Tryptophan is named after the digestive enzymes
trypsin, which were used in its first isolation from casein proteins.[7] It was assigned the
one-letter symbol W based on the double ring being visually suggestive to the bulky letter.[8]
Function
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,[16] and depression.[17]
In bacteria that synthesize tryptophan, high cellular levels of this amino acid activate a
repressor protein, which binds to the
trp operon.[18] 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.
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,[28][29] but consuming purified tryptophan increases the serotonin level in the brain, whereas eating foods containing tryptophan does not.[30]
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".[31] 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.[31][32]
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.[35] Because tryptophan supplementation has not been thoroughly studied in a clinical setting, its
interactions with other drugs are not well known.[31]
Isolation
The isolation of tryptophan was first reported by
Frederick Hopkins in 1901.[36] Hopkins recovered tryptophan from
hydrolysedcasein, recovering 4–8 g of tryptophan from 600 g of crude casein.[37]
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:[38] anthranilate condenses with
phosphoribosylpyrophosphate (PRPP), generating
pyrophosphate as a by-product. The ring of the
ribosemoiety is opened and subjected to reductive
decarboxylation, producing indole-3-glycerol phosphate; this, in turn, is transformed into
indole. In the last step,
tryptophan synthasecatalyzes the formation of tryptophan from indole and the amino acid
serine.
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.[42] 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,[43][44][45] with other countries following suit.[46][47]
Subsequent studies suggested that EMS was linked to specific batches of L-tryptophan supplied by a single large Japanese manufacturer,
Showa Denko.[43][48][49][50] 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.[43][51][52] However, other evidence suggests that tryptophan itself may be a potentially major contributory factor in EMS.[53] There are also claims that a precursor reached sufficient concentrations to form a toxic
dimer.[54]
The FDA loosened its restrictions on sales and marketing of tryptophan in February 2001,[43] but continued to limit the importation of tryptophan not intended for an exempted use until 2005.[55]
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".[56] 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.[57]
A common assertion in the US and the UK[58] 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.[25] However, the amount of tryptophan in turkey is comparable with that of other meats.[24][26]Drowsiness after eating may be caused by other foods eaten with the turkey, particularly
carbohydrates.[59] Ingestion of a meal rich in carbohydrates triggers the release of
insulin.[60][61][62][63] 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).[63][64][65] Once in the CSF, tryptophan is converted into
serotonin in the
raphe nuclei by the normal enzymatic pathway.[61][66] The resultant serotonin is further metabolised into the hormone
melatonin—which is an important mediator of the
circadian rhythm[67]—by the
pineal gland.[11] 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.[60][61][62][66]
Tryptophan affects brain serotonin synthesis when given orally in a purified form and is used to modify serotonin levels for research.[30] Low brain serotonin level is induced by administration of tryptophan-poor protein in a technique called
acute tryptophan depletion.[69] Studies using this method have evaluated the effect of serotonin on mood and social behavior, finding that serotonin reduces aggression and increases agreeableness.[70]
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.
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