Synthesis of serotonin

The asymmetric reductive ring opening of oxabenzonorbomene 53 was applied as a key step in the total synthesis of serotonin re-uptake inhibitor sertraline [77, 80]. 

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. 

Walther DJ, Peter JU, Bashammakh S, Hortnagl H, VbitsM, FinkH, Bader M (2003) Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299 76... 

Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H, Bader M (2003) Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299 76 Wang X, Su H, Copenhagen LD, Vaishnav S, Fieri F, Shope CD, Brownell WE, De Biasi M, Paylor R, Bradley A (2002) Urocortin-deficient mice display normal stress-induced anxiety behavior and autonomic control but an impaired acoustic startle response. Mol Cell Biol 22 6605-6610... 

Serotonergic neurons. Analogous enzymes, transport pumps, and receptors exist in the 5HT neuron (Figs. 5 — 34 through 5—42). For synthesis of serotonin in serotonergic... 

The alkaline hydrolysis of isatin is the first step of a method for the construction of the indazolic ring system354. This method has been applied to the synthesis of serotonin... 

Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan and other large neutral amino acids. The result is that the intestinal absorption of free tryptophan is impaired, although dipeptide absorption is normal. There is a considerable urinary loss of tryptophan (and other amino acids) as a result of the failure of the normal reabsorption mechanism in the renal tubules - renal aminoaciduria. In addition to neurological signs that can be attributed to a deficit of tryptophan for the synthesis of serotonin in the central nervous system, the patients show clinical signs of pellagra, which respond to the administration of niacin. 

There is a great deal of evidence that deficiency of serotonin (5-hydroxytryptamine) is a factor in depressive illness, and many antidepressant drugs act to decrease its catabolism or enhance its interaction with receptors. A key enzyme involved in the synthesis of serotonin (and the catecholamines) is aromatic amino acid decarboxylase, which is pyridoxal phosphate-dependent. Therefore, it has been suggested that vitamin Be deficiency may result in reduced formation of the neurotransmitters and thus be a factor in the etiology of depression. Conversely, it has been suggested that supplements of vitamin Be may increase aromatic amino acid decarboxylase activity, and increase amine synthesis and have a mood-elevating or antidepressant effect. There is little evidence that vitamin Be deficiency affects the activity of aromatic amino acid decarboxylase. In patients with kidney failure, undergoing renal dialysis, the brain concentration of pyridoxal phosphate falls to about 50% of normal, with no effect on serotonin, catecholamines, or their metabolites (Perry etal., 1985). 

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. 

In the brain, serotonergic neurons are located in the brainstem in clusters of cells called the raphe nuclei, within which is the reticular network. These serotonergic neurons send their axonal projections throughout the entire brain. As a neurotransmitter, serotonin is involved in the regulation of numerous behavioral and physiological processes, including mood, appetite, sleep, sexual function, blood flow, body temperature, and more. The fact that both tryptophan and 5-HTP are chemical precursors for the synthesis of serotonin is presumably the reason for the claim of their efficacy in the treatment of problems related to mood, sleep, and appetite (Murray 1999). 

In keeping with the presumed importance of serotonin in the pathophysiology of BN is the finding that a reduction in the synthesis of serotonin in the brain, brought about by a diet deficient in tryptophan, precipitates a loss of eating control and an increased concern with body image in recovered BN patients (Smith et al. 1999). Chronic depletion of plasma tryptophan may be one of the mechanisms by which dieting leads to the development of BN in vulnerable subjects. 

Hydroxyindoles are sometimes obtainable by oxidation of a suitably substituted hydroquinone, as illustrated by the terminal step in a synthesis of serotonine (4). ... 

The involvement of the central nervous system serotonin function in the pathogenesis and treatment of affective disorders has been a subject of intensive research during the past 30 years.33 36 Studies using serotonin precursors and agonists as pharmacologic probes and measurements of cerebrospinal fluid monoamine metabolite levels indicated that alterations in central nervous system serotonin function may be involved in the pathophysiology of depression. Since the synthesis of serotonin depends on dietary intake of the precursor tryptophan, many studies have utilized tryptophan depletion techniques by which patients were fed a tryptophan-free diet for various time intervals. 

Many of the therapeutic uses of L-tryptophan are directed toward its effect on neurotransmission. Actually, diet itself clearly influences neurotransmission. This can best be illustrated in grossly undernourished children. Investigations have reported that starvation can impair neuronal maturation and can have lasting effects upon intellectual and behavior performance. When gross malnutrition does not exist, subtle changes in diet may modulate brain function. L-tryptophan, as well as tyrosine and choline, in the diet are precursors for neuronal synthesis of serotonin, dopamine, and norepinephrine, and acetycholine, respectively. Thus, L-tryptophan may be useful under certain circumstances as a drug in treatment of humans.121 On the other hand, in states of undernutrition, L-tryptophan therapy in itself is not curative, while proper nutrition may be the therapy of choice. 

A particularly useful and high-yielding reaction is that between indoles and oxalyl chloride, which gives ketone-acid-chlorides convertible into a range of compounds, for example tryptamines a synthesis of serotonin utilised this reaction." " ... 

Synthesis of serotonin from the amino acid tryptophan. 

Synthesis of serotonin at the spinal level in the rat modifications induced by nociceptive somatic stimulation, associated or not with administration of morphine... 

Fig. (1). Reaction carried out by the enzyme tryptophan hydroxylase. Tryptophan is supplied by dietary intake and transported actively to the central nervous system (CNS). Tryptophan hydroxylase is the key enzyme controlling the synthesis of serotonin and is predominantly present in neurons located in the raphe nuclei of the brain stem...

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). 

Lithium enhances the uptake of tryptophan and increases the synthesis of serotonin. It is also thought to decrease the reuptake of monamine neurotransmitters (e.g., catecholamines and serotonin). Reactions can be idiosyncratic, however, as lithium also decreases the conversion of thyroxine to triiodothyronine in the CNS. 

---