Tryptophan

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l-Tryptophan
L-Tryptophan - L-Tryptophan.svg
Skeletal formula of L-tryptophan
Tryptophan-from-xtal-3D-bs-17.png
Tryptophan-from-xtal-3D-sf.png
Names
IUPAC name
Tryptophan
Systematic IUPAC name
(2S)-2-amino-3-(1H-indol-3-yl)propanoic acid
Other names
2-Amino-3-(1H-indol-3-yl)propanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.723 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C11H12N2O2/c12-9(11(14)15)5-7-6-13-10-4-2-1-3-8(7)10/h1-4,6,9,13H,5,12H2,(H,14,15)/t9-/m0/s1 Yes check.svgY
    Key: QIVBCDIJIAJPQS-VIFPVBQESA-N Yes check.svgY
  • c1[nH]c2ccccc2c1C[C@H](N)C(=O)O
  • Zwitterion:c1[nH]c2ccccc2c1C[C@H]([NH3+])C(=O)[O-]
Properties
C11H12N2O2
Molar mass 204.229 g·mol−1
Soluble: 0.23 g/L at 0 °C,

11.4 g/L at 25 °C,
17.1 g/L at 50 °C,
27.95 g/L at 75 °C

Solubility Soluble in hot alcohol, alkali hydroxides; insoluble in chloroform.
Acidity (pKa)2.38 (carboxyl), 9.39 (amino) [2]
-132.0·10−6 cm3/mol
Pharmacology
N06AX02 ( WHO )
Supplementary data page
Tryptophan (data page)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Tryptophan (symbol Trp or W) [3] is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromatic beta carbon substituent. Tryptophan is also a precursor to the neurotransmitter serotonin, the hormone melatonin, and vitamin B3 (niacin). [4] It is encoded by the codon UGG.

Like other amino acids, tryptophan is a zwitterion at physiological pH where the amino group is protonated (–NH+
3
; pKa = 9.39) and the carboxylic acid is deprotonated ( –COO; pKa = 2.38). [5]

Humans and many animals cannot synthesize tryptophan: they need to obtain it through their diet, making it an essential amino acid.

Tryptophan is named after the digestive enzymes trypsin, which were used in its first isolation from casein proteins. [6] It was assigned the one-letter symbol W based on the double ring being visually suggestive to the bulky letter. [7]

Function

Metabolism of
l-tryptophan into serotonin and melatonin (left) and niacin (right). Transformed functional groups after each chemical reaction are highlighted in red. Tryptophan metabolism.svg
Metabolism of l-tryptophan into serotonin and melatonin (left) and niacin (right). Transformed functional groups after each chemical reaction are highlighted in red.

Amino acids, including tryptophan, are used as building blocks in protein biosynthesis, and proteins are required to sustain life. Tryptophan is among the less common amino acids found in proteins, but it plays important structural or functional roles whenever it occurs. For instance, tryptophan and tyrosine residues play special roles in "anchoring" membrane proteins within the cell membrane. Tryptophan, along with other aromatic amino acids, is also important in glycan-protein interactions. In addition, tryptophan functions as a biochemical precursor for the following compounds:

The disorder fructose malabsorption causes improper absorption of tryptophan in the intestine, reduced levels of tryptophan in the blood, [15] and depression. [16]

In bacteria that synthesize tryptophan, high cellular levels of this amino acid activate a repressor protein, which binds to the trp operon. [17] Binding of this repressor to the tryptophan operon prevents transcription of downstream DNA that codes for the enzymes involved in the biosynthesis of tryptophan. So high levels of tryptophan prevent tryptophan synthesis through a negative feedback loop, and when the cell's tryptophan levels go down again, transcription from the trp operon resumes. This permits tightly regulated and rapid responses to changes in the cell's internal and external tryptophan levels.

Tryptophan metabolism by human gastrointestinal microbiota ()
Microbiota-derived 3-Indolepropionic acid-notext.svg
Tryptophanase-
expressing
bacteria
IPA
I3A
IPA
I3A
AhR
Intestinal
immune
cells
PXR
Mucosal homeostasis:
TNF-α
Junction protein-
coding mRNAs
T J
Neuroprotectant:
↓Activation of glial cells and astrocytes
4-Hydroxy-2-nonenal levels
DNA damage
Antioxidant
–Inhibits β-amyloid fibril formation
Maintains mucosal reactivity:
IL-22 production
Interactive icon.svg
This diagram shows the biosynthesis of bioactive compounds (indole and certain other derivatives) from tryptophan by bacteria in the gut. [18] Indole is produced from tryptophan by bacteria that express tryptophanase. [18] Clostridium sporogenes metabolizes tryptophan into indole and subsequently 3-indolepropionic acid (IPA), [19] a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals. [18] [20] [21] IPA binds to the pregnane X receptor (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function. [18] Following absorption from the intestine and distribution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer's disease. [18] Lactobacillaceae (Lactobacillus s.l.) species metabolize tryptophan into indole-3-aldehyde (I3A) which acts on the aryl hydrocarbon receptor (AhR) in intestinal immune cells, in turn increasing interleukin-22 (IL-22) production. [18] Indole itself triggers the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells and acts as a ligand for AhR. [18] Indole can also be metabolized by the liver into indoxyl sulfate, a compound that is toxic in high concentrations and associated with vascular disease and renal dysfunction. [18] AST-120 (activated charcoal), an intestinal sorbent that is taken by mouth, adsorbs indole, in turn decreasing the concentration of indoxyl sulfate in blood plasma. [18]

In 2002, the U.S. Institute of Medicine set a Recommended Dietary Allowance (RDA) of 5 mg/kg body weight/day of tryptophan for adults 19 years and over. [22]

Dietary sources

Tryptophan is present in most protein-based foods or dietary proteins. It is particularly plentiful in chocolate, oats, dried dates, milk, yogurt, cottage cheese, red meat, eggs, fish, poultry, sesame, chickpeas, almonds, sunflower seeds, pumpkin seeds, hemp seeds, buckwheat, spirulina, and peanuts. Contrary to the popular belief [23] [24] that cooked turkey contains an abundance of tryptophan, the tryptophan content in turkey is typical of poultry. [25]

Tryptophan (Trp) content of various foods [25] [26]
FoodTryptophan
[g/100 g of food]
Protein
[g/100 g of food]
Tryptophan/protein
[%]
Egg white, dried1.0081.101.23
Spirulina, dried0.9257.471.62
Cod, Atlantic, dried0.7062.821.11
Soybeans, raw0.5936.491.62
Cheese, Parmesan 0.5637.901.47
Chia seeds, dried0.4416.502.64
Sesame seed 0.3717.002.17
Hemp seed, hulled0.3731.561.17
Cheese, Cheddar 0.3224.901.29
Sunflower seed 0.3017.201.74
Pork, chop0.2519.271.27
Turkey 0.2421.891.11
Chicken 0.2420.851.14
Beef 0.2320.131.12
Oats 0.2316.891.39
Salmon 0.2219.841.12
Lamb, chop 0.2118.331.17
Perch, Atlantic 0.2118.621.12
Chickpeas, raw0.1919.300.96
Egg 0.1712.581.33
Wheat flour, white0.1310.331.23
Baking chocolate, unsweetened0.1312.901.23
Milk 0.083.222.34
Rice, white, medium-grain, cooked0.032.381.18
Quinoa, uncooked0.1714.121.20
Quinoa, cooked0.054.401.10
Potatoes, russet0.022.140.84
Tamarind 0.022.800.64
Banana 0.011.030.87

Medical use

Depression

Because tryptophan is converted into 5-hydroxytryptophan (5-HTP) which is then converted into the neurotransmitter serotonin, it has been proposed that consumption of tryptophan or 5-HTP may improve depression symptoms by increasing the level of serotonin in the brain. Tryptophan is sold over the counter in the United States (after being banned to varying extents between 1989 and 2005) and the United Kingdom as a dietary supplement for use as an antidepressant, anxiolytic, and sleep aid. It is also marketed as a prescription drug in some European countries for the treatment of major depression. There is evidence that blood tryptophan levels are unlikely to be altered by changing the diet, [27] [28] but consuming purified tryptophan increases the serotonin level in the brain, whereas eating foods containing tryptophan does not. [29]

In 2001 a Cochrane review of the effect of 5-HTP and tryptophan on depression was published. The authors included only studies of a high rigor and included both 5-HTP and tryptophan in their review because of the limited data on either. Of 108 studies of 5-HTP and tryptophan on depression published between 1966 and 2000, only two met the authors' quality standards for inclusion, totaling 64 study participants. The substances were more effective than placebo in the two studies included but the authors state that "the evidence was of insufficient quality to be conclusive" and note that "because alternative antidepressants exist which have been proven to be effective and safe, the clinical usefulness of 5-HTP and tryptophan is limited at present". [30] The use of tryptophan as an adjunctive therapy in addition to standard treatment for mood and anxiety disorders is not supported by the scientific evidence. [30] [31]

Insomnia

The American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended against the use of tryptophan in the treatment of insomnia due to poor effectiveness. [32]

Side effects

Potential side effects of tryptophan supplementation include nausea, diarrhea, drowsiness, lightheadedness, headache, dry mouth, blurred vision, sedation, euphoria, and nystagmus (involuntary eye movements). [33] [34]

Interactions

Tryptophan taken as a dietary supplement (such as in tablet form) has the potential to cause serotonin syndrome when combined with antidepressants of the MAOI or SSRI class or other strongly serotonergic drugs. [34] Because tryptophan supplementation has not been thoroughly studied in a clinical setting, its interactions with other drugs are not well known. [30]

Isolation

The isolation of tryptophan was first reported by Frederick Hopkins in 1901. [35] Hopkins recovered tryptophan from hydrolysed casein, recovering 4–8 g of tryptophan from 600 g of crude casein. [36]

Biosynthesis and industrial production

As an essential amino acid, tryptophan is not synthesized from simpler substances in humans and other animals, so it needs to be present in the diet in the form of tryptophan-containing proteins. Plants and microorganisms commonly synthesize tryptophan from shikimic acid or anthranilate: [37] anthranilate condenses with phosphoribosylpyrophosphate (PRPP), generating pyrophosphate as a by-product. The ring of the ribose moiety is opened and subjected to reductive decarboxylation, producing indole-3-glycerol phosphate; this, in turn, is transformed into indole. In the last step, tryptophan synthase catalyzes the formation of tryptophan from indole and the amino acid serine.

Tryptophan biosynthesis (en).svg

The industrial production of tryptophan is also biosynthetic and is based on the fermentation of serine and indole using either wild-type or genetically modified bacteria such as B. amyloliquefaciens , B. subtilis , C. glutamicum or E. coli . These strains carry mutations that prevent the reuptake of aromatic amino acids or multiple/overexpressed trp operons. The conversion is catalyzed by the enzyme tryptophan synthase. [38] [39] [40]

Society and culture

Showa Denko contamination scandal

There was a large outbreak of eosinophilia-myalgia syndrome (EMS) in the U.S. in 1989, with more than 1,500 cases reported to the CDC and at least 37 deaths. [41] After preliminary investigation revealed that the outbreak was linked to intake of tryptophan, the U.S. Food and Drug Administration (FDA) recalled tryptophan supplements in 1989 and banned most public sales in 1990, [42] [43] [44] with other countries following suit. [45] [46]

Subsequent studies suggested that EMS was linked to specific batches of L-tryptophan supplied by a single large Japanese manufacturer, Showa Denko. [42] [47] [48] [49] It eventually became clear that recent batches of Showa Denko's L-tryptophan were contaminated by trace impurities, which were subsequently thought to be responsible for the 1989 EMS outbreak. [42] [50] [51] However, other evidence suggests that tryptophan itself may be a potentially major contributory factor in EMS. [52] There are also claims that a precursor reached sufficient concentrations to form a toxic dimer. [53]

The FDA loosened its restrictions on sales and marketing of tryptophan in February 2001, [42] but continued to limit the importation of tryptophan not intended for an exempted use until 2005. [54]

The fact that the Showa Denko facility used genetically engineered bacteria to produce the contaminated batches of L-tryptophan later found to have caused the outbreak of eosinophilia-myalgia syndrome has been cited as evidence of a need for "close monitoring of the chemical purity of biotechnology-derived products". [55] Those calling for purity monitoring have, in turn, been criticized as anti-GMO activists who overlook possible non-GMO causes of contamination and threaten the development of biotech. [56]

Turkey meat and drowsiness hypothesis

A common assertion in the US and the UK [57] is that heavy consumption of turkey meat—as seen during Thanksgiving and Christmas—results in drowsiness, due to high levels of tryptophan contained in turkey. [24] However, the amount of tryptophan in turkey is comparable with that of other meats. [23] [25] Drowsiness after eating may be caused by other foods eaten with the turkey, particularly carbohydrates. [58] Ingestion of a meal rich in carbohydrates triggers the release of insulin. [59] [60] [61] [62] Insulin in turn stimulates the uptake of large neutral branched-chain amino acids (BCAA), but not tryptophan, into muscle, increasing the ratio of tryptophan to BCAA in the blood stream. The resulting increased tryptophan ratio reduces competition at the large neutral amino acid transporter (which transports both BCAA and aromatic amino acids), resulting in more uptake of tryptophan across the blood–brain barrier into the cerebrospinal fluid (CSF). [62] [63] [64] Once in the CSF, tryptophan is converted into serotonin in the raphe nuclei by the normal enzymatic pathway. [60] [65] The resultant serotonin is further metabolised into the hormone melatonin—which is an important mediator of the circadian rhythm [66] —by the pineal gland. [10] Hence, these data suggest that "feast-induced drowsiness"—or postprandial somnolence—may be the result of a heavy meal rich in carbohydrates, which indirectly increases the production of melatonin in the brain, and thereby promotes sleep. [59] [60] [61] [65]

Research

Yeast amino acid metabolism

In 1912 Felix Ehrlich demonstrated that yeast metabolizes the natural amino acids essentially by splitting off carbon dioxide and replacing the amino group with a hydroxyl group. By this reaction, tryptophan gives rise to tryptophol. [67]

Serotonin precursor

Tryptophan affects brain serotonin synthesis when given orally in a purified form and is used to modify serotonin levels for research. [29] Low brain serotonin level is induced by administration of tryptophan-poor protein in a technique called acute tryptophan depletion. [68] Studies using this method have evaluated the effect of serotonin on mood and social behavior, finding that serotonin reduces aggression and increases agreeableness. [69]

Psychedelic effects

Tryptophan produces the head-twitch response (HTR) in rodents when administered at sufficiently high doses. [70] The HTR is induced by serotonergic psychedelics like lysergic acid diethylamide (LSD) and psilocybin and is a behavioral proxy of psychedelic effects. [71] [72] Tryptophan is converted into the trace amine tryptamine and tryptamine is N-methylated by indolethylamine N-methyltransferase (INMT) into N-methyltryptamine (NMT) and N,N-dimethyltryptamine (N,N-DMT), which are known serotonergic psychedelics. [70] [73] [74] [75] [76] [77]

Fluorescence

Tryptophan is an important intrinsic fluorescent probe (amino acid), which can be used to estimate the nature of the microenvironment around the tryptophan residue. Most of the intrinsic fluorescence emissions of a folded protein are due to excitation of tryptophan residues.

See also

Related Research Articles

<i>N</i>,<i>N</i>-Dimethyltryptamine Chemical compound

N,N-Dimethyltryptamine is a substituted tryptamine that occurs in many plants and animals, including humans, and which is both a derivative and a structural analog of tryptamine. DMT is used as a psychedelic drug and prepared by various cultures for ritual purposes as an entheogen.

Eosinophilia–myalgia syndrome is a rare, sometimes fatal neurological condition linked to the ingestion of the dietary supplement L-tryptophan. The risk of developing EMS increases with larger doses of tryptophan and increasing age. Some research suggests that certain genetic polymorphisms may be related to the development of EMS. The presence of eosinophilia is a core feature of EMS, along with unusually severe myalgia.

<span class="mw-page-title-main">Melatonin</span> Hormone released by the pineal gland

Melatonin, an indoleamine, is a natural compound produced by various organisms, including bacteria and eukaryotes. Its discovery in 1958 by Aaron B. Lerner and colleagues stemmed from the isolation of a substance from the pineal gland of cows that could induce skin lightening in common frogs. This compound was later identified as a hormone secreted in the brain during the night, playing a crucial role in regulating the sleep-wake cycle, also known as the circadian rhythm, in vertebrates.

<span class="mw-page-title-main">Tryptamine</span> Metabolite of the amino acid tryptophan

Tryptamine is an indolamine metabolite of the essential amino acid, tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon. The structure of tryptamine is a shared feature of certain aminergic neuromodulators including melatonin, serotonin, bufotenin and psychedelic derivatives such as dimethyltryptamine (DMT), psilocybin, psilocin and others.

<span class="mw-page-title-main">5-Hydroxytryptophan</span> Chemical compound

5-Hydroxytryptophan (5-HTP), used medically as oxitriptan, is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin.

<span class="mw-page-title-main">Indole-3-acetic acid</span> Chemical compound

Indole-3-acetic acid is the most common naturally occurring plant hormone of the auxin class. It is the best known of the auxins, and has been the subject of extensive studies by plant physiologists. IAA is a derivative of indole, containing a carboxymethyl substituent. It is a colorless solid that is soluble in polar organic solvents.

<span class="mw-page-title-main">Indolamines</span> Family of neurotransmitters

Indolamines are a family of neurotransmitters that share a common molecular structure. Indolamines are a classification of monoamine neurotransmitter, along with catecholamines and ethylamine derivatives. A common example of an indolamine is the tryptophan derivative serotonin, a neurotransmitter involved in mood and sleep. Another example of an indolamine is melatonin.

<span class="mw-page-title-main">Indole alkaloid</span> Class of alkaloids

Indole alkaloids are a class of alkaloids containing a structural moiety of indole; many indole alkaloids also include isoprene groups and are thus called terpene indole or secologanin tryptamine alkaloids. Containing more than 4100 known different compounds, it is one of the largest classes of alkaloids. Many of them possess significant physiological activity and some of them are used in medicine. The amino acid tryptophan is the biochemical precursor of indole alkaloids.

<span class="mw-page-title-main">Tryptophan hydroxylase</span> Class of enzymes

Tryptophan hydroxylase (TPH) is an enzyme (EC 1.14.16.4) involved in the synthesis of the monoamine neurotransmitter serotonin. Tyrosine hydroxylase, phenylalanine hydroxylase, and tryptophan hydroxylase together constitute the family of biopterin-dependent aromatic amino acid hydroxylases. TPH catalyzes the following chemical reaction

Aralkylamine <i>N</i>-acetyltransferase Class of enzymes

Aralkylamine N-acetyltransferase (AANAT), also known as arylalkylamine N-acetyltransferase or serotonin N-acetyltransferase (SNAT), is an enzyme that is involved in the day/night rhythmic production of melatonin, by modification of serotonin. It is in humans encoded by the ~2.5 kb AANAT gene containing four exons, located on chromosome 17q25. The gene is translated into a 23 kDa large enzyme. It is well conserved through evolution and the human form of the protein is 80 percent identical to sheep and rat AANAT. It is an acetyl-CoA-dependent enzyme of the GCN5-related family of N-acetyltransferases (GNATs). It may contribute to multifactorial genetic diseases such as altered behavior in sleep/wake cycle and research is on-going with the aim of developing drugs that regulate AANAT function.

<span class="mw-page-title-main">Aromatic amino acid</span> Amino acid having an aromatic ring

An aromatic amino acid is an amino acid that includes an aromatic ring.

<span class="mw-page-title-main">TPH1</span> Protein-coding gene in the species Homo sapiens

Tryptophan hydroxylase 1 (TPH1) is an isoenzyme of tryptophan hydroxylase which in humans is encoded by the TPH1 gene.

<span class="mw-page-title-main">Hypertryptophanemia</span> Medical condition

Hypertryptophanemia is a rare autosomal recessive metabolic disorder that results in a massive buildup of the amino acid tryptophan in the blood, with associated symptoms and tryptophanuria.

<span class="mw-page-title-main">Kynurenine pathway</span> Metabolic pathway that produces the NAD coenzyme

The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+). Metabolites involved in the kynurenine pathway include tryptophan, kynurenine, kynurenic acid, xanthurenic acid, quinolinic acid, and 3-hydroxykynurenine. The kynurenine pathway is responsible for about 95% of total tryptophan catabolism. Disruption in the pathway is associated with certain genetic and psychiatric disorders.

<span class="mw-page-title-main">Oxitriptan</span> OTC medication for depression

Oxitriptan, also known as L-5-hydroxytryptophan (5-HTP) and sold under various brand names, is a medication and over-the-counter dietary supplement used in the treatment of depression and for other indications. It is taken by mouth.

<span class="mw-page-title-main">Indole</span> Chemical compound

Indole is an organic compound with the formula C6H4CCNH3. Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole where one or more of the hydrogen atoms have been replaced by substituent groups. Indoles are widely distributed in nature, most notably as amino acid tryptophan and neurotransmitter serotonin.

<span class="mw-page-title-main">Substituted tryptamine</span> Class of indoles

Substituted tryptamines, or serotonin analogues, are organic compounds which may be thought of as being derived from tryptamine itself. The molecular structures of all tryptamines contain an indole ring, joined to an amino (NH2) group via an ethyl (−CH2–CH2−) sidechain. In substituted tryptamines, the indole ring, sidechain, and/or amino group are modified by substituting another group for one of the hydrogen (H) atoms.

<small>L</small>-Tryptophan decarboxylase Enzyme

L-Tryptophan decarboxylase is an enzyme distinguished by the substrate L-tryptophan.

<span class="mw-page-title-main">Neurotransmitter prodrug</span> A prodrug of a neurotransmitter

A neurotransmitter prodrug, or neurotransmitter precursor, is a drug that acts as a prodrug of a neurotransmitter. A variety of neurotransmitter prodrugs have been developed and used in medicine. They can be useful when the neurotransmitter itself is not suitable for use as a pharmaceutical drug owing to unfavorable pharmacokinetic or physicochemical properties, for instance susceptibility to metabolism or lack of blood–brain barrier permeability. Besides their use in medicine, neurotransmitter prodrugs have also been used as recreational drugs in some cases.

α-Methyltryptophan is a synthetic tryptamine derivative, an artificial amino acid, and a prodrug of α-methylserotonin (αMS). It is the α-methylated derivative of tryptophan, while αMS is the α-methylated analogue of serotonin. αMTP has been suggested for potential therapeutic use in the treatment of conditions thought by some authors to be related to serotonin deficiency, such as depression. In labeled forms, αMTP is also used as a radiotracer in positron emission tomography (PET) imaging to assess serotonin synthesis and certain other processes.

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  18. 1 2 3 4 5 6 7 8 9 Zhang LS, Davies SS (April 2016). "Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions". Genome Med. 8 (1): 46. doi: 10.1186/s13073-016-0296-x . PMC   4840492 . PMID   27102537. Lactobacillus spp. convert tryptophan to indole-3-aldehyde (I3A) through unidentified enzymes [125]. Clostridium sporogenes convert tryptophan to IPA [6], likely via a tryptophan deaminase. ... IPA also potently scavenges hydroxyl radicals
    Table 2: Microbial metabolites: their synthesis, mechanisms of action, and effects on health and disease
    Figure 1: Molecular mechanisms of action of indole and its metabolites on host physiology and disease
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