The AtlasAmino acidsAromatic
TryptophanTrp · W
The rarest amino acid in protein and the largest of the twenty, the source of serotonin and melatonin, and most of all the source of NAD.
Molecule · Trp · 15 heavy atoms
Tryptophan
C11H12N2O2204.23 g/mol
The rarest amino acid in protein and the largest of the twenty, the source of serotonin and melatonin, and most of all the source of NAD.
Built fromthe charted ones open their own entry
- Codes
- Trp · W
- Formula
- C11H12N2O2
- Molar mass
- 204.23 g/mol
- Systematic name
- (2S)-2-amino-3-(1H-indol-3-yl)propanoic acid
- Side chain
- Indol-3-ylmethyl: a benzene ring fused to a pyrrole; the largest standard side chain, aromatic and mostly nonpolar.
- Class
- Aromatic
- In the diet
- Essential
- Carbon skeleton
- Glucogenic and ketogenic
- pKa
- α-COOH 2.38 · α-NH3+ 9.39
- Isoelectric point
- pH 5.89
- Hydropathy
- -0.9 (Kyte–Doolittle)
- Codons
UGG- Main transporters
- SLC7A5 (LAT1, with CD98), SLC6A19 (B0AT1)
pKa and isoelectric point: Nelson and Cox, Lehninger Principles of Biochemistry, table of amino acid properties (free amino acid, 25 °C). Hydropathy: Kyte and Doolittle, J Mol Biol 1982. Essentiality: Reeds, J Nutr 2000. Formula and mass computed from the structure.
In brief
What it is
The largest of the twenty standard amino acids, with a two-ring indole side chain; it is also the least abundant in cells and one of the rarest in proteins 1. It is essential, so it must come from food 2.
Why it matters
It is the only source of serotonin and, from serotonin, of melatonin 3,4. But most tryptophan, about 95% of what is broken down, goes the other way, down the kynurenine pathway, which makes NAD⁺ and can substitute for niacin in the diet 5,6.
Where it runs short
Too little tryptophan and niacin together causes pellagra: dermatitis, diarrhoea, dementia and, untreated, death; in Hartnup disorder poor tryptophan absorption can do the same on a normal diet 7,8.
Where it turns
Tryptophan itself is not very toxic, but in 1989 a contaminated tryptophan supplement caused an epidemic of eosinophilia–myalgia syndrome in the United States 9,10.
The serotonin story is the famous one. The NAD story is the big one.
The molecule
Tryptophan’s side chain is indole, a benzene ring fused to a five-membered ring containing nitrogen. It is the largest of the twenty standard side chains 1.
It is also the most expensive amino acid to build, with the most complex and energy-consuming synthesis, and the least abundant free amino acid in cells; it is one of the rarest in the proteome 1.
Move across the chart to read the charge at any pH.
Computed from its pKa values (α-carboxyl 2.38, α-amino 9.39) by the Henderson–Hasselbalch equation, for the free amino acid in water at 25 °C. Inside a folded protein the same groups can shift by a unit or more. The faint lines are the other amino acids.
Kyte–Doolittle hydropathy index: positive values avoid water and tend to be buried inside a folded protein, negative values sit on its surface. Each letter is an amino acid; choose one to open it.
| 1st ↓ 2nd → | U | C | A | G | 3rd |
|---|---|---|---|---|---|
| U | UUUPhe | UCUSer | UAUTyr | UGUCys | U |
| UUCPhe | UCCSer | UACTyr | UGCCys | C | |
| UUALeu | UCASer | UAAStop | UGAStop | A | |
| UUGLeu | UCGSer | UAGStop | UGGTrp | G | |
| C | CUULeu | CCUPro | CAUHis | CGUArg | U |
| CUCLeu | CCCPro | CACHis | CGCArg | C | |
| CUALeu | CCAPro | CAAGln | CGAArg | A | |
| CUGLeu | CCGPro | CAGGln | CGGArg | G | |
| A | AUUIle | ACUThr | AAUAsn | AGUSer | U |
| AUCIle | ACCThr | AACAsn | AGCSer | C | |
| AUAIle | ACAThr | AAALys | AGAArg | A | |
| AUGMet | ACGThr | AAGLys | AGGArg | G | |
| G | GUUVal | GCUAla | GAUAsp | GGUGly | U |
| GUCVal | GCCAla | GACAsp | GGCGly | C | |
| GUAVal | GCAAla | GAAGlu | GGAGly | A | |
| GUGVal | GCGAla | GAGGlu | GGGGly | G |
Where it comes from
Animals cannot make the indole ring, so tryptophan is essential. The adult requirement is 4 mg per kilogram a day 2; a 2026 study in 23 adults over 60 found an average need of 3.9, with no difference between men and women or between people in their sixties and seventies 11.
Tryptophan also counts towards niacin. About 60 mg of dietary tryptophan is generally taken to yield 1 mg of niacin, and a study in Japanese women estimated 67 6; the ratio is not fixed and changes with how much niacin is already present 12.
EssentialMust come from food. The adult requirement is 4 mg per kilogram a day; a 2026 tracer study in adults over 60 found 3.9 2,11.
Where it is in food
- Any protein. Because 60 mg of tryptophan yields about 1 mg of niacin, a protein-rich diet also supplies niacin 6.
In the bottle · fermentedMade by fermentation in engineered bacteria through the shikimate pathway 13. Fermentation is also how the 1989 disaster happened: one manufacturer changed its bacterial strain and purification, and impurities in its product were linked to eosinophilia–myalgia syndrome 9,10.
What the body does with it
The kynurenine pathway handles about 95% of tryptophan breakdown and makes NAD⁺, the electron carrier of every cell 5. Its first step is the control point: tryptophan 2,3-dioxygenase in the liver, induced by glucocorticoids and regulated by haem, and indoleamine 2,3-dioxygenase in other tissues, induced by interferon-γ 5.
Serotonin is made by tryptophan hydroxylase, the rate-limiting enzyme. TPH1 works in the enterochromaffin cells of the gut, which make almost all of the body’s peripheral serotonin; TPH2 works in the raphe neurons of the brain 3,14. Serotonin does not readily cross the blood–brain barrier, so the gut’s serotonin and the brain’s are separate supplies 3.
In the pineal gland and elsewhere, serotonin is acetylated and then methylated to make melatonin 4.
Gut bacteria take a third route, turning tryptophan into indoles. One of them, indole-3-propionic acid, exists in mice only when gut bacteria are present 15; in people, higher levels go with a more diverse microbiome and a lower risk of developing type 2 diabetes 16,17.
In three sentences each
Mostly to NAD, not to serotonin
About 95% of dietary tryptophan breakdown runs through the kynurenine pathway, 90% of it in the liver, ending in nicotinic acid and NAD⁺; serotonin takes only a small fraction 5,18.
How it is made, moved and broken down
In carcinoid syndrome, a tumour turns large amounts of tryptophan into serotonin and so diverts it from NAD; ten of 36 such patients were biochemically niacin-deficient and one had pellagra 18.
Carbon skeleton · glucogenic and ketogenicClassed as both glucogenic and ketogenic, but its more important product is NAD⁺ 5.
- Tryptophan
- Tryptophan hydroxylaseTPH1, TPH2 · BH4, iron
- 5-Hydroxytryptophan
- Aromatic L-amino acid decarboxylaseDDC · vitamin B6
- Serotonin
- Arylalkylamine N-acetyltransferaseAANAT · acetyl-CoA
- N-Acetylserotonin
- Acetylserotonin O-methyltransferaseASMT · SAM
- Melatonin
- Tryptophan
- TDO (liver) or IDO (elsewhere)TDO2, IDO1 · haem, O₂
- N-Formylkynurenine
- FormamidaseAFMID
- Kynurenine
- Several stepsKMO, KYNU, HAAO, QPRT · vitamin B2, B6
- Quinolinic acid → NAD⁺
- Tryptophan
- Bacterial enzymes
- Indole and indole-3-propionic acid
How it crosses membranes
- SLC7A5 · LAT1, with CD98blood–brain barrier and placenta — shared with the other large neutral amino acids, which compete with tryptophan for entry to the brain 20,21
- SLC6A19 · B0AT1small intestine and kidney — absorbs tryptophan from food and reclaims it from urine; its loss causes Hartnup disorder 8
Where it matters most
When it goes wrong
Too little
Pellagra
Deficiency of niacin, of tryptophan, or both: the four Ds of dermatitis, diarrhoea, dementia and death. Causes today include alcohol, malabsorption and drugs such as isoniazid 7.
How it is foundA clinical diagnosis, confirmed by response to niacin 7.
Inherited
Hartnup disorder
SLC6A19 · autosomal recessive
Named for an English family described in 1956. The gut and kidney cannot transport neutral amino acids, so tryptophan is lost in the urine; some people develop pellagra-like rashes, unsteady gait and psychiatric symptoms 8.
How it is foundNeutral amino acids in the urine, and SLC6A19 sequencing 8.
Acquired
Carcinoid syndrome
Serotonin-secreting neuroendocrine tumours, most often of the small bowel, divert tryptophan into serotonin; niacin deficiency follows in some patients 18. 5-HIAA is the marker, and is most accurate for carcinoid heart disease 23.
Drug
Eosinophilia–myalgia syndrome
The 1989 US epidemic linked to contaminated L-tryptophan from a single manufacturer 9,25. A rat study reproduced some of its muscle-sheath changes with one contaminant, 1,1′-ethylidenebis(tryptophan) 26.
How it is foundEosinophil count and clinical features, with a history of the supplement 9.
Drug
IDO inhibitors in cancer
IDO1
Tumours can use IDO to starve immune cells of tryptophan, so IDO inhibitors were tried with immunotherapy. In the phase 3 ECHO-301 trial in 706 people with melanoma, adding epacadostat to pembrolizumab changed neither progression-free nor overall survival 27.
How it is foundNone in routine use.
How it is measured
Tryptophan’s products are measured more often than tryptophan itself. 5-HIAA follows serotonin-secreting tumours 23; the kynurenine-to-tryptophan ratio follows immune activation in research 19; and niacin status, not tryptophan, is measured when pellagra is suspected 18.
- 5-HIAA, in urine or bloodThe main breakdown product of serotonin, measured to diagnose and follow serotonin-secreting neuroendocrine tumours 23.In midgut neuroendocrine tumours, the 24-hour urine test discriminated with an area under the curve of 0.80, and plasma 0.72; in one comparison, serum at a 135 nmol/L cut-off had 91% sensitivity against urine 23,24.Specificity was only about 62% in that comparison, and the test reflects tumour serotonin, not the serotonin of the brain 3,24.
- Kynurenine-to-tryptophan ratioA blood index of how fast IDO is breaking tryptophan down 19.Research.Tracks immune activation driven by interferon-γ 19.Not specific to any one disease; meaningful only alongside other immune markers 19.
- Plasma tryptophanFree and total tryptophan in plasma; low in Hartnup disorder, where it is lost in the urine 8.A single plasma value does not say how much reaches the brain, which depends on the competing amino acids 20.
Food, supplements and the evidence
Establishedreplicated in people, for a named outcome
- Niacin, and dietary protein, prevent and treat pellagra 7.
Uncertainsmall, short, mixed, surrogate or preclinical
- Tryptophan or 5-HTP for depression. A 2002 review found only two of 108 trials good enough to pool; a 2020 meta-analysis of 5-HTP found large effects from weak studies with few placebo groups 28,29.
- Indole-3-propionic acid as a marker or mediator of metabolic health; the associations are in observational cohorts 16,17.
Sold asthe claim on the label, against the evidence
- “Turkey (or warm milk) makes you sleepy because of the tryptophan.” A protein meal brings in the competing amino acids along with tryptophan, and in rats it raised blood tryptophan without raising brain tryptophan 20.
What is strange about it
In 1989 an epidemic of eosinophilia–myalgia syndrome, with disabling muscle pain and very high eosinophil counts, was traced to tryptophan made by one Japanese company: 29 of 30 cases had taken its product, against 21 of 35 controls 9. Contaminants appeared after it changed its bacterial strain and cut the carbon used to purify the product 9,10; in 2017 one of them, “peak AAA,” was still being structurally identified 25.
Tryptophan supplements vanished from US shelves after the epidemic, and 5-HTP took their place 30.
The serotonin theory of depression rests partly on tryptophan depletion studies. Pooled, they lowered mood in drug-free people who had recovered from depression, slightly in those with a family history, and not at all in healthy volunteers 31,32.
Where it connects
On the map
A star in Gut & microbiome, one of 8. Only a small fraction becomes serotonin; most runs down the kynurenine pathway.
Sources
32 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.
- 1Barik S. The uniqueness of tryptophan in biology: properties, metabolism, interactions and localization in proteins.doi:10.3390/ijms21228776 · PMID 33233627
Largest amino acid; most costly to make; least abundant.
- 2Joint WHO/FAO/UNU Expert Consultation. Protein and amino acid requirements in human nutrition.PMID 18330140
Tryptophan, 4 mg/kg/day.
- 3Jones LA, Sun EW, Martin AM, Keating DJ. The ever-changing roles of serotonin.doi:10.1016/j.biocel.2020.105776 · PMID 32479926
TPH1 in gut, TPH2 in brain; peripheral serotonin from enterochromaffin cells.
- 4Tan DX, Hardeland R, Back K, et al. On the significance of an alternate pathway of melatonin synthesis via 5-methoxytryptamine: comparisons across species.doi:10.1111/jpi.12336 · PMID 27112772
The classic pathway, serotonin to N-acetylserotonin to melatonin.
- 5Badawy AA. Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects.doi:10.1177/1178646917691938 · PMID 28469468
About 95% of tryptophan breakdown; TDO and IDO; NAD⁺.
- 6Fukuwatari T, Ohta M, et al. Conversion ratio of tryptophan to niacin in Japanese women fed a purified diet conforming to the Japanese Dietary Reference Intakes.doi:10.3177/jnsv.50.385 · PMID 15895512
Ten women; about 67 mg tryptophan per mg niacin, against the usual 60.
- 7Prabhu D, Dawe RS, Mponda K. Pellagra a review exploring causes and mechanisms, including isoniazid-induced pellagra.doi:10.1111/phpp.12659 · PMID 33471377
Causes and features of pellagra.
- 8Kleta R, Romeo E, Ristic Z, et al. Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder.doi:10.1038/ng1405 · PMID 15286787
The Hartnup gene.
- 9Belongia EA, Hedberg CW, Gleich GJ, et al. An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use.doi:10.1056/NEJM199008093230601 · PMID 2370887
29 of 30 cases against 21 of 35 controls used one company’s product.
- 10Mayeno AN, Gleich GJ. Eosinophilia-myalgia syndrome and tryptophan production: a cautionary tale.doi:10.1016/0167-7799(94)90035-3 · PMID 7765187
How a manufacturing change introduced the impurities.
- 11Wang Z, Tomlinson C, Pencharz P, et al. Dietary tryptophan requirements in adults aged >60 years is not affected by sex or decades of age.doi:10.1016/j.tjnut.2026.101827 · PMID 42727854
23 older adults; 3.9 mg/kg/day pooled.
- 12Fukuwatari T, Shibata K. Effect of nicotinamide administration on the tryptophan-nicotinamide pathway in humans.doi:10.1024/0300-9831.77.4.255 · PMID 18271280
The conversion ratio changes with niacin intake.
- 13Hirasawa T, Satoh Y, Koma D. Production of aromatic amino acids and their derivatives by Escherichia coli and Corynebacterium glutamicum.doi:10.1007/s11274-025-04264-3 · PMID 39915353
Fermentation through the shikimate pathway.
- 14Walther DJ, Peter JU, Bashammakh S, et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform.doi:10.1126/science.1078197 · PMID 12511643
The discovery of TPH2.
- 15Wikoff WR, Anfora AT, Liu J, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites.doi:10.1073/pnas.0812874106 · PMID 19234110
Mice: indole-3-propionic acid depends entirely on gut bacteria.
- 16Menni C, Hernandez MM, Vital M, et al. Circulating levels of the anti-oxidant indoleproprionic acid are associated with higher gut microbiome diversity.doi:10.1080/19490976.2019.1586038 · PMID 31030641
1,018 women; microbiome explained far more of IPA than diet or genes.
- 17de Mello VD, Paananen J, Lindström J, et al. Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study.doi:10.1038/srep46337 · PMID 28397877
Observational; replicated in a Swedish cohort.
- 18Shah GM, Shah RG, Veillette H, et al. Biochemical assessment of niacin deficiency among carcinoid cancer patients.doi:10.1111/j.1572-0241.2005.00268.x · PMID 16181385
Serotonin is normally a small fraction of tryptophan use; 10 of 36 carcinoid patients niacin-deficient.
- 19Strasser B, Becker K, Fuchs D, Gostner JM. Kynurenine pathway metabolism and immune activation: peripheral measurements in psychiatric and co-morbid conditions.doi:10.1016/j.neuropharm.2016.02.030 · PMID 26924709
The kynurenine-to-tryptophan ratio as an IDO index.
- 20Fernstrom JD, Wurtman RJ. Brain serotonin content: physiological regulation by plasma neutral amino acids.doi:10.1126/science.178.4059.414 · PMID 5077329
Rats: the ratio of tryptophan to competing amino acids sets brain tryptophan.
- 21Scalise M, Galluccio M, Console L, et al. The human SLC7A5 (LAT1): the intriguing histidine/large neutral amino acid transporter and its relevance to human health.doi:10.3389/fchem.2018.00243 · PMID 29988369
LAT1 at the blood–brain barrier.
- 22Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease.doi:10.1016/j.chom.2018.05.003 · PMID 29902437
Serotonin, kynurenine and indole pathways under microbial control.
- 23de Mestier L, Savagner F, Brixi H, et al. Plasmatic and urinary 5-hydroxyindolacetic acid measurements in patients with midgut neuroendocrine tumors: a GTE study.doi:10.1210/clinem/dgaa924 · PMID 33382891
80 tumours, 17 controls; AUROC 0.80 urine, 0.72 plasma.
- 24Ewang-Emukowhate M, Subramaniam K, Lam F, et al. Plasma or serum 5-hydroxyindoleacetic acid can be used interchangeably in patients with neuroendocrine tumours.doi:10.1080/00365513.2023.2286645 · PMID 38112030
135 nmol/L cut-off: sensitivity 91%, specificity 62% against urine.
- 25Klarskov K, Gagnon H, Boudreault PL, et al. Structure determination of disease associated peak AAA from L-tryptophan implicated in the eosinophilia-myalgia syndrome.doi:10.1016/j.toxlet.2017.10.012 · PMID 29037509
The one contaminant statistically linked to cases.
- 26Emslie-Smith AM, Mayeno AN, Nakano S, et al. 1,1′-Ethylidenebis[tryptophan] induces pathologic alterations in muscle similar to those observed in the eosinophilia-myalgia syndrome.doi:10.1212/wnl.44.12.2390 · PMID 7991132
Rats; small animal study.
- 27Long GV, Dummer R, Hamid O, et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study.doi:10.1016/S1470-2045(19)30274-8 · PMID 31221619
706 patients; progression-free survival hazard ratio 1.00.
- 28Shaw K, Turner J, Del Mar C. Are tryptophan and 5-hydroxytryptophan effective treatments for depression? A meta-analysis.doi:10.1046/j.1440-1614.2002.01046.x · PMID 12169147
Two of 108 trials met quality criteria.
- 29Javelle F, Lampit A, Bloch W, et al. Effects of 5-hydroxytryptophan on distinct types of depression: a systematic review and meta-analysis.doi:10.1093/nutrit/nuz039 · PMID 31504850
13 studies; weak designs, high heterogeneity.
- 30Preuss HG, Echard B, Talpur N, et al. Does 5-hydroxytryptophan cause acute and chronic toxic perturbations in rats?doi:10.1080/15376520500195616 · PMID 20021026
Tryptophan withdrawn and replaced by 5-HTP on the market; rat toxicity study.
- 31Ruhé HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies.doi:10.1038/sj.mp.4001949 · PMID 17389902
Tryptophan depletion lowers mood only in vulnerable groups.
- 32Moncrieff J, Cooper RE, Stockmann T, et al. The serotonin theory of depression: a systematic umbrella review of the evidence.doi:10.1038/s41380-022-01661-0 · PMID 35854107
Depletion had no effect in 566 healthy volunteers. Contested.
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