Tryptophan Amino Acids: Properties, Function, Benefits, and Sources

What is tryptophan?

Tryptophan, often known as Trp, is an essential amino acid that contains indole and is required for both appropriate child development and growth as well as for adults to maintain nitrogen balance. By giving mice a diet deficient in tryptophan, Sydney W. Cole and Sir Frederick Gowland Hopkins were able to extract tryptophan from the milk protein casein for the first time in 1901. It is the least prevalent of all the necessary amino acids. It is a protein that serves a variety of purposes in the body and is a component of numerous endogenous compounds. It is a precursor to melatonin since it is also a precursor to serotonin. As a result, it has been studied as a hypnotic, and some study indicates that it works. However, there is a dearth of research including children and adolescents.

Tryptophan structure

The distinctive indole ring structure of tryptophan, an important aromatic amino acid, is made up of a pyrrole ring with a nitrogen atom linked to a benzene ring. It can interact in protein active sites and take part in hydrogen bonding because of its side chain, C₈H₆N, which provides it both hydrophobic and somewhat polar characteristics. Tryptophan is a typical amino acid for protein synthesis because of its amino group (-NH₂) and carboxyl group (-COOH) connected to the α-carbon. Tryptophan is a necessary amino acid that must be consumed through diet. It is important for the production of serotonin and other crucial biological functions. The largest and most hydrophobic amino acid, tryptophan, gives big proteins crucial folding cues. Tryptophan typically makes up one to two percent of the protein weight, making it the least utilized amino acid in the structure of protein molecules. Tryptophan has only one code in the basic genetic code, "UGG," which is bordered by stop codons on UAA, UAG, and UGA. However, tryptophan is the source of numerous significant compounds, such as the DNA nucleic acids adenosine and thymidine.

Chemical structure of L-tryptophan. (Overcash A., et al., 2022)

Tryptophan pKa

There are two primary pKa values for tryptophan: one for the α-carboxyl group, which is around 2.38, and another for the α-amino group, which is about 9.4. Tryptophan exists in a zwitterionic state when the carboxyl group is deprotonated to generate -COO^- and the amino group is protonated to form -NH₃⁺ at physiological pH (~7.4). There is no effect on the pKa values from the indole ring on the tryptophan side chain since it is not ionizable. Due to the absence of a charge on the side chain, tryptophan maintains an overall neutrality at physiological pH.

The pka and isoelectric point values of lysine, methionine, and tryptophan. (Brandão-Lima L C., et al., 2021)

Sources of tryptophan

Tryptophan can be found in the diets of both children and adults in the following foods: eggs, meat, fish, bananas, oats, pumpkin and sesame seeds, chocolate, dried dates, soy, tofu, tree nuts, peanuts, and dairy products such as whole milk, cheese, and whey alpha-lactalbumin. For men, the daily minimum is 250 mg, and for women, it is 150 mg. Disorders including anorexia nervosa, anxiety, depression, hyperactivity, and behavioral impulsivity can develop when brain serotonin levels are too low, which happens when people don't eat enough tryptophan or suffer from malnutrition. In humans, tryptophan is used to treat anxiety, sadness, and sleeplessness. Physical and neurological development in youngsters depend on getting enough of this amino acid in their diet. Infants who are nursing get most of their tryptophan from breast milk. It may be essential to include tryptophan in infant formula for babies who do not breastfeed in order to enhance their brain activity, synaptogenesis, neuronal development, and overall growth and development. Infant formulas with tryptophan in them have a better chance of lowering oxidative stress and inflammation since they are more nutrient dense, antioxidant, and anti-inflammatory.

Tryptophan amounts in common foods. (Nayak B N., et al., 2022)

Tryptophan synthesis

Tryptophan is an aromatic amino acid synthesized from chorismate to anthranilate. Chorismate derives from the shikimate pathway. l-Tryptophan is synthesized by a biosynthetic route comprising five enzymatically regulated stages. The initial step involves the synthesis of anthranilate from chorismate. This process is facilitated by the enzyme anthranilate synthase (AS, E.C. 4.1.3.27). The subsequent step involves the synthesis of N-(5-phosphoribosyl) anthranilate, catalyzed by the enzyme phosphoribosyl diphosphate (PR)-anthranilate transferase (E.C. 4.1.1.48). The third stage involves the production of 1-(O-carboxyphenylamino)-1-deoxyribulose phosphate. This process is facilitated by the enzyme PR-anthranilate isomerase (E.C. 5.3.1.24). The subsequent step involves the synthesis of indole-3-glycerol phosphate. This process is facilitated by the enzyme indole-3-glycerol phosphate synthase (E.C. 4.1.1.48). The subsequent stage involves the synthesis of indole, catalyzed by the enzyme tryptophan synthase alpha (E.C. 4.2.1.20). The final stage involves the synthesis of l-tryptophan, catalyzed by the enzyme tryptophan synthase β (E.C. 4.2.1.20). This enzyme was identified by proteomics as being upregulated during alkaloid biosynthesis induction.

Biosynthesis of L-tryptophan. (El-Sayed M., et al., 2007)

Tryptophan amino acids at Creative Peptides

Tryptophan metabolism

As a substrate for protein synthesis, tryptophan is a vital and essential amino acid that plays critical physiological roles. Additionally, the catabolism of tryptophan is an important microenvironmental element that is implicated in the immune cell responses of cancer cells. There are three primary pathways that are responsible for the metabolism of tryptophan (Trp). The kynurenine pathway is responsible for the metabolism of more than 90 percent of the dietary tryptophan. This pathway is responsible for the production of several active metabolites, including kynurenine (Kyn), kynurenic acid (Kna), 3-hydroxykynurenine (3-OHKyn), 3-hydroxyanthranilic acid (3HAA), and quinolinic acid. The enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are responsible for regulating this pathway, which is triggered by proinflammatory stimuli. There is evidence that suggests that cancer, neurological disorders, and psychiatric problems are all associated with dysregulation of the kynurenine pathway. Some indole derivatives, such as indole, indole-3-acetic acid (IAA), and indole-3-propionic acid (IPA), are produced by the gut microbiota through the indole route. This process takes place predominantly in the gut microbiota. The indole pathway is responsible for the metabolism of approximately five percent of the tryptophan that is consumed through the diet. The serotonin pathway in the gut and brain is responsible for the synthesis of serotonin and melatonin, and the leftover tryptophan is utilized for this conversion.

The three major pathways of tryptophan metabolism. (Hou Y., et al., 2023)

Function of tryptophan

(1) Protein synthesis

The primary function of tryptophan in the human body is as a component of protein synthesis. Tryptophan, being present in the lowest amounts among amino acids, is comparatively less accessible and is believed to serve a rate-limiting function in protein synthesis. Tryptophan serves as the precursor for two significant metabolic pathways: kynurenine production and serotonin synthesis.

(2) Kynurenine synthesis

The synthesis of kynurenine is the second most common metabolic pathway of tryptophan, behind protein synthesis; it is responsible for around 90% of tryptophan catabolism. Not only is kynurenine an essential building block for many metabolites, but it is also the first step in the production of kynurenic and quinolinic acids. Specifically, quinolinic acid is an agonist for glutamate receptors while kynurenic acid is an antagonist for these receptors; both of these metabolites may influence other neurotransmitters. The role of kynurenine as an ultraviolet (UV) filter in protecting the eye's retina from UV damage is one of several recognized pathways involving this compound. Because this protection loses some of its efficacy with age, it helps explain why our lenses naturally undergo changes in color and fluorescence that can impair our vision and even contribute to cataract development in certain people.

(3) Serotonin synthesis

Approximately 95% of serotonin in mammals is located in the gut, but only 3% of the tryptophan in our food is converted into serotonin by several biological pathways. However, there is a lot of focus on serotonin production because it is a crucial tryptophan route. Although the amount of serotonin in the brain is relatively low compared to the rest of the body, it has a wide-ranging effect as a neurotransmitter and neuromodulator and has been linked to many mental disorders and psychological processes. It is estimated that only 1% of the tryptophan consumed by the body is converted into serotonin in the brain.

(4) Tryptamine synthesis

There are three main biological functions for tryptophan: protein synthesis, kynurenine production, and serotonin biosynthesis. Another biologically active molecule generated from tryptophan is tryptamine. An essential neuromodulator of serotonin, tryptamine is synthesized from tryptophan by rapid decarboxylation (ng/g). In certain cases, tryptamine serves as a neurotransmitter with specialized receptors that are separate from serotonin activity; in others, animal studies have shown that tryptamine regulates the balance between serotonin's excitatory and inhibitory effects.

(5) Melatonin synthesis

Melatonin is a hormone that controls the body's circadian rhythms, impacts the immune system, digestion, and gastrointestinal motility. It is created in the body through the tryptophan/serotonin pathway. The blue light spectrum, which includes both natural and artificial light, regulates melatonin synthesis. Circadian rhythms govern physiology, behavior, and sleep cycles; it is actively released by the pineal gland during dark times to generate endocrine and neurological effects.

(6) NAD/NADP synthesis

Tryptophan serves as a substrate for the production of the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD and NADP are coenzymes vital for electron transfer reactions (i.e., redox reactions) in all living cells. These enzymes can be generated de novo from consumed tryptophan or from the intake of niacin (i.e., vitamin B3).

(7) Niacin synthesis

Tryptophan serves as a substrate for niacin production via the kynurenine/quinolinic acid pathway. Nonetheless, this represents an inefficient utilization of tryptophan, as roughly 60 mg of tryptophan is required to produce one milligram of niacin. The advised daily intake of niacin is 16 mg for men and 14 mg for women. The median dietary intake of niacin for adults in the United States is roughly 41 mg/day for men and 28 mg/day for women, resulting in minimal necessity for supplementary synthesis from tryptophan.

What is tryptophan used for?

(1) Reduce stress response

The prolonged impact of dietary tryptophan alterations on the neuroendocrine stress response has been noted in both mammals and teleost fish. In pigs, increased dietary tryptophan (Trp) exhibited stress-reducing benefits, characterized by heightened hypothalamic serotonin (5-HT) and decreased post-stress plasma cortisol levels, with these effects reaching their zenith after 5 days of dietary Trp supplementation. Likewise, post-stress plasma cortisol concentrations reverted to baseline more rapidly following social stress in pigs that consumed Trp-enriched diet for seven days. Notably, a comparable duration for the inhibitory effects of dietary tryptophan supplementation on glucocorticoid secretion has been seen in fish. Research on rainbow trout indicates that the inhibition of the neuroendocrine stress response occurs after 7 days, but not after 3 or 28 days of dietary tryptophan supplementation. Moreover, previous research demonstrating a suppressive impact of increased dietary tryptophan on the neuroendocrine response to an acute stressor examined the effects during or immediately after a phase of dietary tryptophan supplementation. Recent investigations on seawater-reared Atlantic salmon (Salmo salar) indicate that the inhibitory effect on post-stress plasma cortisol manifests between 2 and 8 days following the cessation of tryptophan administration. Furthermore, in Atlantic salmon, this inhibitory effect persisted for 21 days following Trp administration. The Basic team proposed that the gradual Trp-induced changes in HPI-axis reactivity may be associated with smoltification, a process through which salmonid fish acclimatize to seawater. Furthermore, these prolonged alterations in HPI axis reactivity were not associated with modifications in hypothalamic 5-HT neurochemistry. Instead, they coincided with alterations in dopaminergic neurochemistry in this brain region, effects potentially linked to heightened activity of the kynurenic pathway, as elaborated in the section on The Kynurenic Pathway. The study conducted by Höglund's team demonstrated analogous results, indicating that 5-HTergic activity in the hypothalamus did not align with the prolonged tryptophan-induced suppression of post-stress cortisol levels.

Effects of dietary tryptophan supplementation on the behavioral and endocrine stress response. (Höglund E., et al., 2019)

(2) Enhance sleep quality

The study's results indicated that Trp supplementation may reduce wakefulness following sleep start. The group receiving ≥1 g Trp supplementation exhibited a shorter wake following sleep initiation compared to the group with Trp < 1 g supplementation (Trp < 1 g vs Trp ≥ 1 g: 56.55 vs 28.91 min; P = 0.001). Nonetheless, Trp supplementation did not influence other aspects of sleep. Supplementation with tryptophan, particularly at doses of 1 g or greater, can enhance sleep quality.

(3) Mitigate non-alcoholic fatty liver disease

The metabolism of intestinal serotonin (5-hydroxytryptamine, 5-HT) is believed to influence gut functioning via modulating motility, permeability, and other intestinal activities. A study examined the impact of tryptophan (TRP), a precursor of 5-HT, supplementation on intestinal barrier functioning and non-alcoholic fatty liver disease (NAFLD). The current investigation utilized a validated mice model of NAFLD induced by a fructose-enriched diet (N group). TRP was orally delivered for 8 weeks to C57BL/6J control and NAFLD mice. Parameters associated with NAFLD (hepatic TAG and Oil Red O staining), intestinal barrier integrity (tight-junction protein occludin and portal plasma lipopolysaccharides (LPS)), and 5-HT-related metrics (5-HT, 5-HT transporter (SERT), and motility) were assessed. In the N group, we noted diminished duodenal occludin protein levels (P= 0.0007), increased portal plasma LPS levels (P= 0.005), and a heightened liver weight to body weight ratio (P= 0.01) relative to the control group. TRP supplementation resulted in elevated occludin levels (P= 0.0009) and subsequently decreased the liver weight to body weight ratio (P= 0.009), along with a reduction in total hepatic fat accumulation in the N group (P= 0.05). The N group demonstrated reduced SERT protein expression (P= 0.002), which was restored by TRP supplementation (P= 0.02). The results suggest for the first time that oral TRP supplementation mitigates experimental NAFLD in mice.

The possible influence of tryptophan (TRP) on non-alcoholic fatty liver disease (NAFLD). (Ritze Y., et al., 2014)

(4) Improve intestinal mucosal barrier function

The piglets were given a maize and soybean meal diet that was supplemented with 0, 0.1, 0.2, or 0.4% Trp for four weeks after they were weaned. Methods based on the bacterial 16S rRNA gene for high-throughput sequencing were used to examine the small-intestinal microbiota, while high-performance liquid chromatography was employed to examine the serum amino acids. We used real-time PCR to determine the mRNA levels for host defense genes in the jejunum and Western blotting to measure the abundances of tight-junction proteins in the duodenum. There was a dose-dependent increase in the serum Trp concentrations of piglets given Trp supplementation. Dietary supplementation with 0.2-0.4% Trp had different effects on the jejunum microbiome compared to the control group. It decreased the abundances of Clostridium sensu stricto and Streptococcus, increased the abundances of Lactobacillus and Clostridium XI (two species of bacteria that can metabolize Trp), and increased the concentrations of secretory immunoglobulin A (sIgA) and mRNA levels for porcine β-defensins 2 and 3 in jejunal tissues. In addition, the levels of tight-junction proteins (claudin-1, zonula occludens (ZO)-1, and ZO-3) in the jejunum and duodenum were elevated when dietary Trp supplementation activated the mammalian target of rapamycin signaling. Dietary Trp improves mucosal health, function, and integrity, and we postulate that Trp-metabolizing bacteria in the small intestine of weaned pigs mostly mediate these benefits.

Tryptophan supplementation enhances the intestinal mucosal barrier function. (Liang H., et al., 2018)

(5) Decrease fatigue perception

It is not always muscular tiredness but rather insufficient serotonergic brain drive that causes people to stop exercising. Neuronal drive can be influenced by changes in the availability of L-tryptophan, a precursor of serotonin, which can modify the activity levels of the serotonergic system. Using a protocol that is similar to that of team sports in terms of combining aerobic exercise with short bursts of supramaximal intensity, we investigated how L-tryptophan supplementation affected performance. Twenty athletic young men, with an average age of 21.2 ± 0.7 years, engaged in a 10-minute submaximal exercise on a cycle ergometer, with a workload equal to 50% of their VO2 max, and then a 30-second maximum intensity exercise. Each participant continued to exercise at his best sustained speed for 20 minutes after the fourth iteration of this sequence, which was repeated three times. Two separate, blinded runs of this protocol were conducted: one with and one without L-tryptophan supplementation. When compared to placebo-treated trials, those that included L-tryptophan showed significant improvements in peak power output, average anaerobic power output, and power output in the final 20 minutes of the experiment. In the final 20 minutes of the study, the participants taking L-tryptophan reached 12,526 ± 1,617 meters, while those on placebo covered 11,959 ± 1,753 meters (p <.05). Last but not least, enhancing physical performance in some exercise kinds may be possible through serotonergic system modulation.

FAQ

Is tryptophan polar or nonpolar?

The hydrophobic indole ring of tryptophan gives it its primary classification as a nonpolar amino acid. Because of its hydrophobicity, tryptophan is apt to be located deep within proteins. Nevertheless, tryptophan is able to engage in hydrogen bonding and interact with other molecules due to the modest polarity introduced by the nitrogen in the indole ring. Tryptophan is a nonpolar amino acid with amphipathic qualities, meaning it has both hydrophobic and somewhat polar properties, despite its polar component. Its overall structure is nonpolar.

References

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