Serotonin from tryptophan

Back to the individual chemical stories. This commentary will cover the scatter of beta-carbolines that might play some major role in the human nervous system, other than the harmine trilogy. Harmine, harmaline and tetrahydroharmine all have the oxygen at the 7-position, and mostly have their origins in the botanical world. The 6-position oxygen can come directly from serotonin or hydroxy-tryptophan, and are found both in plants and animals. Similarly, the hydrogen derivatives (unsubstituted) derive from tryptamine and tryptophan, again from both plants and animals. 

The brain synthesizes serotonin from tryptophan, an essential amino acid found in a variety of foods. The ingestion of large amounts of tryptophan increases the production of serotonin. 

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. 

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. 

Decarboxylations of amino acids are involved in the production of serotonin from tryptophan and of dopamine from tyrosine. 

C. Products derived from tryptophan —Serotonin, melatonin, and the nicotinamide moiety of NAD and... 

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. 

Strain differences in the activity of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis, have been reported in rats22-23 and in mice.24 Chaouloff et al.22 reported that the activity of tryptophan hydroxylase was decreased in Lewis rats compared with Fisher 344 rats. Kulikov et al.23 reported that in vitro central tryptophan hydroxylase activity was higher in the Lewis strain of rats than in spontaneously hypertensive rats. In mice, Knapp and Mandell24 reported that midbrain tryptophan hydroxylase from two behaviorally different mouse strains, C57B1/6J and A/J, had different stabilities and regulatory properties. 

In addition to the quantitative findings in regard to tryptophan, another early report revealed an important and unique property of tryptophan within the blood. In 1957, McMenemy et al.180 described a unique property of tryptophan — that it was the only amino acid in plasma that was largely bound to protein. This attribute, specifically the ratio of free to bound tryptophan in the blood, has much physiological significance. For example, only the small free fraction of plasma tryptophan has access to the brain. Factors that influence the equilibrium between free and bound tryptophan in the plasma have been considered to alter the availability of tryptophan to the brain, where it has special importance as a precursor of the neurotransmitter 5-hydroxytryptamine (serotonin).181183 Tryptophan differs from other amino acids in that its concentration in the plasma of rats increases (30 to 40%) after fasting, after insulin administration, or after consuming a carbohydrate meal.184... 

Total citations on Medline for 5-year periods from 1961 to 2000. L-tryptophan = serotonin = and melatonin = . 

Synthesis of serotonin from the amino acid tryptophan. 

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). 

Fig (2). Aromatic L-amino acid decarboxylase also known as tryptophan decarboxylase, catalyses the synthesis of 5-bydnoxyiriplaminc (serotonin) from 5-hydroxytryptophan. lire reaction consists of a decarboxylation activity that is found in many human tissue cells... 

Glycine and glutamate are amino acids that serve directly as neurotransmitters are. y-Aminobutyric acid (GABA), the decarboxylation product of glutamate, is also a neurotransmitter. Amino acid metabolites that function in neurotransmission include histamine (from histidine), serotonin (from tryptophan), and catecholamines (epinephrine, dopamine, and norepinephrine), which are derived from tyrosine. 

The pathway for the synthesis of serotonin from tryptophan is very similar to the pathway for the synthesis of norepinephrine from tyrosine (Fig. 48.7). The first enzyme of the pathway, tryptophan hydroxylase, uses an enzymic mechanism similar to that of tyrosine and phenylalanine hydroxylase and requires BH4 to hydroxylate the ring structure of tryptophan. The second step of the pathway is a decarboxylation reaction... 

Vitamin. Bg helps in the production of serotonin from the amino acid known as L-tryptophan. Some research suggests that B6 might help address premenstrual syndrome (PMS), autism, and some seizure disorders, as well as help prevent many chronic diseases associated with inflammation. A study also found that supplementation helped antidepressants work better in an elderly population who also had cognitive dysfunction. I recommend 10 to 50 mg twice a day of the pyridoxal-5-phosphate (or pyridoxine ), the active form of Bg. Ideally, you should take the dosage between meals, but if it causes nausea, take it with food. Be careful not to exceed the recommended dose, particularly because doses over 300 mg daily may lead to peripheral neuropathy (numbness and tingling in the hands and feet). 

Hydroxytryptamine (serotonine), which occurs in both the animal and plant kingdom, is formed by hydroxylation and decarboxylation of tryptophan. Serotonine has attracted attention above all in human physiology. It is regarded along with adrenaline and acetylcholine as the third active substance in the transfer of the nerve stimulus in synapses or from nerve ends to the effector. 

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. ... 

Some amines are derived from tyramine (e. g., hordenine, synephrine, octopamine, dopamine and noradrenaline cf. Formula 18.3) and others from tryptophan (serotonin, tryptamine, melatonin Formula 18.4). The occurrence of... 

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