Tryptophan

L-Tryptophan
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
ATC code N06AX02
73-22-3 Yes
ChEBI CHEBI:27897 
ChEMBL ChEMBL54976 Yes
ChemSpider 6066 Yes
DrugBank DB00150 Yes
IUPHAR ligand 717
Jmol-3D images Image
KEGG D00020 Yes
PubChem 6305
UNII 8DUH1N11BX Yes
Properties
Molecular formula
 C11H12N2O2
Molar mass 204.23 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)[1]
Supplementary data page
Refractive index (n),
Dielectric constant (εr), etc.
Thermodynamic
data
 Phase behaviour
solid–liquid–gas
UV, IR, NMR, MS
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
  verify (what is: Yes/?)
Infobox references

Tryptophan (IUPAC-IUBMB abbreviation: Trp or W; IUPAC abbreviation: L-Trp or D-Trp; sold for medical use as Tryptan)[2] is one of the 22 standard amino acids and an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG. Only the L-stereoisomer of tryptophan is used in structural or enzyme proteins, but the R-stereoisomer is occasionally found in naturally produced peptides (for example, the marine venom peptide contryphan).[3] The distinguishing structural characteristic of tryptophan is that it contains an indole functional group.

Isolation

The isolation of tryptophan was first reported by Frederick Hopkins in 1901[4] through hydrolysis of casein. From 600 grams of crude casein one obtains 4-8 grams of tryptophan.[5]

Biosynthesis and industrial production

Plants and microorganisms commonly synthesize tryptophan from shikimic acid or anthranilate.[6] The latter condenses with phosphoribosylpyrophosphate (PRPP), generating pyrophosphate as a by-product. After ring opening of the ribose moiety and following reductive decarboxylation, indole-3-glycerinephosphate is produced, which 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.[7][8][9]

Function

Metabolism of L-tryptophan into serotonin and melatonin (left) and niacin (right). Transformed functional groups after each chemical reaction are highlighted in red.

For many organisms (including humans), tryptophan is an essential amino acid. This means that it is essential for human life, cannot be synthesized by the organism, and therefore must be part of our diet. Amino acids, including tryptophan, act as building blocks in protein biosynthesis. In addition, tryptophan functions as a biochemical precursor for the following compounds (see also figure to the right):

The disorder fructose malabsorption causes improper absorption of tryptophan in the intestine, reduced levels of tryptophan in the blood,[15] and depression.[16] The authors did not find reduced tryptophan in cases of lactose maldigestion.[15]

In bacteria that synthesize tryptophan, high cellular levels of this amino acid activate a repressor protein, which binds to the trp operon.[17] 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.

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, sunflower seeds, pumpkin seeds, spirulina, bananas, and peanuts.[18] Contrary to the popular belief [19][20][21] that turkey has a particularly high amount of tryptophan, the amount of tryptophan in turkey is typical of most poultry.[22] There is also a myth that plant protein lacks tryptophan; in fact, tryptophan is present in significant amounts in almost all forms of plant protein, and abundant in some.

Tryptophan (Trp) Content of Various Foods[22][23]
Food Tryptophan
[g/100 g of food]		 Protein
[g/100 g of food]		 Tryptophan/Protein [%]
egg white, dried
1.00
81.10
1.23
spirulina, dried
0.93
57.47
1.62
cod, atlantic, dried
0.70
62.82
1.11
soybeans, raw
0.59
36.49
1.62
cheese, Parmesan
0.56
37.90
1.47
sesame seed
0.37
17.00
2.17
cheese, cheddar
0.32
24.90
1.29
sunflower seed
0.30
17.20
1.74
pork, chop
0.25
19.27
1.27
turkey
0.24
21.89
1.11
chicken
0.24
20.85
1.14
beef
0.23
20.13
1.12
oats
0.23
16.89
1.39
salmon
0.22
19.84
1.12
lamb, chop
0.21
18.33
1.17
perch, Atlantic
0.21
18.62
1.12
chickpeas, raw
0.19
19.30
0.96
egg
0.17
12.58
1.33
wheat flour, white
0.13
10.33
1.23
baking chocolate, unsweetened
0.13
12.9
1.23
milk
0.08
3.22
2.34
Rice, white, medium-grain, cooked
0.028
2.38
1.18
Quinoa, uncooked
0.167
14.12
1.2
Quinoa, cooked
0.052
4.40
1.1
potatoes, russet
0.02
2.14
0.84
tamarind
0.018
2.80
0.64
banana
0.01
1.03
0.87

Use as a dietary supplement and drug

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.[24] Small studies have been performed using 5-HTP and tryptophan as adjunctive therapy in addition to standard treatment for depression. While some studies had positive results, they were criticized for having methodological flaws, and a more recent study did not find sustained benefit from their use.[25] The safety of these medications has not been well studied.[24] 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.[24][25]

There is evidence that blood tryptophan levels are unlikely to be altered by changing the diet,[26] but tryptophan is available in health food stores as a dietary supplement.[27] Consuming purified tryptophan increases brain serotonin whereas eating foods containing tryptophan does not.[28] 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.[29] High plasma levels of other large neutral amino acids prevent the plasma concentration of tryptophan from increasing brain concentration levels.[29]

Metabolites

A metabolite of tryptophan, 5-hydroxytryptophan (5-HTP), has been suggested as a treatment for epilepsy[30] and depression, since 5-HTP readily crosses the blood–brain barrier and in addition is rapidly decarboxylated to serotonin (5-hydroxytryptamine or 5-HT).[31] Clinical trials, however, are regarded as inconclusive and lacking.[32] Serotonin has a relatively short half-life since it is rapidly metabolized by monoamine oxidase.

Due to the conversion of 5-HTP into serotonin by the liver, there may be a significant risk of heart valve disease from serotonin's effect on the heart.[33][34]

Tryptophan is marketed in Europe for depression and other indications under the brand names Cincofarm and Tript-OH. In the United States, 5-HTP does not require a prescription, as it is covered under the Dietary Supplement Act. Since the quality of dietary supplements is now regulated by the U.S. Food and Drug Administration, manufacturers are required to market products whose ingredients match the labeling, but are not required to establish efficacy of the product.[35]

The primary product of the liver enzyme tryptophan dioxygenase is kynurenine.[13][36]

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.[37]

Tryptophan supplements and EMS

There was a large outbreak of eosinophilia-myalgia syndrome (EMS) in the U.S. in 1989, which caused 1,500 cases of permanent disability and at least thirty-seven deaths. After preliminary investigation revealed that the outbreak was linked to intake of tryptophan, the U.S. Food and Drug Administration (FDA) banned most tryptophan from sale in the US in 1991, and other countries followed suit.[38]

Subsequent epidemiological studies[39][40][41] however, were able to pinpoint the syndrome to those exposed to specific batches of L-tryptophan supplied by a single large Japanese manufacturer, Showa Denko KK.[42] It eventually became clear that the cause had not been the tryptophan itself, but rather that flaws in Showa Denko's 1980s manufacturing process (long since corrected) had allowed trace impurities to contaminate these batches, and those impurities were in turn responsible for the 1989 EMS outbreak.[38][42][43][44] Against this backdrop, the FDA rescinded its restriction on sales and marketing of tryptophan in February 2001, but continued to ban importation.[42]

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."[45] 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.[46]

Turkey meat and drowsiness

A common assertion is that heavy consumption of turkey meat results in drowsiness, due to high levels of tryptophan contained in turkey.[19][21] However, the amount of tryptophan in turkey is comparable to that contained in most other meats.[20][22] Furthermore, post-meal drowsiness may have more to do with what is consumed along with the turkey, carbohydrates in particular.[47] It has been demonstrated in both animal models[48] and humans[49][50][51] 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 (an aromatic amino acid) 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).[52][53] Once in the CSF, tryptophan is converted into serotonin in the raphe nuclei by the normal enzymatic pathway.[48][50] The resultant serotonin is further metabolised into melatonin by the pineal gland.[12] 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.[48][49][50][51]

Research

Tryptophan affects brain serotonin synthesis when given orally in a purified form and is used to modify serotonin levels for research in psychology.[28] Low brain serotonin is induced by administration of tryptophan-poor protein in a technique called 'acute tryptophan depletion'.[54] Studies using this method have evaluated the effect of serotonin on mood and social behavior, finding that serotonin reduces aggression and increases agreeableness.[55]

Tryptophan is an important intrinsic fluorescent probe (amino acid), which can be used to estimate the nature of microenvironment of the tryptophan. Most of the intrinsic fluorescence emissions of a folded protein are due to excitation of tryptophan residues.

See also

References

  1. ↑ Dawson RMC et al. (1969). Data for Biochemical Research. Oxford: Clarendon Press. ISBN 0-19-855338-2.
  2. ↑ IUPAC-IUBMB Joint Commission on Biochemical Nomenclature. "Nomenclature and Symbolism for Amino Acids and Peptides". Recommendations on Organic & Biochemical Nomenclature, Symbols & Terminology etc. Retrieved 2007-05-17.
  3. ↑ Pallaghy PK, Melnikova AP, Jimenez EC, Olivera BM, Norton RS (1999). "Solution structure of contryphan-R, a naturally-occurring disulfide-bridged octapeptide containing D-tryptophan: comparison with protein loops". Biochemistry 38 (35): 11553–9. doi:10.1021/bi990685j. PMID 10471307.
  4. ↑ Hopkins FG, Cole SW (1901). "A contribution to the chemistry of proteids: Part I. A preliminary study of a hitherto undescribed product of tryptic digestion". J. Physiol. (Lond.) 27 (4–5): 418–28. doi:10.1113/jphysiol.1901.sp000880. PMC 1540554. PMID 16992614.
  5. ↑ Cox GJ, King H (1943). "L-Tryptophane". Org. Synth.; Coll. Vol. 2, pp. 612–616
  6. ↑ Radwanski ER, Last RL (1995). "Tryptophan biosynthesis and metabolism: biochemical and molecular genetics". Plant Cell 7 (7): 921–34. doi:10.1105/tpc.7.7.921. PMC 160888. PMID 7640526.
  7. ↑ Ikeda M (2002). "Amino acid production processes". Adv. Biochem. Eng. Biotechnol. Advances in Biochemical Engineering/Biotechnology 79: 1–35. doi:10.1007/3-540-45989-8_1. ISBN 978-3-540-43383-5. PMID 12523387.
  8. ↑ Becker J, Wittmann C (2012). "Bio-based production of chemicals, materials and fuels -Corynebacterium glutamicum as versatile cell factory". Curr. Opin. Biotechnol. 23 (4): 631–40. doi:10.1016/j.copbio.2011.11.012. PMID 22138494.
  9. ↑ Conrado RJ, Varner JD, DeLisa MP (2008). "Engineering the spatial organization of metabolic enzymes: mimicking nature's synergy". Curr. Opin. Biotechnol. 19 (5): 492–9. doi:10.1016/j.copbio.2008.07.006. PMID 18725290.
  10. ↑ Fernstrom JD (1983). "Role of precursor availability in control of monoamine biosynthesis in brain". Physiol. Rev. 63 (2): 484–546. PMID 6132421.
  11. ↑ Schaechter JD, Wurtman RJ (1990). "Serotonin release varies with brain tryptophan levels" (PDF). Brain Res. 532 (1–2): 203–10. doi:10.1016/0006-8993(90)91761-5. PMID 1704290.
  12. ↑ 12.0 12.1 Wurtman RJ, Anton-Tay F (1969). "The mammalian pineal as a neuroendocrine transducer" (PDF). Recent Prog. Horm. Res. 25: 493–522. doi:10.1016/b978-0-12-571125-8.50014-4. PMID 4391290.
  13. ↑ 13.0 13.1 Ikeda M, Tsuji H, Nakamura S, Ichiyama A, Nishizuka Y, Hayaishi O (1965). "Studies on the biosynthesis of nicotinamide adenine dinucleotide. II. A role of picolinic carboxylase in the biosynthesis of nicotinamide adenine dinucleotide from tryptophan in mammals". J. Biol. Chem. 240 (3): 1395–401. PMID 14284754.
  14. ↑ Palme K, Nagy F (April 2008). "A new gene for auxin synthesis". Cell 133 (1): 31–2. doi:10.1016/j.cell.2008.03.014. PMID 18394986.
  15. ↑ 15.0 15.1 Ledochowski M, Widner B, Murr C, Sperner-Unterweger B, Fuchs D (2001). "Fructose malabsorption is associated with decreased plasma tryptophan". Scand. J. Gastroenterol. 36 (4): 367–71. doi:10.1080/003655201300051135. PMID 11336160.
  16. ↑ Ledochowski M, Sperner-Unterweger B, Widner B, Fuchs D (1998). "Fructose malabsorption is associated with early signs of mental depression". Eur. J. Med. Res. 3 (6): 295–8. PMID 9620891.
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  18. ↑ Tryptophan background
  19. ↑ 19.0 19.1 Helmenstine AM. "Does Eating Turkey Make You Sleepy?". About.com. Retrieved 2013-11-13.
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  22. ↑ 22.0 22.1 22.2 Joanne Holden, Nutrient Data Laboratory, Agricultural Research Service. "USDA National Nutrient Database for Standard Reference, Release 22". United States Department of Agriculture. Retrieved 2009-11-29.
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  32. ↑ Turner EH, Loftis JM, Blackwell AD (2006). "Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan". Pharmacol Ther 109 (3): 325–38. doi:10.1016/j.pharmthera.2005.06.004. PMID 16023217.
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  34. ↑ Xu J, Jian B, Chu R, Lu Z, Li Q, Dunlop J, Rosenzweig-Lipson S, McGonigle P, Levy RJ, Liang B (December 2002). "Serotonin mechanisms in heart valve disease II: the 5-HT2 receptor and its signaling pathway in aortic valve interstitial cells". Am. J. Pathol. 161 (6): 2209–18. doi:10.1016/S0002-9440(10)64497-5. PMC 1850896. PMID 12466135.
  35. ↑ "Dietary Supplements: Background Information". Retrieved 2011-05-10.
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  37. ↑ Jackson RW (1930). "A synthesis of tryptophol" (PDF). Journal of Biological Chemistry 88 (3): 659–662.
  38. ↑ 38.0 38.1 "COT statement on tryptophan and the eosinophilia-myalgia syndrome" (PDF). UK Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment. June 2004, updated December 2005. Check date values in: |date= (help)
  39. ↑ Slutsker L, Hoesly FC, Miller L, Williams LP, Watson JC, Fleming DW (1990). "Eosinophilia-myalgia syndrome associated with exposure to certain specific batches of tryptophan from a single manufacturer". JAMA 264 (2): 213–7. doi:10.1001/jama.264.2.213. PMID 2355442.
  40. ↑ Back EE, Henning KJ, Kallenbach LR, Brix KA, Gunn RA, Melius JM (1993). "Risk factors for developing eosinophilia myalgia syndrome among L-tryptophan users in New York". J. Rheumatol. 20 (4): 666–72. PMID 8496862.
  41. ↑ Kilbourne EM, Philen RM, Kamb ML, Falk H (1996). "Tryptophan produced by Showa Denko and epidemic eosinophilia-myalgia syndrome". The Journal of rheumatology. Supplement 46: 81–8; discussion 89–91. PMID 8895184.
  42. ↑ 42.0 42.1 42.2 "Information Paper on L-tryptophan and 5-hydroxy-L-tryptophan". FU. S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Nutritional Products, Labeling, and Dietary Supplements. 2001-02-01. Archived from the original on 2005-02-25. Retrieved 2012-02-08.
  43. ↑ Mayeno AN, Lin F, Foote CS, Loegering DA, Ames MM, Hedberg CW, Gleich GJ (1990). "Characterization of "peak E," a novel amino acid associated with eosinophilia-myalgia syndrome". Science 250 (4988): 1707–8. doi:10.1126/science.2270484. PMID 2270484.
  44. ↑ Ito J, Hosaki Y, Torigoe Y, Sakimoto K (1992). "Identification of substances formed by decomposition of peak E substance in tryptophan". Food Chem. Toxicol. 30 (1): 71–81. doi:10.1016/0278-6915(92)90139-C. PMID 1544609.
  45. ↑ Mayeno AN, Gleich GJ (September 1994). "Eosinophilia-myalgia syndrome and tryptophan production: a cautionary tale". Trends Biotechnol. 12 (9): 346–52. doi:10.1016/0167-7799(94)90035-3. PMID 7765187.
  46. ↑ Raphals P (2000). "Does medical mystery threaten biotech?". Science 250 (4981): 4981. doi:10.1126/science.2237411. PMID 2237411.
  47. ↑ "Food & mood. (neuroscience professor Richard Wurtman) (Interview)". Nutrition Action Healthletter (HighBeam Research). September 1992.
  48. ↑ 48.0 48.1 48.2 Fernstrom JD, Wurtman RJ (1971). "Brain serotonin content: increase following ingestion of carbohydrate diet". Science 174 (4013): 1023–5. doi:10.1126/science.174.4013.1023. PMID 5120086.
  49. ↑ 49.0 49.1 Lyons PM, Truswell AS (1988). "Serotonin precursor influenced by type of carbohydrate meal in healthy adults" (PDF). Am. J. Clin. Nutr. 47 (3): 433–9. PMID 3279747.
  50. ↑ 50.0 50.1 50.2 Wurtman RJ, Wurtman JJ, Regan MM, McDermott JM, Tsay RH, Breu JJ (2003). "Effects of normal meals rich in carbohydrates or proteins on plasma tryptophan and tyrosine ratios". Am. J. Clin. Nutr. 77 (1): 128–32. PMID 12499331.
  51. ↑ 51.0 51.1 Afaghi A, O'Connor H, Chow CM (2007). "High-glycemic-index carbohydrate meals shorten sleep onset". Am. J. Clin. Nutr. 85 (2): 426–30. PMID 17284739.
  52. ↑ Pardridge WM, Oldendorf WH (1975). "Kinetic analysis of blood–brain barrier transport of amino acids". Biochim. Biophys. Acta 401 (1): 128–36. doi:10.1016/0005-2736(75)90347-8. PMID 1148286.
  53. ↑ Maher TJ, Glaeser BS, Wurtman RJ (1984). "Diurnal variations in plasma concentrations of basic and neutral amino acids and in red cell concentrations of aspartate and glutamate: effects of dietary protein intake". Am. J. Clin. Nutr. 39 (5): 722–9. PMID 6538743.
  54. ↑ Young SN (2013). "Acute tryptophan depletion in humans: a review of theoretical, practical and ethical aspects". J Psychiatry Neurosci 38 (5): 294–305. doi:10.1503/jpn.120209. PMC 3756112. PMID 23428157.
  55. ↑ Young SN (2013). "The effect of raising and lowering tryptophan levels on human mood and social behaviour". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 368 (1615): 20110375. doi:10.1098/rstb.2011.0375. PMC 3638380. PMID 23440461.

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