and turnover, an initial enhancement followed by a later inhibition.111 The initial enhancement is caused by an increase in circulating free tryptophan availability to brain, probably secondary to a catecholamine-dependent lipolysis and a nonesteri-fied fatty acid-mediated displacement of the albumin-bound amino acid, whereas the later inhibition of serotonin synthesis and turnover is the result of a decrease in circulating free and albumin-bound tryptophan availability to the brain secondary to activation of hepatic tryptophan 2,3-dioxygenase (TP) by the earlier increase in free tryptophan to the liver. The activation of hepatic TP by acute ethanol administration, which is substrate (tryptophan) mediated, has been described in rats by Badawy and Evans.111127128... 

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 ... 

The hydroxylation of tryptophan produces 5-hydroxytryptophan, which can then be decarboxylated, catalyzed by tryptophan decarboxylase, a PALP-requiring enzyme, to 5-hydroxy tryptamine, also known as serotonin. Serotonin is an important compound in normal brain function and tranquility. Therefore, any disturbance of tryptophan metabolism via this pathway can lead to mental disturbances. Serotonin can be destroyed by the enzyme monoamine oxidase (a flavo protein), which catalyzes the formation of ammonia and 5-hydroxyindole acetaldehyde in an irreversible reaction. The aldehyde is rapidly oxidized enzymatically, utilizing NAD+ to form 5-hydroxy indoleacetate, which is then usually excreted. The formation and turnover of serotonin can be estimated by 5-hydroxy indoleacetate output in the urine. 

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. 

Serotonin - The metabolic biosynthetic pathway from tryptophan to serotonin is shown here. 

Tryptophan is an essential amino acid which is ingested by Americans in quantities that exceed the normal daily requirements for protein synthesis (Rl), and considerable amounts are converted to nonprotein substances such as nicotinic acid and serotonin (Fig. 1). The tryptophan-niacin pathway, which is also known as the kynurenine pathway (Fig. 1), is important for production of the vitamin, nicotinic acid, and provides also a means for degrading tryptophan to acetoacetyl-CoA, carbon dioxide, and ammonia (P7). The amount of tryptophan metabolized by the various pathways available depends greatly on the amount of... 

Pathways of metabolism have been outlined which indicate how tryptophan is a source of auxin, niacin, serotonin, ommochrome, and energy. Many other compounds are formed as side-products of these pathways and still others are formed by further reactions. Yet additional pathways remain to be elucidated to describe the formation of gramine (V-dimethyl-indole-3-methylamine), abrine (A -methyltryptophan), the a-hydroxy-tryptophan component of phalloidin, skatole, and possibly other complex compounds containing the indole nucleus. The reactions involved in these transformations include examples of various types of oxidation, transamination, cleavage, elimination, decarboxylation, and condensation as well as cis-trans isomerization. The wealth of biochemical variety already revealed in these studies is a stimulus toward exploration of the still unknown reactions of tryptophan metabolism. 

Vitamin B-6 and oral contraceptive agents—Recent studies indicate that the vitamin B-6 requirement for most oral contraceptive users is approximately the same as that for nonusers thus, the current evidence does not appear to justify the routine supplementation of the dietary vitamin B-6 with pyri-doxine. However, some women report that depression occurs when they are taking oral contraceptives, probably as a result of the failure to convert tryptophan to serotonin, a neurotransmitter in the brain. When this problem occurs, the physician may suggest higher levels of vitamin B-6 (about 30 mg daily) in order to normaiize tryptophan metabolism. 

The outcome of the different lines of investigation is that a number of pathways of tryptophan metabolism have been established. In the vertebrate organism the two well-known pathways are the kynurenine-hydroxyanthranilic acid and the serotonin pathways. Studies with Pseudomonas bacteria led Stanier and Hayaishi (876) to propose two pathways for the dissimilation of the products of tryptophan metabolism starting at the level of kynurenine. One of these is through anthranilic acid and catechol, referred to as the aromatic pathway, and the other through kynurenic acid, named the quinoline pathway. 

Tryptophan is a precursor for a series of metabolic reactions. Two tryptophan catabolizing pathways are well characterized (i) tryptophan converts to serotonin (ii) tryptophan is also converted to kynurenine. 

Certain amino acids and their derivatives, although not found in proteins, nonetheless are biochemically important. A few of the more notable examples are shown in Figure 4.5. y-Aminobutyric acid, or GABA, is produced by the decarboxylation of glutamic acid and is a potent neurotransmitter. Histamine, which is synthesized by decarboxylation of histidine, and serotonin, which is derived from tryptophan, similarly function as neurotransmitters and regulators. /3-Alanine is found in nature in the peptides carnosine and anserine and is a component of pantothenic acid (a vitamin), which is a part of coenzyme A. Epinephrine (also known as adrenaline), derived from tyrosine, is an important hormone. Penicillamine is a constituent of the penicillin antibiotics. Ornithine, betaine, homocysteine, and homoserine are important metabolic intermediates. Citrulline is the immediate precursor of arginine. 

The amino acid L-tryptophan is the precursor for the synthesis of 5-HT. The synthesis and primary metabolic pathways of 5-HT are shown in Figure 13-5. The initial step in the synthesis of serotonin is the facilitated transport of the amino acid L-tryptophan from blood into brain. The primary source of tryptophan is dietary protein. Other neutral amino acids, such as phenylalanine, leucine and methionine, are transported by the same carrier into the brain. Therefore, the entry of tryptophan into brain is not only related to its concentration in blood but is also a function of its concentration in relation to the concentrations of other neutral amino acids. Consequently, lowering the dietary intake of tryptophan while raising the intake of the amino acids with which it competes for transport into brain lowers the content of 5-HT in brain and changes certain behaviors associated with 5-HT function. This strategy for lowering the brain content of 5-HT has been used clinically to evaluate the importance of brain 5-HT in the mechanism of action of psychotherapeutic drugs. 

The affect of Li+ on the metabolism of serotonin (5-hydroxytryp-tamine, 5-HT) is equivocal. A number of studies consistently find a Li+-induced increase in the levels of the major metabolite, 5-hydroxyin-doleacetic acid (5-HIAA), in rat brain and in human CSF [155], which appears to reflect an increase in the rate of synthesis of 5-HT [156]. Li+-induced increases in the level of the amino acid precursor, tryptophan, and in the uptake of tryptophan by brain have also been reported [157], implying elevated tryptophan availability during Li+ treatment. In rat brain, chronic Li+ decreases the activity of tryptophan hydroxylase, the enzyme which, when activated by a Ca2+ and calmodulin-dependent protein kinase, leads to the synthesis of 5-HT [158]. Ca2+ increases the strength of binding of tryptophan to the enzyme, whereas Li+ has the opposite effect [159]. Tryptophan uptake is coupled to 5-HT utilization by a negative feedback mechanism and, therefore, the Li+-induced inhibition of tryptophan hydroxylase with a resultant decrease in 5-HT utilization could produce the observed increase in tryptophan uptake. 

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

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