Tryptophan: Functions

The amino acid tryptophan cannot be produced by the human body and is therefore essential. It is a proteinogenic α-amino acid [synonym for L-tryptophan: (S)-tryptophan] with an aromatic indole ring system.

The human body needs this amino acid to produce two important messengers:

  • Serotonin (also 5-hydroxytryptamine (5-HT)) – the “happiness hormone” – ensures mental well-being.
  • Melatonin – the well-known sleep hormone – provides for the sleep rhythm and thus for the comfortable sleep.

As an important building block, tryptophan is still important for liver metabolism and can be converted, among other things, into the vitamin niacin and the coenzyme nicotinamide adenine dinucleotide (NAD).

L-tryptophan

Because of its strong lipophilicity (readily soluble in fats and oils), L-tryptophan is bound to the transport protein albumin for transport to the bloodbrain barrier. After being released from this binding, tryptophan can be transported to the brain. At the bloodbrain barrier, however, L-tryptophan competes with five other amino acids for the same transport system that allows it to enter the central nervous system (CNS). These are the branched-chain amino acids (abbreviated BCAA for English Branched-Chain Amino Acids) L-valine, L-leucine and L-isoleucine and the aromatic amino acids L-phenylalanine and L-tyrosine. To reduce the competitive pressure and increase the central availability of L-tryptophan, the following influencing factors play a role:

  • Diet: after a protein-rich meal, the intake of fast-acting carbohydrates increases insulin levels. As a result, competing branched-chain amino acids are shuttled into muscle cells and the percentage of tryptophan in the blood is increased. Thus, this can preferentially pass the blood-brain barrier.
  • Sports: intense endurance exercise leads to increased branched-chain amino acids being absorbed into the muscle cells under the influence of insulin. As a result, the percentage of tryptophan in the blood increases as well. The same applies to a short intense strength training.

L-tryptophan has an indirect effect on sleep via the formation of serotonin and on the general mood via the antidepressant effect. Tryptophan kynurenine metabolismOnly 3% of the ingested tryptophan is used for the synthesis of serotonin and melatonin in the CNS. For the most part, tryptophan is important for protein building, the formation of vitamin B3 and the coenzyme NAD. Tryptophan-kynurenine metabolism plays a role in this process.In the liver, tryptophan degradation begins with the cleavage of the pyrrole ring. This step is catalyzed (accelerated) by the enzyme tryptophan pyrrolase (or tryptophan 2,3-dioxygenase) and N-formylkynurenine is formed. With the help of kynurenine formylase, the non-proteinogenic aromatic amino acid kynurenine is formed. This is converted to 3-hydroxykynurenine by kynurenine-2-monooxygenase. In the next reaction step, L-alanine is cleaved with the help of kynureninase, and 3-hydroxyanthranilate is formed. Now the 3-hydroxy-anthranilate dioxygenase catalyzes the conversion to acroleyl-β-aminofumarate. After further reactions, acetyl-CoA is finally formed. The biosynthetic pathway for nicotinic acid (niacin, vitamin B3) branches off after the formation of acroleyl-β-aminofumarate. After the formation of quinolate, the NAD+ precursor nicotinic acid mononucleotide is formed. Tryptophan pyrrolase is located in the liver and regulates plasma tryptophan levels. If too much tryptophan is present in plasma, the tryptophan-degrading enzyme tryptophan pyrrolase (or tryptophan 2,3-dioxygenase) is activated. Disorders of tryptophan-kynurenine metabolismVitamin B6 deficiencyIn the case of vitamin B6 deficiency (specifically pyridoxal phosphate), the activity of kynureninase decreases and kynurenine and 3-hydroxykynurenine accumulate. In this case, kynurenine spontaneously forms kynurenic acid and 3-hydroxykynurenine forms xanthurenic acid. Kynurenic acid inhibits glutamate and dopamine release in the synaptic cleft. Immune responseIndolamine-2,3-dioxygenase (IDO) is an isoenzyme of tryptophan pyrrolase expressed by peripheral tissue. Proinflammatory cytokines such as IFN-γ or TNF-α activate the isoenzyme IDO.In the presence of an immune response, tryptophan is depleted by IDO, thus reducing its availability to, for example, virus-infected or cancer cells. The depletion of tryptophan has a cytostatic effect on the cells (inhibits cell growth). Furthermore, metabolites (intermediates) such as 3-hydroxykynurenine have a cytotoxic effect (acting as a cell toxin). Activation of the IDO enzyme is therefore a defense mechanism. Accordingly, serotonin/melatonin deficiency can be treated by tryptophan supplementation. However, inflammatory markers should not be present in high concentrations as they activate IDO.StressThe increased cortisol level due to chronic stress activates the tryptophan-degrading enzyme tryptophan pyrrolase. Note:Due to chronic stress and pro-inflammatory cytokines, tryptophan may be degraded. This leads to a decreased conversion of L-tryptophan to 5-hydroxytryptophan (5-HTP). 5-HTP is a precursor of serotonin.

Serotonin

Serotonin is one of the neurotransmitters (messenger substances). Its effects are mainly related to the nervous system (mood), the cardiovascular system (vasoconstriction), and the intestine (intestinal peristalsis ↑). Serotonin is built from the amino acid L-tryptophan in a two-step reaction:

  • Step 1: The intermediate is formed: the non-proteinogenic amino acid 5-hydroxytryptophan (5-HTP) (catalyst is the enzyme tryptophan hydroxylase).
  • 2nd step: decarboxylation to the final product serotonin (catalyst is the enzyme aromatic-L-amino acid decarboxylase or hydroxytryptophan decarboxylase).

Vitamins B6 and B3 and magnesium are involved in the synthesis. In addition, vitamin B3 inhibits the activity of the tryptophan-degrading enzyme tryptophan pyrrolase and thus supports the synthesis of tryptophan to 5-HTP. Serotonin action is mediated via 5-HT receptors. Starting from the so-called raphe nuclei, which are localized in the brain stem, serotonin is active in all regions of the brain via these nerve pathways. They influence, for example, memory performance, state of mind, sleep-wake rhythm, and pain perception.

Melatonin

Melatonin is a hormone produced by the pineal gland, a part of the diencephalon. Melatonin is synthesized in the brain from tryptophan via the intermediate serotonin (see below). It is synthesized only at night with onset of darkness. Maximum formation is reached between 2:00 and 4:00 a.m., after which it drops again. Daylight reaching the eye inhibits melatonin secretion. This is especially true of morning light, which has the highest blue light content. During the course of the day, the blue light content continuously decreases and the melatonin level slowly builds up towards the evening. Melatonin induces deep sleep and is a stimulus for the release of the growth hormone somatotropic hormone (STH) (synonym: somatotropin). The concentration of melatonin is age-dependent. Infants have the highest concentration. After that, melatonin production decreases continuously. Therefore, the average sleep duration decreases with age and sleep problems occur more frequently. Disturbances in somatotropin production induce premature somatopause. Somatopause is the progressive decline in STH secretion (somatotropic hormone (STH), human growth hormone (HGH)) with consecutive STH deficiency in middle-aged and older adults. Melatonin is synthesized (produced) in the brain from tryptophan via the intermediate serotonin in two steps:

  • Step 1: Serotonin is N-acetylated with acetyl-coenzyme A, (catalyst is the enzyme serotonin N-acetyltransferase (AANAT)).
  • Step 2: N-acetylserotonin is methylated with S-adenosylmethionine by acetylserotonin O-methyltransferase (transfer of a methyl group).

Melatonin has a sleep-promoting effect and controls the day-night rhythm.

Niacin

Niacin is a collective term for chemical structures of pyridine-3-carboxylic acid, which includes nicotinic acid, its acid amide nicotinamide, and the biologically active coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). L-tryptophan is the provitamin (precursor of vitamins) of niacin (vitamin B3). Niacin plays a crucial role in the body’s energy supply and is involved in a variety of different metabolic processes (protein/protein, lipid/fat, carbohydrate metabolism) in the body.