Tryptophan (abbreviated as Trp or W; encoded by the codon UGG) is an ?-amino acid that is used in the biosynthesis of proteins. It contains an ?-amino group, an ?-carboxylic acid group, and a side chain indole, classifying it as a non-polar, aromatic amino acid. It is essential in humans, meaning the body cannot synthesize it and thus it must be obtained from the diet. Tryptophan is also a precursor to the neurotransmitter serotonin and the hormone melatonin.
Like other amino acids, tryptophan is a zwitterion at physiological pH where the amino group is protonated (-NH3+; pKa = 9.39) and the carboxylic acid is deprotonated ( -COO-; pKa = 2.38).
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Isolation
The isolation of tryptophan was first reported by Frederick Hopkins in 1901 through hydrolysis of casein. From 600 grams of crude casein one obtains 4-8 grams of tryptophan.
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Biosynthesis and industrial production
As an essential amino acid, tryptophan is not synthesized from more basic substances in humans and other animals, who must ingest tryptophan or tryptophan-containing proteins. Plants and microorganisms commonly synthesize tryptophan from shikimic acid or anthranilate by the following process: 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-glycerinephosphate; 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.
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 either mutations that prevent the reuptake of aromatic amino acids or multiple/overexpressed trp operons. The conversion is catalyzed by the enzyme tryptophan synthase.
Function
For many organisms (including humans), tryptophan is needed to prevent illness or death, but cannot be synthesized by the organism and must be ingested; in short, it is an essential amino acid. Amino acids, including tryptophan, act as building blocks in protein biosynthesis, and proteins are required to sustain life. Tryptophan residues are among the less common amino acids found in proteins, but are known to play important structural or functional roles whenever they occur. For instance, tryptophan (and tyrosine) residues play special roles in "anchoring" membrane proteins within the membrane, based on studies of membrane proteins and model transmembrane peptides. In addition, tryptophan functions as a biochemical precursor for the following compounds (see also figure to the right):
- Serotonin (a neurotransmitter), synthesized via tryptophan hydroxylase. Serotonin, in turn, can be converted to melatonin (a neurohormone), via N-acetyltransferase and 5-hydroxyindole-O-methyltransferase activities.
- Niacin, also known as vitamin B3, is synthesized from tryptophan via kynurenine and quinolinic acids as key biosynthetic intermediates.
- Auxins (a class of phytohormones) are synthesized from tryptophan.
The disorder fructose malabsorption causes improper absorption of tryptophan in the intestine, reduced levels of tryptophan in the blood, and depression. Some studies did not find reduced tryptophan in cases of lactose maldigestion.
In bacteria that synthesize tryptophan, high cellular levels of this amino acid activate a repressor protein, which binds to the trp operon. 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 are reduced, transcription from the trp operon resumes. The genetic organisation of the trp operon thus permits tightly regulated and rapid responses to changes in the cell's internal and external tryptophan levels.
Requirements
The Food and Nutrition Board (FNB) of the U.S. Institute of Medicine set Recommended Dietary Allowances (RDAs) for essential amino acids in 2002. For tryptophan, for adults 19 years and older, the recommendation is 5 mg/kg body weight/day.
Dietary sources
Tryptophan is a routine constituent of 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, buckwheat, spirulina, and peanuts. Contrary to the popular belief that turkey contains an abundance of tryptophan, the tryptophan content in turkey is typical of poultry.
Turkey meat and drowsiness
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. However, the amount of tryptophan in turkey is comparable to that contained in other meats. Drowsiness after eating may be caused by other foods eaten with the turkey, particularly carbohydrates. It has been demonstrated in both animal and human tests that ingestion of a meal rich in carbohydrates triggers release of insulin. 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). Once in the CSF, tryptophan is converted into serotonin in the raphe nuclei by the normal enzymatic pathway. The resultant serotonin is further metabolised into melatonin by the pineal gland. Hence, this data suggests that "feast-induced drowsiness"--or postprandial somnolence--may be the result of a heavy meal rich in carbohydrates, which indirectly increases the production of sleep-promoting melatonin in the brain.
Use as a dietary supplement
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 indication of major depression under various trade names.
Since tryptophan is converted into 5-hydroxytryptophan (5-HTP) which is subsequently converted into the neurotransmitter serotonin, it has been proposed that consumption of tryptophan or 5-HTP may therefore improve depression symptoms by increasing the level of serotonin in the brain. 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". 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. Due to the lack of high-quality studies and preliminary nature of studies showing effectiveness and the lack of adequate study on their safety, the use of tryptophan and 5-HTP is not highly recommended or thought to be clinically useful.
There is evidence that blood tryptophan levels are unlikely to be altered by changing the diet, but tryptophan is available in health food stores as a dietary supplement. Consuming purified tryptophan increases brain serotonin level, whereas eating foods containing tryptophan does not. This is because the transport system, which brings tryptophan across the blood-brain barrier, is also selective for the other amino acids, which are contained in protein food sources. High blood plasma levels of other large neutral amino acids prevent the plasma concentration of tryptophan from increasing brain concentration levels.
Side effects
Potential side effects of tryptophan include nausea, diarrhea, drowsiness, lightheadedness, headache, dry mouth, blurred vision, sedation, euphoria, and nystagmus (involuntary eye movements). Because tryptophan has not been thoroughly studied in a clinical setting, possible side effects and interactions with other drugs are not well known.
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.
Research
In 1912 Felix Ehrlich demonstrated that yeast attacks the natural amino acids essentially by splitting off carbon dioxide and replacing the amino group with hydroxyl. By this reaction, tryptophan gives rise to tryptophol.
Tryptophan affects brain serotonin synthesis when given orally in a purified form and is used to modify serotonin levels for research. Low brain serotonin level is induced by administration of tryptophan-poor protein in a technique called "acute tryptophan depletion". Studies using this method have evaluated the effect of serotonin on mood and social behavior, finding that serotonin reduces aggression and increases agreeableness.
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.
Safety
Eosinophilia-myalgia syndrome
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. 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, with other countries following suit.
Subsequent epidemiological studies suggested that EMS was linked to specific batches of L-tryptophan supplied by a single large Japanese manufacturer, Showa Denko. 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. However, other evidence suggests that tryptophan itself may be a potentially major contributory factor in EMS.
The FDA loosened its restrictions on sales and marketing of tryptophan in February 2001, but continued to limit the importation of tryptophan not intended for an exempted use until 2005.
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". 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.
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