Tryptophan

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Contents

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 or (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
  • InChI=1/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
    Key: QIVBCDIJIAJPQS-VIFPVBQEBP
  • 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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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. It is essential in humans, meaning that the body cannot synthesize it and it must be obtained from the diet. Tryptophan is also a precursor to the neurotransmitter serotonin, the hormone melatonin, and vitamin B3. [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]

Many animals (including humans) cannot synthesize tryptophan: they need to obtain it through their diet, making it an essential amino acid.

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. Many animals (including humans) cannot synthesize tryptophan: they need to obtain it through their diet, making it an essential amino acid. 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, [13] and depression. [14]

In bacteria that synthesize tryptophan, high cellular levels of this amino acid activate a repressor protein, which binds to the trp operon. [15] 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. [16] Indole is produced from tryptophan by bacteria that express tryptophanase. [16] Clostridium sporogenes metabolizes tryptophan into indole and subsequently 3-indolepropionic acid (IPA), [17] a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals. [16] [18] [19] IPA binds to the pregnane X receptor (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function. [16] Following absorption from the intestine and distribution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer's disease. [16] Lactobacillus 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. [16] Indole itself triggers the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells and acts as a ligand for AhR. [16] 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. [16] 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. [16]

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. [20]

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 [21] [22] that cooked turkey contains an abundance of tryptophan, the tryptophan content in turkey is typical of poultry. [23]

Tryptophan (Trp) content of various foods [23] [24]
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, dried0.43616.52.64
Sesame seed 0.3717.002.17
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, unsweetened0.1312.91.23
Milk 0.083.222.34
Rice, white, medium-grain, cooked0.0282.381.18
Quinoa, uncooked0.16714.121.2
Quinoa, cooked0.0524.401.1
Potatoes, russet0.022.140.84
Tamarind 0.0182.800.64
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, [25] [26] but consuming purified tryptophan increases the serotonin level in the brain, whereas eating foods containing tryptophan does not. [27]

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". [28] 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. [28] [29]

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. [30]

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). [31] [32]

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. [32] Because tryptophan supplementation has not been thoroughly studied in a clinical setting, its interactions with other drugs are not well known. [28]

Isolation

The isolation of tryptophan was first reported by Frederick Hopkins in 1901. [33] Hopkins recovered tryptophan from hydrolysed casein, recovering 4–8 g of tryptophan from 600 g of crude casein. [34]

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: [35] 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. [36] [37] [38]

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. [39] 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, [40] [41] [42] with other countries following suit. [43] [44]

Subsequent studies suggested that EMS was linked to specific batches of L-tryptophan supplied by a single large Japanese manufacturer, Showa Denko. [40] [45] [46] [47] 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. [40] [48] [49] However, other evidence suggests that tryptophan itself may be a potentially major contributory factor in EMS. [50] There are also claims that a precursor reached sufficient concentrations to form a toxic dimer [51]

The FDA loosened its restrictions on sales and marketing of tryptophan in February 2001, [40] but continued to limit the importation of tryptophan not intended for an exempted use until 2005. [52]

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". [53] 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. [54]

Turkey meat and drowsiness hypothesis

A common assertion in the US is that heavy consumption of turkey meat results in drowsiness, due to high levels of tryptophan contained in turkey. [22] However, the amount of tryptophan in turkey is comparable to that contained in other meats. [21] [23] Drowsiness after eating may be caused by other foods eaten with the turkey, particularly carbohydrates. [55] Ingestion of a meal rich in carbohydrates triggers the release of insulin. [56] [57] [58] [59] 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). [59] [60] [61] Once in the CSF, tryptophan is converted into serotonin in the raphe nuclei by the normal enzymatic pathway. [57] [62] The resultant serotonin is further metabolised into melatonin by the pineal gland. [8] 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. [56] [57] [58] [62]

Research

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. [63]

Tryptophan affects brain serotonin synthesis when given orally in a purified form and is used to modify serotonin levels for research. [27] Low brain serotonin level is induced by administration of tryptophan-poor protein in a technique called acute tryptophan depletion. [64] Studies using this method have evaluated the effect of serotonin on mood and social behavior, finding that serotonin reduces aggression and increases agreeableness. [65]

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

Tyrosine Amino acid

L-Tyrosine or tyrosine or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Greek tyrós, meaning cheese, as it was first discovered in 1846 by German chemist Justus von Liebig in the protein casein from cheese. It is called tyrosyl when referred to as a functional group or side chain. While tyrosine is generally classified as a hydrophobic amino acid, it is more hydrophilic than phenylalanine. It is encoded by the codons UAC and UAU in messenger RNA.

Phenylalanine Type of α-amino acid

Phenylalanine is an essential α-amino acid with the formula C
9
H
11
NO
2
. It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino acid is classified as neutral, and nonpolar because of the inert and hydrophobic nature of the benzyl side chain. The L-isomer is used to biochemically form proteins coded for by DNA. Phenylalanine is a precursor for tyrosine, the monoamine neurotransmitters dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and the skin pigment melanin. It is encoded by the codons UUU and UUC.

Eosinophilia–myalgia syndrome is a rare, sometimes fatal neurological condition linked to the ingestion of contaminated L-tryptophan, a dietary supplement and essential amino acid. 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.

Isoleucine Chemical compound

Isoleucine is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group, an α-carboxylic acid group, and a hydrocarbon side chain with a branch. It is classified as a non-polar, uncharged, branched-chain, aliphatic amino acid. It is essential in humans, meaning the body cannot synthesize it, and must be ingested in our diet. Isoleucine is synthesized from pyruvate employing leucine biosynthesis enzymes in other organisms such as bacteria. It is encoded by the codons AUU, AUC, and AUA.

An essential amino acid, or indispensable amino acid, is an amino acid that cannot be synthesized from scratch by the organism fast enough to supply its demand, and must therefore come from the diet. Of the 21 amino acids common to all life forms, the nine amino acids humans cannot synthesize are phenylalanine, valine, threonine, tryptophan, methionine, leucine, isoleucine, lysine, and histidine.

Melatonin Hormone released by the pineal gland

Melatonin is a natural product found in plants and animals. It is primarily known in animals as a hormone released by the pineal gland in the brain at night, and has long been associated with control of the sleep–wake cycle.

Tryptamine 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 (third aromatic atom, with the first one being the heterocyclic nitrogen). 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. Tryptamine has been shown to activate trace amine-associated receptors expressed in the mammalian brain, and regulates the activity of dopaminergic, serotonergic and glutamatergic systems. In the human gut, symbiotic bacteria convert dietary tryptophan to tryptamine, which activates 5-HT4 receptors and regulates gastrointestinal motility. Multiple tryptamine-derived drugs have been developed to treat migraines, while trace amine-associated receptors are being explored as a potential treatment target for neuropsychiatric disorders.

5-Hydroxytryptophan Chemical compound

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

Aromatic <small>L</small>-amino acid decarboxylase Class of enzymes

Aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase (DDC), tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase, is a lyase enzyme, located in region 7p12.2-p12.1.

Hartnup disease Metabolic disorder

Hartnup disease is an autosomal recessive metabolic disorder affecting the absorption of nonpolar amino acids. Niacin is a precursor to nicotinamide, a necessary component of NAD+.

Indolamines

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.

Kynurenine Chemical compound

l-Kynurenine is a metabolite of the amino acid l-tryptophan used in the production of niacin.

Tryptophan hydroxylase Class of enzymes

Tryptophan hydroxylase (TPH) is an enzyme (EC 1.14.16.4) involved in the synthesis of the 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

Aromatic amino acid

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

TPH1 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.

Postprandial somnolence State of drowsiness or lassitude following a meal

Postprandial somnolence is a normal state of drowsiness or lassitude following a meal. Postprandial somnolence has two components: a general state of low energy related to activation of the parasympathetic nervous system in response to mass in the gastrointestinal tract, and a specific state of sleepiness. While there are numerous theories surrounding this behavior, such as decreased blood flow to the brain, neurohormonal modulation of sleep through digestive coupled signaling, or vagal stimulation, very few have been explicitly tested. To date, human studies have loosely examined the behavioral characteristics of postprandial sleep, demonstrating potential shifts in EEG spectra and self-reported sleepiness. To date, the only clear animal models for examining the genetic and neuronal basis for this behavior are the fruit fly, the mouse, and the nematode Caenorhabditis elegans.

Hypertryptophanemia 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.

Kynurenine pathway

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 total catabolization of tryptophan about 95%. Disruption in the pathway is associated with certain genetic and psychiatric disorders.

Richard ("Dick") Wurtman is a medical doctor who spent his career doing basic and translational neuroscience research at Massachusetts Institute of Technology.

Central nervous system fatigue, or central fatigue, is a form of fatigue that is associated with changes in the synaptic concentration of neurotransmitters within the central nervous system which affects exercise performance and muscle function and cannot be explained by peripheral factors that affect muscle function. In healthy individuals, central fatigue can occur from prolonged exercise and is associated with neurochemical changes in the brain, primarily involving serotonin (5-HT), noradrenaline, and dopamine. Central fatigue plays an important role in endurance sports and also highlights the importance of proper nutrition in endurance athletes.

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    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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    IPA metabolism diagram
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