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| 'Tryptophan' | |
|---|---|
 Chemical structure of Tryptophan  Chemical structure of Tryptophan | |
| Systematic name | (''S'')-2-Amino-3-(1H-indol-3-yl)- propionic acid |
| Abbreviations | 'Trp, W' |
| Chemical formula | C11H12N2O2 |
| Molecular mass | 204.225 g mol−1 |
| Melting point | 289 °C |
| Density | 1.34 g cm-3 (solid) |
| Isoelectric point | 5.89 |
| p''K''a | 2.38, 9.34 |
| PubChem | 6305 |
| CAS number | [73-22-3] |
| EINECS number | 200-795-6 |
| SMILES | |
'Tryptophan' is an essential amino acid involved in human nutrition. It is one of the 20 amino acids encoded by the genetic code (as codon ''UGG''). Only the L-stereoisomer appears in mammalian protein, but the D-stereoisomer is occasionally found in natural materials (for example, the marine venom peptide contryphan).[1] A distinguishing structural characteristic of tryptophan is that it contains an indole functional group.
Isolation
The isolation of tryptophan was first reported by Sir Frederick Hopkins in 1901.[2] It has been obtained by hydrolysis of casein. From 600 g of crude casein, one obtains ca. 4-8 grams of tryptophan.[3]
Biosynthesis and industrial production
Plants and microorganisms can synthesize tryptophan, from among other things shikimic acid and/or anthranilate.[4] 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 finally produced, which in turn is transformed into indole. In the last step, tryptophan synthethase catalyzes the formation of tryptophan from indole and serine.
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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 ''E. coli''. The conversion is catalyzed by the enzyme tryptophan synthase.[5]
Function
For many organisms including humans, tryptophan is an essential amino acid. This means that it cannot be synthesized by the organism and therefore must be part of its diet. The principle function of amino acids including tryptophan are as building blocks in protein biosynthesis. In addition, tryptophan functions as a biochemical precursor for the following (see also figure to the right):
★ Serotonin (a neurotransmitter), via tryptophan hydroxylase.[6][7] Serotonin, in turn, can be converted to melatonin (a neurohormone), via N-acetyltransferase and 5-hydroxyindole-O-methyltransferase.[8]
★ Niacin via kynurenine and quinolinic acids as key biosynthetic intermediates.[9]
In organisms that synthesize tryptophan, high levels of this amino acid activate a repressor protein which in turn binds to the trp operon. Binding of this repressor to its operon prevents transcription of downstream DNA that codes for the enzymes involved in the biosynthesis of tryptophan. Hence high levels of tryptophan prevent additional tryptophan synthesis through a negative feedback loop. Conversely, if the cell's tryptophan level drops, transcription of the operon's genes resumes. This is one example of how gene expression responds rapidly to changes in the cell's internal and external environment.
Dietary sources
Tryptophan, found as a component of dietary protein, is particularly plentifulTryptophan background in chocolate, oats, bananas, dried dates, milk, yogurt, cottage cheese, red meat, eggs, fish, poultry, sesame, chickpeas, sunflower seeds, pumpkin seeds, spirulina and peanuts. It is found in turkey at a level typical of poultry in general. United States Department of Agriculture (USDA) National Nutrient Database for Standard Reference, Release 19
| turkey | | | |
| chicken | | | |
| beef | | | |
| lamb, chop | | | |
| pork, chop | | | |
| salmon | | | |
| perch, Atlantic | | | |
| milk | | | |
| egg | | | |
| wheat flour, white | | | |
| potatoes, russet | | | |
| rice, white | | | |
Use as a dietary supplement
For some time, tryptophan was available in health food stores as a dietary supplement. Many people found tryptophan to be a safe and reasonably effective sleep aid, probably due to its ability to increase brain levels of serotonin (a calming neurotransmitter when present in moderate levels)[11] and/or melatonin (a sleep-inducing hormone secreted by the pineal gland in response to darkness or low light levels).[12][13]
Clinical research tended to confirm tryptophan's effectiveness as a sleep aid[14][15] and for a growing variety of other conditions typically associated with low serotonin levels or activity in the brain[16] such as premenstrual dysphoric disorder
[17] and seasonal affective disorder.[18][19] In particular, tryptophan showed considerable promise as an antidepressant alone,[20] and as an "augmenter" of antidepressant drugs.20[21] However others have questioned the reliability of these clinical trials.[22][23]
Metabolites
5-Hydroxytryptophan (5-HTP), a metabolite of tryptophan, has been suggested as a treatment for epilepsy[24] and depression although clinical trials are inconclusive and lacking.[25]
5-HTP readily crosses the blood brain barrier and in addition is rapidly decarboxylated to serotonin (5-hydroxytryptamine or 5-HT)[26] and therefore may be useful for the treatment of depression. However serotonin has a relatively short half life since it is rapidly metabolized by monoamine oxidase therefore is likely to have limited efficacy. It is marketed in Europe for depression and other indications under brand names like Cincofarm and Tript-OH.
In the United States, 5-HTP does not require a prescription as it is covered under the Dietary Supplement Act. However, since the quality of dietary supplements are not regulated by the FDA, the quality of dietary and nutritional supplements tends to vary and there is no guarantee that the label accurately depicts what the bottle contains. Most health-food stores sell 5-HTP to avoid the artificially high cost of the amino acid itself.
Tryptophan supplements and EMS
In 1989, a large outbreak (1500 cases including at least 37 deaths) of a disabling autoimmune illness called eosinophilia-myalgia syndrome (EMS) was traced by some epidemiological studies[27][28][29] to L-tryptophan supplied by a Japanese manufacturer, Showa Denko KK.FDA Information Paper on L-tryptophan and 5-hydroxy-L-tryptophan It was further hypothesized that one or more trace impurities produced during the manufacture of tryptophan may have been responsible for the EMS outbreak.[30][31] However, many people who consumed Showa Denko L-tryptophan did not develop EMS and cases of EMS have occurred prior to and after the 1989 epidemic. Furthermore the methodology used in the initial epidemiological studies has been criticized.[32][33] An alternative explanation for the 1989 EMS outbreak is that large doses of tryptophan produce metabolites which inhibit the normal degradation of histamine and excess histamine in turn has been proposed to cause EMS.[34]
Most tryptophan was banned from sale in the US in 1991, and other countries followed suit. Tryptophan from one manufacturer, of six, continued to be sold for manufacture of baby formulas. A Rutgers Law Journal article observed, "Political pressures have played a role in the FDA's decision to ban L-tryptophan as well as its desire to increase its regulatory power over dietary supplements."[35]
At the time of the ban the FDA did not know, or did not indicate, that EMS was caused by a contaminated batch,FDA Tryptophan Recall[36] and yet even when the contamination was discovered and the purification process fixed, the FDA maintained that L-tryptophan was unsafe. In February 2001 the FDA loosened the restrictions on marketing (though not on importation), but still expressed the following concern:
: ''"Based on the scientific evidence that is available at the present time, we cannot determine with certainty that the occurrence of EMS in susceptible persons consuming L-tryptophan supplements derives from the content of L-tryptophan, an impurity contained in the L-tryptophan, or a combination of the two in association with other, as yet unknown, external factors."''
Since 2002, L-tryptophan has been sold in the U.S. in its original form. Several high quality sources of L-tryptophan do exist, and are sold in many of the largest health food stores nationwide. Indeed, tryptophan has continued to be used in clinical and experimental studies employing human patients and subjects.
In recent years in the U.S., compounding pharmacies and some mail-order supplement retailers have begun selling tryptophan to the general public. Tryptophan has also remained on the market as a prescription drug (Tryptan), which some psychiatrists continue to prescribe, particularly as an augmenting agent for people who are unresponsive to antidepressant drugs.
Turkey meat and drowsiness
One widely held urban myth is that heavy consumption of turkey meat (as for example in a Thanksgiving feast) results in drowsiness and this effect has been attributed to high levels of tryptophan contained in turkey. About.com: Does Eating Turkey Make You Sleepy? Howstuffworks.com: Is there something in turkey that makes you sleepy? Chemistry.org: Thanksgiving, Turkey, and Tryptophan While turkey does contain high levels of tryptophan, the amount is comparable to that contained in most other meats. Furthermore postprandial Thanksgiving sedation may have more to do with what is consumed along with the turkey, and in particular carbohydrates, rather than the turkey itself.
It has been demonstated in both animal models[37] and in humans[38][39][40] 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 (LNAA) but not tryptophan (trp) into muscle increasing the ratio of trp to LNAA in the blood stream. The resulting increased ratio of tryptophan to large neutral amino acids in the blood reduces competition with other amino acids for the large neutral amino acid transporter protein for uptake of tryptophan across the blood-brain barrier into the central nervous system (CNS).[41][42] Once inside the CNS, tryptophan is converted into serotonin in the raphe nuclei by the normal enzymatic pathway.3739 The resultant serotonin is further metabolised into melatonin by the pineal gland.8 Hence, these data suggest that "feast-induced drowsiness", and particularly, the common American post-thanksgiving dinner drowsiness, may be the result of a heavy meal rich in carbohydrates which via an indirect mechanism, increases the production of sleep promoting serotonin and melatonin in the brain.37383940
Fluorescence
The fluorescence of a folded protein is a mixture of the fluorescence from individual aromatic residues. Most of the intrinsic fluorescence emissions of a folded protein are due to excitation of tryptophan residues, with some emissions due to tyrosine and phenylalanine. Typically, tryptophan has a wavelength of maximum absorption of 280 nm and a wavelength of maximum fluorescence emission of 350 nm. However these fluorescence parameters are strongly dependent on the environment that the tryptophan residue is in, for example the degree of solvent exposure.[43] Hence protein fluorescence may be used as a diagnostic of the conformational state a protein.[44]
Furthermore, tryptophan fluorescence is strongly influenced by the proximity of other residues (''i.e.'', nearby protonated acidic groups such as Asp or Glu can cause quenching of Trp fluorescence). In addition, tryptophan is a relatively rare amino acid therefore many proteins contain only one or a few tryptophan residues. Therefore, tryptophan fluorescence is a very sensitive measurement of the conformational state of individual tryptophan residues.
Fictional references
★ In James Cameron's TV series ''Dark Angel'', genetically engineered Max Guevara and the other escaped X-5s need to take tryptophan supplements to control their seizures which were the result of a faulty gene.
★ In U.S. TV show an episode of ''Seinfeld'', Jerry and George use turkey and boxed wine to cause Jerry's girlfriend to fall asleep so they can play with her extensive antique toy collection. When Jerry's girlfriend asks what is it in turkey that makes people drowsy, Jerry and George immediately and simultaneously respond "Tryptophan!"
★ In the U.S. TV series ''Reno 911!'', the faux-information documentary "Keeping it Real, Real Safe" claims that tryptophan is as dangerous as alcohol when it comes to driving.
★ In the episode "Psycho Therapy" of the MTV animated series Daria, Daria tells her father, Jake, of tryptophan in milk and its calming influences. This serves as a running gag through the episode.
★ In the U.S. TV series "Titus", Christopher Titus believed it was tryptophan that caused sleepiness during a turkey dinner. It was in fact the bottle of antidepressants his mother put in their food.
References
1. Solution structure of contryphan-R, a naturally occurring disulfide-bridged octapeptide containing D-tryptophan: comparison with protein loops, Pallaghy PK, Melnikova AP, Jimenez EC, Olivera BM, Norton RS, , , Biochemistry, 1999
2. A contribution to the chemistry of proteids: Part I. A preliminary study of a hitherto undescribed product of tryptic digestion, Hopkins FG, Cole SW, , , J. Physiol. (Lond.), 1901
3. L-Tryptophane, Cox GJ, King H, , , Organic Syntheses, 1943
4. Tryptophan biosynthesis and metabolism: biochemical and molecular genetics, Radwanski ER, Last RL, , , Plant Cell, 1995
5. Amino acid production processes, Ikeda M, , , Adv. Biochem. Eng. Biotechnol., 2002
6. Role of precursor availability in control of monoamine biosynthesis in brain, Fernstrom JD, , , Physiol. Rev., 1983
7. Serotonin release varies with brain tryptophan levels, Schaechter JD, Wurtman RJ, , , Brain Res., 1990
8. The mammalian pineal as a neuroendocrine transducer, Wurtman RJ, Anton-Tay F, , , Recent Prog. Horm. Res., 1969
9. 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, Ikeda M, Tsuji H, Nakamura S, Ichiyama A, Nishizuka Y, Hayaishi O, , , J. Biol. Chem., 1965
10. [The contribution of cocoa additive to cigarette smoking addiction], Rambali B, Andel I van, Schenk E, Wolterink G, Werken G van de, Stevenson H, Vleeming W, , , RIVM, 2002 - The National Institute for Public Health and the Environment (Netherlands)
11. Precursor control of neurotransmitter synthesis, Wurtman RJ, Hefti F, Melamed E, , , Pharmacol. Rev., 1980
12. Formation of melatonin and 5-hydroxyindole acetic acid from 14C-tryptophan by rat pineal glands in organ culture, Wurtman RJ, Larin F, Axelrod J, Shein HM, Rosasco K, , , Nature, 1968
13. Tryptophan metabolism in the central nervous system: medical implications, Ruddick JP, Evans AK, Nutt DJ, Lightman SL, Rook GA, Lowry CA, , , Expert reviews in molecular medicine, 2006
14. Effects of L-tryptophan on sleepiness and on sleep, Hartmann E, , , Journal of psychiatric research, 1982
15. Evaluation of L-tryptophan for treatment of insomnia: a review, Schneider-Helmert D, Spinweber CL, , , Psychopharmacology (Berl.), 1986
16. research summary of Dr. Richard Wurtman, MIT
17. A placebo-controlled clinical trial of L-tryptophan in premenstrual dysphoria, Steinberg S, Annable L, Young SN, Liyanage N, , , Biol. Psychiatry, 1999
18. L-tryptophan augmentation of light therapy in patients with seasonal affective disorder, Lam RW, Levitan RD, Tam EM, Yatham LN, Lamoureux S, Zis AP, , , Canadian journal of psychiatry. Revue canadienne de psychiatrie, 1997
19. Current perspectives on the management of seasonal affective disorder, Jepson TL, Ernst ME, Kelly MW, , , J Am Pharm Assoc (Wash), 1999
20. The treatment of depression in general practice: a comparison of L-tryptophan, amitriptyline, and a combination of L-tryptophan and amitriptyline with placebo, Thomson J, Rankin H, Ashcroft GW, Yates CM, McQueen JK, Cummings SW, , , Psychological medicine, 1982
21. Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects, Levitan RD, Shen JH, Jindal R, Driver HS, Kennedy SH, Shapiro CM, , , Journal of psychiatry & neuroscience : JPN, 2000
22. Use of neurotransmitter precursors for treatment of depression, Meyers S, , , Alternative medicine review : a journal of clinical therapeutic, 2000
23. Tryptophan and 5-hydroxytryptophan for depression, Shaw K, Turner J, Del Mar C, , , Cochrane database of systematic reviews (Online), 2002
24. Brain serotonin and epileptic seizures in mice: a pharmacological and biochemical study, Kostowski W, Bidzinski A, Hauptmann M, Malinowski JE, Jerlicz M, Dymecki J, , , Pol J Pharmacol Pharm, 1978
25. Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan, Turner EH, Loftis JM, Blackwell AD, , , Pharmacol Ther, 2006
26. Barrier mechanisms for neurotransmitter monoamines and their precursors at the blood-brain interface, Hardebo JE, Owman C, , , Ann NeurolAnn Neurol, 1980
27. Eosinophilia-myalgia syndrome associated with exposure to tryptophan from a single manufacturer, Slutsker L, Hoesly FC, Miller L, Williams LP, Watson JC, Fleming DW, , , JAMA, 1990
28. Risk factors for developing eosinophilia myalgia syndrome among L-tryptophan users in New York, Back EE, Henning KJ, Kallenbach LR, Brix KA, Gunn RA, Melius JM, , , J. Rheumatol., 1993
29. Tryptophan produced by Showa Denko and epidemic eosinophilia-myalgia syndrome, Kilbourne EM, Philen RM, Kamb ML, Falk H, , , The Journal of rheumatology. Supplement, 1996
30. Characterization of "peak E," a novel amino acid associated with eosinophilia-myalgia syndrome, Mayeno AN, Lin F, Foote CS, Loegering DA, Ames MM, Hedberg CW, Gleich GJ, , , Science, 1990
31. Identification of substances formed by decomposition of peak E substance in tryptophan, Ito J, Hosaki Y, Torigoe Y, Sakimoto K, , , Food Chem. Toxicol., 1992
32. Epidemiologic studies of the association of L-tryptophan with the eosinophilia-myalgia syndrome: a critique, Shapiro S, , , The Journal of rheumatology. Supplement, 1996
33. Bias or biology: evaluating the epidemiologic studies of L-tryptophan and the eosinophilia-myalgia syndrome, Horwitz RI, Daniels SR, , , The Journal of rheumatology. Supplement, 1996
34. A heretofore undisclosed crux of eosinophilia-myalgia syndrome: compromised histamine degradation, Smith MJ, Garrett RH, , , Inflamm. Res., 2005
35. Dietary Supplements and Their Discontents: FDA Regulation and the Dietary Supplement Health and Education Act of 1994 (L-tryptophan Section), Beisler JH, , , Rutgers Law Journal, 2000
36. Does medical mystery threaten biotech?, Raphals P, , , Science, 2000
37. Brain serotonin content: increase following ingestion of carbohydrate diet, Fernstrom JD, Wurtman RJ, , , Science, 1971
38. Serotonin precursor influenced by type of carbohydrate meal in healthy adults, Lyons PM, Truswell AS, , , Am. J. Clin. Nutr., 1988
39. Effects of normal meals rich in carbohydrates or proteins on plasma tryptophan and tyrosine ratios, Wurtman RJ, Wurtman JJ, Regan MM, McDermott JM, Tsay RH, Breu JJ, , , Am. J. Clin. Nutr., 2003
40. High-glycemic-index carbohydrate meals shorten sleep onset, Afaghi A, O'Connor H, Chow CM, , , Am. J. Clin. Nutr., 2007
41. Kinetic analysis of blood-brain barrier transport of amino acids, Pardridge WM, Oldendorf WH, , , Biochim. Biophys. Acta, 1975
42. 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, Maher TJ, Glaeser BS, Wurtman RJ, , , Am. J. Clin. Nutr., 1984
43. Intrinsic Fluorescence of Proteins and Peptides
44. Mechanisms of tryptophan fluorescence shifts in proteins, Vivian JT, Callis PR, , , Biophys J, 2006
See also
★ Serotonin
★ 5-HTP
★ Tryptamines
External links
★ Tryptophan catabolism (early stages)
★ Tryptophan catabolism (later stages)
★ Computational Chemistry Wiki
★ Thanksgiving, Turkey, and Tryptophan
★ FDA Information Paper on L-tryptophan and 5-hydroxy-L-tryptophan
★ Snopes article debunking the turkey–drowsiness connection
★ The FDA Ban of L-Tryptophan: Politics, Profits and Prozac
★ Effects of Tryptophan Depletion on the Performance of an Iterated Prisoner's Dilemma Game in Healthy Adults - Nature Neuropsychopharmacology
★
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