Humans and many animals cannot synthesize tryptophan: they need to obtain it through their diet, making it anessential amino acid.
Tryptophan is named after the digestive enzymestrypsin, which were used in its first isolation fromcasein proteins.[6] It was assigned theone-letter symbol W based on the double ring being visually suggestive to the bulky letter.[7]
Metabolism ofl-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 inprotein biosynthesis, andproteins 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 andtyrosine residues play special roles in "anchoring"membrane proteins within thecell membrane. Tryptophan, along with otheraromatic amino acids, is also important inglycan-protein interactions. In addition, tryptophan functions as a biochemicalprecursor for the followingcompounds:
The disorderfructose 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 arepressor protein, which binds to thetrp operon.[17] Binding of this repressor to the tryptophan operon preventstranscription of downstream DNA that codes for the enzymes involved in the biosynthesis of tryptophan. So high levels of tryptophan prevent tryptophan synthesis through anegative feedback loop, and when the cell's tryptophan levels go down again, transcription from thetrp operon resumes. This permits tightly regulated and rapid responses to changes in the cell's internal and external tryptophan levels.
Because tryptophan is converted into5-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 soldover the counter in theUnited States (after beingbanned to varying extents between 1989 and 2005) and theUnited Kingdom as adietary supplement for use as anantidepressant,anxiolytic, andsleep aid. It is also marketed as aprescription drug in some European countries for the treatment ofmajor 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 aCochrane 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 thanplacebo 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 anadjunctive therapy in addition to standard treatment for mood and anxiety disorders is not supported by the scientific evidence.[30][31]
Tryptophan taken as a dietary supplement (such as in tablet form) has the potential to causeserotonin syndrome when combined with antidepressants of theMAOI orSSRI class or other strongly serotonergic drugs.[34] Because tryptophan supplementation has not been thoroughly studied in a clinical setting, itsinteractions with other drugs are not well known.[30]
The isolation of tryptophan was first reported byFrederick Hopkins in 1901.[35] Hopkins recovered tryptophan fromhydrolysedcasein, recovering 4–8 g of tryptophan from 600 g of crude casein.[36]
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 andmicroorganisms commonly synthesize tryptophan fromshikimic acid oranthranilate:[37] anthranilate condenses withphosphoribosylpyrophosphate (PRPP), generatingpyrophosphate as a by-product. The ring of theribosemoiety is opened and subjected to reductivedecarboxylation, producing indole-3-glycerol phosphate; this, in turn, is transformed intoindole. In the last step,tryptophan synthasecatalyzes the formation of tryptophan from indole and the amino acidserine.
There was a largeoutbreak ofeosinophilia-myalgia syndrome (EMS) in the U.S. in 1989, with more than 1,500 cases reported to theCDC 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 ofL-tryptophan supplied by a single large Japanese manufacturer,Showa Denko.[42][47][48][49] It eventually became clear that recent batches of Showa Denko'sL-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 toxicdimer.[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 usedgenetically engineered bacteria to produce the contaminated batches ofL-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]
A common assertion in the US and the UK[57] is that heavy consumption ofturkey meat—as seen duringThanksgiving andChristmas—results indrowsiness, 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, particularlycarbohydrates.[58] Ingestion of a meal rich in carbohydrates triggers the release ofinsulin.[59][60][61][62] Insulin in turn stimulates the uptake of large neutralbranched-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 thelarge neutral amino acid transporter (which transports both BCAA and aromatic amino acids), resulting in more uptake of tryptophan across theblood–brain barrier into thecerebrospinal fluid (CSF).[62][63][64] Once in the CSF, tryptophan is converted intoserotonin in theraphe nuclei by the normal enzymatic pathway.[60][65] The resultant serotonin is further metabolised into the hormonemelatonin—which is an important mediator of thecircadian rhythm[66]—by thepineal gland.[10] Hence, these data suggest that "feast-induced drowsiness"—orpostprandial 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]
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 calledacute 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]
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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^Chyan YJ, Poeggeler B, Omar RA, Chain DG, Frangione B, Ghiso J, Pappolla MA (July 1999)."Potent neuroprotective properties against the Alzheimer beta-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid".J. Biol. Chem.274 (31):21937–21942.doi:10.1074/jbc.274.31.21937.PMID10419516.S2CID6630247.[Indole-3-propionic acid (IPA)] has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. ... In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity.
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^Kozlenkov A, González-Maeso J (2013). "Animal Models and Hallucinogenic Drugs".The Neuroscience of Hallucinations. New York, NY: Springer New York. pp. 253–277.doi:10.1007/978-1-4614-4121-2_14.ISBN978-1-4614-4120-5.
^Carbonaro TM, Gatch MB (September 2016)."Neuropharmacology of N,N-dimethyltryptamine".Brain Res Bull.126 (Pt 1):74–88.doi:10.1016/j.brainresbull.2016.04.016.PMC5048497.PMID27126737.Endogenous DMT is synthesized from the essential amino acid tryptophan, which is decarboxylated to tryptamine. Tryptamine is then transmethylated by the enzyme indolethylamine-N-methyltransferase (INMT) (using S-adenosyl methionine as a substrate), which catalyzes the addition of methyl groups resulting in the production of N-methyltryptamine (NMT) and DMT. NMT can also act as a substrate for INMT-dependent DMT biosynthesis (Barker et al., 1981).
^Barker SA (2018)."N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function".Front Neurosci.12: 536.doi:10.3389/fnins.2018.00536.PMC6088236.PMID30127713.After the discovery of an indole-N-methyl transferase (INMT; Axelrod, 1961) in rat brain, researchers were soon examining whether the conversion of tryptophan (2, Figure 2) to tryptamine (TA; 3, Figure 2) could be converted to DMT in the brain and other tissues from several mammalian species. Numerous studies subsequently demonstrated the biosynthesis of DMT in mammalian tissue preparations in vitro and in vivo (Saavedra and Axelrod, 1972; Saavedra et al., 1973). In 1972, Juan Saavedra and Julius Axelrod reported that intracisternally administered TA was converted to N-methyltryptamine (NMT; 4, Figure 2) and DMT in the rat, the first demonstration of DMT's formation by brain tissue in vivo.
^Cameron LP, Olson DE (October 2018)."Dark Classics in Chemical Neuroscience: N, N-Dimethyltryptamine (DMT)"(PDF).ACS Chem Neurosci.9 (10):2344–2357.doi:10.1021/acschemneuro.8b00101.PMID30036036.Like serotonin and melatonin, DMT is a product of tryptophan metabolism.25 Following tryptophan decarboxylation, tryptamine is methylated by an N-methyltransferase (i.e., INMT) with S-adenosylmethionine serving as the methyl donor. A second enzymatic methylation produces DMT (Figure 3A).26 [...] The enzyme indolethylamine N-methyltransferase (INMT) catalyzes the methylation of a variety of biogenic amines, and is responsible for converting tryptamine into DMT in mammals.140
^Colosimo FA, Borsellino P, Krider RI, Marquez RE, Vida TA (26 February 2024)."The Clinical Potential of Dimethyltryptamine: Breakthroughs into the Other Side of Mental Illness, Neurodegeneration, and Consciousness".Psychoactives.3 (1). MDPI AG:93–122.doi:10.3390/psychoactives3010007.ISSN2813-1851.The metabolism of DMT within the body begins with its synthesis. Endogenous DMT is made from tryptophan after decarboxylation transforms it into tryptamine [22,25]. Tryptamine then undergoes transmethylation mediated by indolethylamine-N-methyltransferase (INMT) with S-adenosyl methionine (SAM) as a substrate, morphing into N-methyltryptamine (NMT) and eventually producing N,N-DMT [26]. Intriguingly, INMT is distributed widely across the body, predominantly in the lungs, thyroid, and adrenal glands, with a dense presence in the anterior horn of the spinal cord. Within the cerebral domain, regions such as the uncus, medulla, amygdala, frontal cortex, fronto-parietal lobe, and temporal lobe exhibit INMT activity, primarily localized in the soma [26]. INMT transcripts are found in specific brain regions, including the cerebral cortex, pineal gland, and choroid plexus, in both rats and humans. Although the rat brain is capable of synthesizing and releasing DMT at concentrations similar to established monoamine neurotransmitters like serotonin [27], the possibility that DMT is an authentic neurotransmitter is still speculative. This issue has been controversial for decades [28] and requires the demonstration of an activity-dependent release (i.e., Ca2+-stimulated) of DMT at a synaptic cleft to be fully established in the human brain.
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