Serotonin synthesis from tryptophan

Typically, neurotoxic effects of drugs on monoamine neurons have been assessed from reductions in brain levels of monoamines and their metabolites, decreases in the maximal activity of synthetic enzymes activity, and decreases in the active uptake carrier. In the present study, the traditional markers described above have been used, including the measurement of the content of monoamines and their metabolites in brain at several different timepoints following drug administration. Since reports in the literature have documented that MDMA and MDA can inhibit the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis (Stone et al. 1986 Stone et al. 1987). it is unclear whether MDMA-induced reductions in the content of serotonin and its metabolite 5-hydroxyin-doleacetic acid (5-HlAA) may be due to suppressed neurotransmission in otherwise structurally intact serotonin neurons or may represent the eonsequenee of the destruction of serotonin neurons and terminals. 

From L-tryptophan, the serotonin synthesis pathway also begins. Serotonin is 5-hydroxytryptamine. It is derived from L-tryptophan, which at first is simply hydroxylated to 5-hydroxy-L-tryptophan, and subsequently to the serotonin (Figure 39). Structurally, serotonin is also a 5-HT monoamine neurotransmitter. 

Bischler-Napieralski reactions, 4, 279 carboline synthesis from, 4, 516 Mannich-type reactions, 4, 279 sulfur isosteres, biological activity, 4, 913 synthesis, 4, 337, 913 Tryptophan biosynthesis, 1, 264 carboline synthesis from, 4, 516 molecular structure, 4, 162 Tryptophan hydroxylase in serotonin biosynthesis, 1, 261 Tryptophan oxygenase... 

Like histamine, serotonin is widely distributed in nature, being found in plant and animal tissues, venoms, and stings. It is an indoleethylamine formed in biologic systems from the amino acid L-tryptophan by hydroxylation of the indole ring followed by decarboxylation of the amino acid (Figure 16-3). Hydroxylation at C5 is the rate-limiting step and can be blocked by p-chlorophenylalanine (PCPA fenclonine) and by /i-chloroamphetamine. These agents have been used experimentally to reduce serotonin synthesis in carcinoid syndrome. 

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. 

Earlier, Hemandez-Rodriguez and Chagoya28 reported on the effect of prenatal tryptophan supplementation on serotonin synthesis and the activity of Na+,K+ ATPase in the rat cerebral cortex during postnatal development, from birth up to day 30. Elevated levels of both were observed in comparison to controls. 

Tryptophan is also the initial substrate for the 5-hydroxytryptamine (serotonin) pathway (Fig. 1). Administration of hydrocortisone to the rat results in decreased serotonin levels in brain and induction of tryptophan pyrrolase activity in the liver (C16, K6). In the gerbil, in which corticosteroids do not induce hepatic tryptophan pyrrolase, hydrocortisone does not result in any change in brain serotonin concentrations (G6). Although these findings are not conclusive proof, they suggest that if tryptophan pyrrolase is induced, particularly in the liver, tryptophan in brain may be diverted from the serotonin pathway to the kynurenine pathway, resulting in decreased serotonin synthesis in brain (C16). 

By increasing the activity of the kynurenine pathway, estrogens could also increase the requirements for PLP and make less available to act as the coenzyme for 5-hydroxytryptophan decarboxylase, or estrogen conjugates could displace PLP from the decarboxylase coenzyme directly. Even though in nonhuman mammals tryptophan hydroxylase, not the decarboxylase, is thought to be rate-limiting in serotonin synthesis (Jl), levels of decarboxylase are said to be so low in human brain... 

Assay of phenylalanine hydroxylase in a liver biopsy from one patient showed 20% of normal adult control values, but dihydropteridine reductase activity (Fig. 20.2) was less than 1% of normal in the liver, brain, and other tissues. This latter deficiency presents regeneration of tetrahydrobiopterin, the cofactor for the hydroxylase reaction. Since the reductase enzyme reaction regenerates the cofactor for tyrosine and tryptophan hydroxylase, catecholamine and serotonin synthesis are compromised as well. Patient studies are scanty, but in one patient dopamine and serotonin were decreased in the cerebrospinal fluid, brain, and various other tissues, while norepinephrine metabolites were normal. While phenylalanine hydroxylase activity was lower than that of adult controls, it was not determined whether this value represented significantly decreased activity in children. 

Dopa decarboxylase is an enzyme catalyzing the synthesis of dopamine from l-DOPA or of serotonin (= 5-hydroxytryptamine) from L-tryptophan. Inhibitors of this enzyme, which do not pass through the... 

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... 

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. 

Amino acid decarboxylations are involved in the synthesis of several metabolically important amines, e.g., 5-hydroxytryptamine (serotonin) from tryptophan, histamine from histidine, and y-aminohutyric acid (GABA) from glutamate. 

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. 

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). 

Hyperserotonemia has been a consistent finding in subjects with autism, which may be due to activity of serotonin-associated platelet proteins (Hranilovic et al., 2008, 2009). Interestingly, 99% of blood serotonin is contained in platelets (Anderson et al., 1987) and studies have shown that there is an approximate 50% increase in blood-levels of serotonin in subjects with autism vs. controls (McBride et al., 1998). Hypotheses for increased serotonin include increased synthesis of serotonin by tryptophan hydroxylase (TPHl), increased uptake of serotonin into platelets via serotonin transporters (5-HTT), diminished release of serotonin from platelets via serotonin 2A receptor, and decreased breakdown of serotonin by monoamine oxidase (MAOA) (Hranilovic et al., 2008). A study by Hranilovic et al. (2008) identified polymorphisms of tryptophan hydroxylase and MAOA with increased serum serotonin levels. Similarly, haplotype analysis has shown a significant association between polymorphisms of TPHl and increased serotonin in whole blood (Cross et al., 2008). 

It contains the highest levels of the enzyme tryptophan hydroxylase, which is essential in the synthesis of serotonin from tryptophan. The pineal also is the only organ containing the enzyme HIOMT, which converts serotonin to melatonin. We have already noted that the pineal contains the hallucinogenic compound 6-methoxyharmalan. 

Purines and pyrimidines are derived largely from amino acids. The biosynthesis of these precursors of DNA, RNA, and numerous coenzymes will be discussed in detail in Chapter 25. The reactive terminus of sphingosine, an intermediate in the synthesis of sphingolipids, comes from serine. Histamine, a potent vasodilator, is derived from histidine by decarboxylation. Tyrosine is a precursor of the hormones thyroxine (tetraiodothyronine) and epinephrine and of melanin, a complex polymeric pigment. The neurotransmitter serotonin (5-hydroxytryptamine) and the nicotinamide ring of NAD + are synthesized from tryptophan. Let us now consider in more detail three particularly important biochemicals derived from amino acids. 

Boyadzhiev L and Yordanov B. Pertraction of Indole Alkaloids from Vinca minor L. Sep Sci Tech, 2004 39(6) 1321-1329. Coucouvanis D. Dell Rosa and Jay Pike recognition and transport of amphiphilic molecules by a new class of inorganic ditopic receptors. The synthesis of M- Bu - salphen-3n-cr-n complexes and their use (M = Mn,Fe, n = 6) in the transport of tryptophan and serotonin across bulk liquid membranes. Comptes Rendus Chimie, 2003 6(3) 317-327. 

Tryptophan (fig. 8) is one of the twenty amino acids used by all of life on Earth to build proteins. Although plants, fungi, bacteria, and some other organisms can biosynthesize tryptophan from smaller carbon molecules, humans cannot and must ingest tryptophan as part of their diet. That is, tryptophan is one of the essential amino acids. In fungi and plants, tryptophan is the chemical precursor for the biosynthesis of tryptamines such as DMT and psilocybin. In humans and other animals, tryptophan is the precursor for the synthesis of the neurotransmitter serotonin, 5-hydroxytryptamine (5-HT fig. 9). 

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. 

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