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'''Tryptophan''' is an [[amino acid]] and [[Essential amino acid|essential]] in [[human]] nutrition. It is one of the 20 amino acids in the [[genetic code]] ([[codon]] ''UGG''). Only the L-[[stereoisomer]] appears in mammalian protein.</p><br />
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'''Tryptophan''' (abbreviated as '''Trp''' or '''W''')<ref>{{cite web | author=IUPAC-IUBMB Joint Commission on Biochemical Nomenclature | title=Nomenclature and Symbolism for Amino Acids and Peptides | work=Recommendations on Organic & Biochemical Nomenclature, Symbols & Terminology etc | url=http://www.chem.qmul.ac.uk/iupac/AminoAcid/ | accessdate=2007-05-17}}</ref> is one of the 20 [[List of standard amino acids|standard amino acids]], as well as an [[essential amino acid]] in the [[human]] diet. It is encoded in genetic code as the [[codon]] ''UGG''. Only the L-[[stereoisomer]] of tryptophan is used in [[Fibrous protein|structural]] or [[enzyme]] proteins, but the D-[[stereoisomer]] is occasionally found in naturally produced [[peptide]]s (for example, the marine venom [[peptide]] [[contryphan]]).<ref name="Pallaghy_1999">{{cite journal |author=Pallaghy PK, Melnikova AP, Jimenez EC, Olivera BM, Norton RS|title=Solution structure of contryphan-R, a naturally-occurring disulfide-bridged octapeptide containing D-tryptophan: comparison with protein loops|journal= Biochemistry |volume= 38 |issue= 35 |pages= 11553-9 |year= 1999 |pmid= 10471307}}</ref> The distinguishing structural characteristic of tryptophan is that it contains an [[indole]] functional group.
   
<!--==Synthesis==
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==Isolation==
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The isolation of tryptophan was first reported by [[Frederick Hopkins| Sir Frederick Hopkins]] in 1901 <ref name="pmid16992614">{{cite journal | author = Hopkins FG, Cole SW | title = A contribution to the chemistry of proteids: Part I. A preliminary study of a hitherto undescribed product of tryptic digestion | journal = J. Physiol. (Lond.) | volume = 27 | issue = 4-5 | pages = 418-28 | year = 1901 | pmid = 16992614 | doi = | issn = | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1540554}}</ref> through hydrolysis of [[casein]]. From 600 [[gram]]s of crude casein one obtains 4-8 grams of tryptophan.<ref name="Cox_1943">{{cite journal | author = Cox GJ, King H | title = L-Tryptophane | journal = Organic Syntheses | volume = Collected Volume 2 | issue = | pages = 612-616 | year = 1943 | pmid = | doi = | issn = | url = http://www.orgsyn.org/orgsyn/pdfs/CV2P0612.pdf}}</ref>
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== Biosynthesis and industrial production ==
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Plants and [[microorganism]]s commonly synthesize tryptophan from [[shikimic acid]] or [[anthranilic acid|anthranilate]].<ref name="pmid7640526">{{cite journal | author = Radwanski ER, Last RL | title = Tryptophan biosynthesis and metabolism: biochemical and molecular genetics | journal = Plant Cell | volume = 7 | issue = 7 | pages = 921-34 | year = 1995 | pmid = 7640526 | doi = 10.1105/tpc.7.7.921 | issn = }}</ref> 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]].
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[[Image:Tryptophan biosynthesis.png|center|750px|test]]
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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]].<ref name="pmid12523387">{{cite journal | author = Ikeda M | title = Amino acid production processes | journal = Adv. Biochem. Eng. Biotechnol. | volume = 79 | issue = | pages = 1-35 | year = 2002 | pmid = 12523387 | doi = | issn = | url = http://www.springerlink.com/content/226q8plt36351kck}}</ref>
   
 
==Function==
 
==Function==
Tryptophan is an [[essential amino acid]] that humans cannot live without consuming. Amino acids function as building blocks in [[protein biosynthesis]].
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[[Image:Tryptophan metabolism.png|thumb|365px|Metabolism of L-tryptophan into serotonin and melatonin (left) and niacin (right). Transformed functional groups after each chemical reaction are highlighted in red.]]
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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 principal function of amino acids including tryptophan are as building blocks in [[protein biosynthesis]]. In addition, tryptophan functions as a biochemical [[Precursor (chemistry)|precursor]] for the following compounds (see also figure to the right):
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* [[Serotonin]] (a [[neurotransmitter]]), synthesized via [[tryptophan hydroxylase]].<ref name="pmid6132421">{{cite journal | author = Fernstrom JD | title = Role of precursor availability in control of monoamine biosynthesis in brain | journal = Physiol. Rev. | volume = 63 | issue = 2 | pages = 484-546 | year = 1983 | pmid = 6132421 | doi = | issn = | url = http://physrev.physiology.org/cgi/reprint/63/2/484}}</ref><ref name="pmid1704290">{{cite journal | author = Schaechter JD, Wurtman RJ | title = Serotonin release varies with brain tryptophan levels | journal = Brain Res. | volume = 532 | issue = 1-2 | pages = 203-10 | year = 1990 | pmid = 1704290 | doi = 10.1016/0006-8993(90)91761-5 | issn = | url = http://wurtmanlab.mit.edu/publications/pdf/790.pdf}}</ref> Serotonin, in turn, can be converted to [[melatonin]] (a [[neurohormone]]), via [[N-Acetyltransferase|N-acetyltransferase]] and [[5-hydroxyindole-O-methyltransferase]] activities.<ref name="pmid4391290">{{cite journal | author = Wurtman RJ, Anton-Tay F | title = The mammalian pineal as a neuroendocrine transducer | journal = Recent Prog. Horm. Res. | volume = 25 | issue = | pages = 493-522 | year = 1969 | pmid = 4391290 | doi = | issn = | url = http://wurtmanlab.mit.edu/publications/pdf/104.pdf}}</ref>
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* [[Niacin]] is synthesized from tryptophan via [[kynurenine]] and quinolinic acids as key biosynthetic intermediates.<ref name="pmid14284754">{{cite journal | author = Ikeda M, Tsuji H, Nakamura S, Ichiyama A, Nishizuka Y, Hayaishi O | title = 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 | journal = J. Biol. Chem. | volume = 240 | issue = | pages = 1395-401 | year = 1965 | pmid = 14284754 | doi = | issn = | url = http://www.jbc.org/cgi/reprint/240/3/1395 }}</ref>
   
Tryptophan is a [[precursor]] for [[serotonin]] (a [[neurotransmitter]]), [[melatonin]] (a neuro[[hormone]]), and [[niacin]]. The functional group of tryptophan is [[indole]]; see that article for more on its chemical properties.
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The disorder [[Fructose malabsorption|Fructose Malabsorption]] causes improper absorption of tryptophan in the intestine, reduced levels of tryptophan in the blood<ref>{{cite journal |author=Ledochowski M, Widner B, Murr C, Sperner-Unterweger B, Fuchs D |title=Fructose malabsorption is associated with decreased plasma tryptophan |journal=Scand. J. Gastroenterol. |volume=36 |issue=4 |pages=367-71 |year=2001 |pmid=11336160 |doi=}}</ref> and depression.<ref>{{cite journal |author=Ledochowski M, Sperner-Unterweger B, Widner B, Fuchs D |title=Fructose malabsorption is associated with early signs of mental depression |journal=Eur. J. Med. Res. |volume=3 |issue=6 |pages=295-8 |year=1998 |pmid=9620891 |doi=}}</ref>
   
Tryptophan has been implicated as a possible cause of [[schizophrenia]] in people who cannot metabolize it properly. When improperly metabolized, it creates a waste product in the brain that is toxic, causing hallucinations and delusions. Tryptophan has also been indicated as an aid for schizophrenic patients.
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In bacteria that synthesize tryptophan, high cellular levels of this amino acid activate a [[repressor]] protein, which binds to the [[trp operon]]. {{Fact|date=October 2007}} 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 organization of the trp operon thus permits tightly regulated and rapid responses to changes in the cell's internal and external tryptophan levels.
   
 
==Dietary sources==
 
==Dietary sources==
Tryptophan, found as a component of dietary protein, is particularly plentiful in chocolate, oats, bananas, dried dates, milk, cottage cheese, meat, fish, turkey, chicken, sesame and peanuts.
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Tryptophan is a routine constituent of most protein-based foods or dietary proteins. It is particularly plentiful in [[chocolate]], [[oat]]s, [[banana]]s, [[mango]]es, dried [[Date Palm|date]]s, [[milk]], [[yogurt]], [[cottage cheese]], [[red meat]], [[egg (food)|eggs]], [[fish]], [[poultry]], [[sesame]], [[chickpea]]s, [[sunflower seeds]], [[pumpkin seeds]], [[spirulina]], and [[peanut]]s.<ref name= Tryptophan_background >[http://www.vitamins-supplements.org/amino-acids/tryptophan.php Tryptophan background]</ref> It is also found in [[turkey (bird)|turkey]] at a level typical of poultry in general.<ref name = "USDA">{{cite web|title= USDA National Nutrient Database for Standard Reference, Release 20 | |publisher= United States Department of Agriculture | author = Joanne Holden, Nutrient Data Laboratory, Agricultural Research Service | url=http://www.ars.usda.gov/nutrientdata | accessdate = 2007-10-02}}</ref>
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{| class="wikitable sortable" style="background:white"
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|+ Tryptophan (Trp) Content of Various Foods<ref name = "USDA" /><ref name="Rambali">{{cite journal | author=Rambali B, Andel I van, Schenk E, Wolterink G, Werken G van de, Stevenson H, Vleeming W | title=[The contribution of cocoa additive to cigarette smoking addiction] | journal=RIVM | year=2002 | url=http://rivm.nl/bibliotheek/rapporten/650270002.pdf | format=PDF | issue=report 650270002/2002}}- The National Institute for Public Health and the Environment (Netherlands)</ref></center>
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|-
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!width="120 pt"|Food
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!width="240 pt"|Protein <br>[g/100 g of food]
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!width="200 pt"|Tryptophan <br>[g/100 g of food]
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!width="180 pt"|Tryptophan/Protein [%]
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|-
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| turkey || <center>21.89</center> || <center>0.24</center> || <center>1.11</center>
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|-
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| cheese, cheddar || <center>24.90</center> || <center>0.32</center> || <center>1.29</center>
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|-
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| chicken || <center>20.85</center> || <center>0.24</center> || <center>1.14</center>
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|-
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| beef || <center>20.13</center> || <center>0.23</center> || <center>1.12</center>
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|-
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| lamb, chop || <center>18.33</center> || <center>0.21</center> || <center>1.17</center>
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|-
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| pork, chop || <center>19.27</center> || <center>0.25</center> || <center>1.27</center>
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|-
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| salmon || <center>19.84</center> || <center>0.22</center> || <center>1.12</center>
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|-
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| perch, Atlantic || <center>18.62</center> || <center>0.21</center> || <center>1.12</center>
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|-
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| milk || <center>3.22</center> || <center>0.08</center> || <center>2.34</center>
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|-
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| egg || <center>12.58</center> || <center>0.17</center> || <center>1.33</center>
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|-
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| wheat flour, white || <center>10.33</center> || <center>0.13</center> || <center>1.23</center>
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|-
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| potatoes, russet || <center>2.14</center> || <center>0.02</center> || <center>0.84</center>
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|-
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| rice, white || <center>7.13</center> || <center>0.08</center> || <center>1.16</center>
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|}
   
 
===Use as a dietary supplement===
 
===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) and/or [[melatonin]] (a sleep-inducing [[hormone]] secreted by the [[pineal gland]] in response to darkness or low light levels). Clinical research tended to confirm tryptophan's effectiveness as a natural [[sleep aid]] and for a growing variety of other conditions typically associated with low serotonin levels or activity in the brain. In particular, tryptophan showed considerable promise as an [[antidepressant]] alone, and as an "augmentor" of [[antidepressant]] drugs. Other promising indications included relief of [[chronic pain]] and reduction of impulsive, violent, [[mania| manic]], [[addiction| addictive]], [[obsession| obsessive]], or [[compulsion| compulsive]] behaviours and disorders. Tryptophan has also been indicated as an aid for schizophrenic patients.
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For some time, tryptophan was available in health food stores as a [[dietary supplement]], although it is common in dietary protein. 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)<ref name="pmid6115400">{{cite journal | author = Wurtman RJ, Hefti F, Melamed E | title = Precursor control of neurotransmitter synthesis | journal = Pharmacol. Rev. | volume = 32 | issue = 4 | pages = 315-35 | year = 1980 | pmid = 6115400 | doi = | issn = | url = http://wurtmanlab.mit.edu/publications/pdf/466.pdf }}</ref> and/or [[melatonin]] (a sleep-inducing [[hormone]] secreted by the [[pineal gland]] in response to darkness or low light levels).<ref name="pmid5300432">{{cite journal | author = Wurtman RJ, Larin F, Axelrod J, Shein HM, Rosasco K | title = Formation of melatonin and 5-hydroxyindole acetic acid from 14C-tryptophan by rat pineal glands in organ culture | journal = Nature | volume = 217 | issue = 5132 | pages = 953-4 | year = 1968 | pmid = 5300432 | doi = 10.1038/217953a0 | issn = }}</ref><ref name="pmid16942634">{{cite journal | author = Ruddick JP, Evans AK, Nutt DJ, Lightman SL, Rook GA, Lowry CA | title = Tryptophan metabolism in the central nervous system: medical implications | journal = Expert reviews in molecular medicine | volume = 8 | issue = 20 | pages = 1-27 | year = 2006 | pmid = 16942634 | doi = 10.1017/S1462399406000068 | issn = }}</ref>
   
In 1989, a large outbreak of a new, disabling, and in some cases deadly [[autoimmune]] illness called [[eosinophilia-myalgia syndrome]] (EMS) was traced to L-tryptophan. The bacterial culture used to synthesize tryptophan by a major Japanese manufacturer, Showa Denko KK, had recently been genetically engineered to increase tryptophan production; with the higher tryptophan concentration in the culture medium, the purification process had also been streamlined to reduce costs, and a purification step that used charcoal absorption to remove impurities had been omitted. This allowed another bacterial metabolite through the purification, resulting in the presence of an end-product contaminant responsible for the toxic effects. The FDA was unable to establish with certainty that this was the sole cause of the outbreak. Tryptophan was banned from sale in the US, and other countries followed suit.
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Clinical research tends to confirm tryptophan's effectiveness as a sleep aid<ref name="pmid6764927">{{cite journal | author = Hartmann E | title = Effects of L-tryptophan on sleepiness and on sleep | journal = Journal of psychiatric research | volume = 17 | issue = 2 | pages = 107-13 | year = 1982 | pmid = 6764927 | doi = 10.1016/0022-3956(82)90012-7 | issn = }}</ref><ref name="pmid3090582">{{cite journal | author = Schneider-Helmert D, Spinweber CL | title = Evaluation of L-tryptophan for treatment of insomnia: a review | journal = Psychopharmacology (Berl.) | volume = 89 | issue = 1 | pages = 1-7 | year = 1986 | pmid = 3090582 | doi = 10.1007/BF00175180 | issn = }}</ref><ref name="pmid4097755">{{cite journal | author = Wyatt RJ, Engelman K, Kupfer DJ, Fram DH, Sjoerdsma A, Snyder F. | title = Effects of L-tryptophan (a natural sedative) on human sleep. | journal = Lancet | volume = 1970 Oct 24,2 | issue = 7678 | pages = 842-6 | year = 1970 Oct 24| pmid = 4097755 | doi = | issn = 0140-6736}}</ref> and for a growing variety of other conditions typically associated with low serotonin levels or activity in the brain<ref>{{cite web|title=research summary of Dr. Richard Wurtman, MIT|url=http://web.mit.edu/bcs/people/wurtman.shtml|accessdate = 2007-08-12}}</ref> such as [[premenstrual dysphoric disorder]]
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<ref name="pmid10023508">{{cite journal | author = Steinberg S, Annable L, Young SN, Liyanage N | title = A placebo-controlled clinical trial of L-tryptophan in premenstrual dysphoria | journal = Biol. Psychiatry | volume = 45 | issue = 3 | pages = 313-20 | year = 1999 | pmid = 10023508 | doi = 10.1016/S0006-3223(98)00005-5 | issn = }}</ref> and [[seasonal affective disorder]].<ref name="pmid9114947">{{cite journal | author = Lam RW, Levitan RD, Tam EM, Yatham LN, Lamoureux S, Zis AP | title = L-tryptophan augmentation of light therapy in patients with seasonal affective disorder | journal = Canadian journal of psychiatry. Revue canadienne de psychiatrie | volume = 42 | issue = 3 | pages = 303-6 | year = 1997 | pmid = 9114947 | doi = | issn = | url = http://ww1.cpa-apc.org:8080/Publications/Archives/CJP/1997/April/apr97_bc1.htm }}</ref><ref name="Jepson_1999">{{cite journal |author=Jepson TL, Ernst ME, Kelly MW|title=Current perspectives on the management of seasonal affective disorder|journal= J Am Pharm Assoc (Wash) |volume= 39 |issue= 6 |pages= 822-9 |year= 1999 |pmid= 10609448}}</ref> In particular, tryptophan has been showing considerable promise as an [[antidepressant]] alone,<ref name="pmid7156248">{{cite journal | author = Thomson J, Rankin H, Ashcroft GW, Yates CM, McQueen JK, Cummings SW | title = The treatment of depression in general practice: a comparison of L-tryptophan, amitriptyline, and a combination of L-tryptophan and amitriptyline with placebo | journal = Psychological medicine | volume = 12 | issue = 4 | pages = 741-51 | year = 1982 | pmid = 7156248 | doi = | issn = }}</ref> and as an "augmenter" of [[antidepressant]] drugs.<ref name="pmid7156248" /><ref name="pmid11022398">{{cite journal | author = Levitan RD, Shen JH, Jindal R, Driver HS, Kennedy SH, Shapiro CM | title = Preliminary randomized double-blind [[placebo]]-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects | journal = Journal of psychiatry & neuroscience : JPN | volume = 25 | issue = 4 | pages = 337-46 | year = 2000 | pmid = 11022398 | doi = | issn = | url = http://www.cma.ca/index.cfm/ci_id/12652/la_id/1.htm}}</ref> However others have questioned the reliability of these clinical trials.<ref name="pmid10696120">{{cite journal | author = Meyers S | title = Use of neurotransmitter precursors for treatment of depression | journal = Alternative medicine review : a journal of clinical therapeutic | volume = 5 | issue = 1 | pages = 64-71 | year = 2000 | pmid = 10696120 | doi = | issn = | url = http://www.thorne.com/altmedrev/.fulltext/5/1/64.pdf }}</ref><ref name="pmid11869656">{{cite journal | author = Shaw K, Turner J, Del Mar C | title = Tryptophan and 5-hydroxytryptophan for depression | journal = Cochrane database of systematic reviews (Online) | volume = | issue = 1 | pages = CD003198 | year = 2002 | pmid = 11869656 | doi = 10.1002/14651858.CD003198 | issn = }}</ref>
   
Though it is indisputable that Showa Denko KK did produce and sell a contaminated batch of L-tryptophan, there are some concerns that the FDA's handling of this accident unfairly favoured the pharmaceutical industry and the new antidepressant Prozac if only because of its curiously fortuitous timing. The March 22, 1990 ban on public sale of L-tryptophan came only four days before the media announcement of Prozac on March 26, 1990 in Newsweek magazine [http://www.youngagain.com/enemies.html]. Both L-tryptophan and Prozac affect serotonin in the brain, though in different ways, and were promising in the treatment of depression. At the time of the ban the FDA did not know, or did not indicate, that EMS was caused by a contaminated batch [http://www.fda.gov/bbs/topics/NEWS/NEW00064.html], and yet even when the contamination was discovered and the 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:
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===Metabolites===
: ''"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."'' [http://vm.cfsan.fda.gov/~dms/ds-tryp1.html].
 
   
In recent years, 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 [[psychiatrist]]s continue to prescribe, particularly as an augmenting agent for people who are unresponsive to antidepressant drugs. Also, most health-food stores sell a cheap [[metabolite]] of tryptophan called [[5-HTP]] to get around the ban and the resulting artificially high cost of the amino acid itself. Indeed, tryptophan has continued to be used in clinical and experimental studies employing human patients and subjects. Several of these studies suggest tryptophan can effectively treat the fall/winter depression variant of [[seasonal affective disorder]] (SAD).
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[[5-Hydroxytryptophan]] (5-HTP), a metabolite of tryptophan, has been suggested as a treatment for [[epilepsy]]<ref name="Kostowski_1978">{{cite journal |author=Kostowski W, Bidzinski A, Hauptmann M, Malinowski JE, Jerlicz M, Dymecki J|title=Brain serotonin and epileptic seizures in mice: a pharmacological and biochemical study|journal= Pol J Pharmacol Pharm |volume= 30 |issue= 1 |pages= 41-7 |year= 1978 |pmid= 148040}}</ref> and [[Clinical depression|depression]], although clinical trials are regarded inconclusive and lacking.<ref name="Turner_2006">{{cite journal |author=Turner EH, Loftis JM, Blackwell AD|title=Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan|journal= Pharmacol Ther |volume= 109 |issue= 3 |pages= 325-38 |year= 2006 |pmid= 16023217}}</ref>
   
===Tryptophan and turkey===
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5-HTP readily crosses the [[blood-brain barrier]] and in addition is rapidly decarboxylated to [[serotonin]] (5-hydroxytryptamine or 5-HT)<ref name="Hardebo_1980">{{cite journal |author=Hardebo JE, Owman C|title=Barrier mechanisms for neurotransmitter monoamines and their precursors at the blood-brain interface|journal= Ann NeurolAnn Neurol |volume= 8 |issue= 1 |pages= 1-31 |year= 1980 |pmid= 6105837}}</ref> 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]], and therefore is likely to have limited efficacy. It is marketed in Europe for depression and other indications under the brand names Cincofarm and Tript-OH.
Contrary to popular belief, tryptophan in turkey meat does not cause drowsiness [http://physorg.com/news8453.html]. Turkey does contain tryptophan, which does have a documented sleep-inducing effect. However, tryptophan is effective only when taken on its own as a free [[amino acid]]. Tryptophan in turkey is found as part of a protein, and, in small enough amounts, this mechanism seems unlikely [http://www.snopes.com/food/ingredient/turkey.asp].
 
   
A more-likely hypothesis is that the ingestion of large quantities of food, such as at a Thanksgiving feast, means that large quantities of both [[carbohydrate]]s and [[branched-chain amino acids]] are consumed. Like carbohydrates, branched-chain amino acids require [[insulin]] to be [[transducer|transduced]] through the [[myocyte]] membranes, which, after a large meal, creates a competition among the amino acids and glucose for insulin, while simultaneously creating tryptophan's reduced competition with other amino acids for the [[Large Neutral Amino Acid Transporter]] protein for transduction across the [[blood-brain barrier]]. The result is a greater availability of tryptophan, via the Large Neutral Amino Acid Transporter, for conversion into serotonin by the [[raphe nuclei]], which is then available for conversion into melatonin by the [[pineal gland]]. Drowsiness is the outcome.
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In the United States, 5-HTP does not require a prescription, as it is covered under the [[Dietary Supplement Health and Education Act|Dietary Supplement Act]]. However, since the quality of dietary supplements is 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.
   
==Medicinal uses==
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=== Tryptophan supplements and EMS ===
  +
Although currently available for purchase, in 1989 a large outbreak (1500 cases of permanent disability including at least 37 deaths) of a disabling [[autoimmune]] illness called [[eosinophilia-myalgia syndrome]] (EMS) was traced by some epidemiological studies<ref name="pmid2355442">{{cite journal | author = Slutsker L, Hoesly FC, Miller L, Williams LP, Watson JC, Fleming DW | title = Eosinophilia-myalgia syndrome associated with exposure to tryptophan from a single manufacturer | journal = JAMA | volume = 264 | issue = 2 | pages = 213-7 | year = 1990 | pmid = 2355442 | doi = | issn = }}</ref><ref name="pmid8496862">{{cite journal | author = Back EE, Henning KJ, Kallenbach LR, Brix KA, Gunn RA, Melius JM | title = Risk factors for developing eosinophilia myalgia syndrome among L-tryptophan users in New York | journal = J. Rheumatol. | volume = 20 | issue = 4 | pages = 666-72 | year = 1993 | pmid = 8496862 | doi = | issn = }}</ref><ref name="pmid8895184">{{cite journal | author = Kilbourne EM, Philen RM, Kamb ML, Falk H | title = Tryptophan produced by Showa Denko and epidemic eosinophilia-myalgia syndrome | journal = The Journal of rheumatology. Supplement | volume = 46 | issue = | pages = 81-8; discussion 89-91 | year = 1996 | pmid = 8895184 | doi = | issn = }}</ref> to L-tryptophan supplied by a Japanese manufacturer, [[Showa Denko]] KK.<ref name= FDA_Tryptophan_Info >[http://vm.cfsan.fda.gov/~dms/ds-tryp1.html FDA Information Paper on L-tryptophan and 5-hydroxy-L-tryptophan]</ref> It was further hypothesized that one or more trace impurities produced during the manufacture of tryptophan may have been responsible for the EMS outbreak.<ref name="pmid2270484">{{cite journal | author = Mayeno AN, Lin F, Foote CS, Loegering DA, Ames MM, Hedberg CW, Gleich GJ | title = Characterization of "peak E," a novel amino acid associated with eosinophilia-myalgia syndrome | journal = Science | volume = 250 | issue = 4988 | pages = 1707-8 | year = 1990 | pmid = 2270484 | doi = 10.1126/science.2270484 | issn = }}</ref><ref name="pmid1544609">{{cite journal | author = Ito J, Hosaki Y, Torigoe Y, Sakimoto K | title = Identification of substances formed by decomposition of peak E substance in tryptophan | journal = Food Chem. Toxicol. | volume = 30 | issue = 1 | pages = 71-81 | year = 1992 | pmid = 1544609 | doi = 10.1016/0278-6915(92)90139-C | issn = }}</ref> 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.<ref name="pmid8895181">{{cite journal | author = Shapiro S | title = Epidemiologic studies of the association of L-tryptophan with the eosinophilia-myalgia syndrome: a critique | journal = The Journal of rheumatology. Supplement | volume = 46 | issue = | pages = 44-58; discussion 58-9 | year = 1996 | pmid = 8895181 | doi = | issn = }}</ref><ref name="pmid8895182">{{cite journal | author = Horwitz RI, Daniels SR | title = Bias or biology: evaluating the epidemiologic studies of L-tryptophan and the eosinophilia-myalgia syndrome | journal = The Journal of rheumatology. Supplement | volume = 46 | issue = | pages = 60-72 | year = 1996 | pmid = 8895182 | doi = | issn = }}</ref> 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.<ref name="pmid16307217">{{cite journal | author = Smith MJ, Garrett RH | title = A heretofore undisclosed crux of eosinophilia-myalgia syndrome: compromised histamine degradation | journal = Inflamm. Res. | volume = 54 | issue = 11 | pages = 435-50 | year = 2005 | pmid = 16307217 | doi = 10.1007/s00011-005-1380-7 | issn = }}</ref>
   
[[5-Hydroxytryptophan]] (5-HTP), a metabolite of tryptophan, has been suggested as a treatment for epilepsy<ref name="Kostowski_1978">{{cite journal |author=Kostowski W, Bidzinski A, Hauptmann M, Malinowski JE, Jerlicz M, Dymecki J|title=Brain serotonin and epileptic seizures in mice: a pharmacological and biochemical study|journal= Pol J Pharmacol Pharm |volume= 30 |issue= 1 |pages= 41-7 |year= 1978 |pmid= 148040}}</ref> and depression though clinical trials are inconclusive and lacking.<ref name="Turner_2006">{{cite journal |author=Turner EH, Loftis JM, Blackwell AD|title=Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan|journal= Pharmacol Ther |volume= 109 |issue= 3 |pages= 325-38 |year= 2006 |pmid= 16023217}}</ref>
+
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."<ref name="Beisler_2000">{{cite journal |author= Beisler JH|title=Dietary Supplements and Their Discontents: FDA Regulation and the Dietary Supplement Health and Education Act of 1994 (L-tryptophan Section)|journal= Rutgers Law Journal |volume= |issue= |pages= |year= 2000 |url = http://www.seedsofdeception.com/utility/showArticle/?objectID=263/}}</ref>
   
5-HTP readily crosses the blood brain barrier and in addition is rapidly decarboxylated to [[serotonin]] (5-hydroxytryptamine or 5-HT)<ref name="Hardebo_1980">{{cite journal |author=Hardebo JE, Owman C|title=Barrier mechanisms for neurotransmitter monoamines and their precursors at the blood-brain interface|journal= Ann NeurolAnn Neurol |volume= 8 |issue= 1 |pages= 1-31 |year= 1980 |pmid= 6105837}}</ref> and therefore may 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.
+
At the time of the ban, the FDA did not know, or did not indicate, that EMS was caused by a contaminated batch,<ref name= FDA_Tryptophan_Recall >[http://www.fda.gov/bbs/topics/NEWS/NEW00064.html FDA Tryptophan Recall]</ref><ref>{{cite journal |author= Raphals P|title=Does medical mystery threaten biotech?|journal= Science |volume= 250 |issue= |pages= 4981 |year= 2000 |pmid = 2237411 | doi = 10.1126/science.2237411}}</ref> 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."''<ref name= FDA_Tryptophan_Info />
   
In the United States, 5-HTP does not require a prescription as it is covered under the [[Dietary Supplement Health and Education Act|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.{{Fact|date=February 2007}}
+
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, compounding [[pharmacy|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 [[psychiatrist]]s continue to prescribe, particularly as an augmenting agent for people who are unresponsive to antidepressant drugs.{{Fact|date=February 2007}} Also, most health-food stores sell 5-HTP to get around the resulting artificially high cost of the amino acid itself. But 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. Several of these studies suggest tryptophan can effectively treat the fall/winter depression variant of [[seasonal affective disorder]].<ref name="Jepson_1999">{{cite journal |author=Jepson TL, Ernst ME, Kelly MW|title=Current perspectives on the management of seasonal affective disorder|journal= J Am Pharm Assoc (Wash) |volume= 39 |issue= 6 |pages= 822-9 |year= 1999 |pmid= 10609448}}</ref>
+
In recent years in the U.S., compounding [[pharmacy|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 [[psychiatrist]]s continue to prescribe, particularly as an augmenting agent for people who are unresponsive to antidepressant drugs.{{Fact|date=February 2007}}
   
  +
===Turkey meat and drowsiness===
  +
One widely-held belief is that heavy consumption of [[turkey (bird)|turkey]] meat (as for example in a Thanksgiving feast) results in drowsiness, which has been attributed to high levels of tryptophan contained in turkey.<ref name = "Helmenstine">{{cite web|title=About.com: Does Eating Turkey Make You Sleepy? | url=http://chemistry.about.com/od/holidaysseasons/a/tiredturkey.htm | accessdate = 2007-08-17}}</ref><ref name = "howstuffworks">{{cite web|title=Howstuffworks.com: Is there something in turkey that makes you sleepy? | url=http://home.howstuffworks.com/question519.htm | accessdate = 2007-08-17}}</ref><ref name = "McCue">{{cite web|title=Chemistry.org: Thanksgiving, Turkey, and Tryptophan | url=http://www.chemistry.org/portal/a/c/s/1/feature_ent.html?DOC=enthusiasts%5Cent_tryptophan.html | accessdate = 2007-08-17}}</ref> While turkey does contain high levels of tryptophan, the amount is comparable to that contained in most other meats.<ref name = "USDA" /> Furthermore, postprandial Thanksgiving [[sedation]] may have more to do with what is consumed along with the turkey, in particular [[carbohydrate]]s, rather than the turkey itself.
   
  +
It has been demonstrated in both animal models<ref name="pmid5120086">{{cite journal | author = Fernstrom JD, Wurtman RJ | title = Brain serotonin content: increase following ingestion of carbohydrate diet | journal = Science | volume = 174 | issue = 13 | pages = 1023-5 | year = 1971 | pmid = 5120086 | doi = 10.1126/science.174.4013.1023 | issn = }}</ref> and in humans<ref name="pmid3279747">{{cite journal | author = Lyons PM, Truswell AS | title = Serotonin precursor influenced by type of carbohydrate meal in healthy adults | journal = Am. J. Clin. Nutr. | volume = 47 | issue = 3 | pages = 433-9 | year = 1988 | pmid = 3279747 | doi = | issn = | url = http://www.ajcn.org/cgi/reprint/47/3/433.pdf}}</ref><ref name="pmid12499331">{{cite journal | author = Wurtman RJ, Wurtman JJ, Regan MM, McDermott JM, Tsay RH, Breu JJ | title = Effects of normal meals rich in carbohydrates or proteins on plasma tryptophan and tyrosine ratios | journal = Am. J. Clin. Nutr. | volume = 77 | issue = 1 | pages = 128-32 | year = 2003 | pmid = 12499331 | doi = | issn = | url = http://www.ajcn.org/cgi/content/abstract/77/1/128}}</ref><ref name="pmid17284739">{{cite journal | author = Afaghi A, O'Connor H, Chow CM | title = High-glycemic-index carbohydrate meals shorten sleep onset | journal = Am. J. Clin. Nutr. | volume = 85 | issue = 2 | pages = 426-30 | year = 2007 | pmid = 17284739 | doi = | issn = |url = http://www.ajcn.org/cgi/content/full/85/2/426}}</ref> 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).<ref name="pmid1148286">{{cite journal | author = Pardridge WM, Oldendorf WH | title = Kinetic analysis of blood-brain barrier transport of amino acids | journal = Biochim. Biophys. Acta | volume = 401 | issue = 1 | pages = 128-36 | year = 1975 | pmid = 1148286 | doi = 10.1016/0005-2736(75)90347-8 | issn = }}</ref><ref name="pmid6538743">{{cite journal | author = Maher TJ, Glaeser BS, Wurtman RJ | title = 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 | journal = Am. J. Clin. Nutr. | volume = 39 | issue = 5 | pages = 722-9 | year = 1984 | pmid = 6538743 | doi = | issn = }}</ref> Once inside the CNS, tryptophan is converted into [[serotonin]] in the [[raphe nuclei]] by the normal enzymatic pathway.<ref name="pmid5120086" /><ref name="pmid12499331" /> The resultant serotonin is further metabolised into [[melatonin]] by the [[pineal gland]].<ref name="pmid4391290" /> Hence, these data suggest that "feast-induced drowsiness," and in particular, 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.<ref name="pmid5120086" /><ref name="pmid3279747" /><ref name="pmid12499331" /><ref name="pmid17284739" />
   
-----
 
   
==See also==
 
* [[5-hydroxytryptophan]]
 
* [[Tryptamines]]
 
   
==References & Bibliography==
+
==References==
<References/>
+
{{reflist|2}}
==Key texts==
 
===Books===
 
   
===Papers===
+
== See also ==
  +
* [[5-Hydroxytryptophan]]
  +
* [[Serotonin]]
  +
* [[5-HTP]]
  +
* [[Tryptamines]]
  +
* [[Tetrophan]]
   
==Additional material==
+
== External links ==
===Books===
+
*[http://www.genome.jp/dbget-bin/www_bget?path:hsa00380 Tryptophan metabolism]
 
===Papers===
 
*[http://scholar.google.com/scholar?sourceid=mozclient&num=50&scoring=d&ie=utf-8&oe=utf-8&q=Depression+women Google Scholar]
 
 
==External links==
 
 
*[http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/AminoAcid/TrpCat1.html Tryptophan catabolism (early stages)]
 
*[http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/AminoAcid/TrpCat1.html Tryptophan catabolism (early stages)]
 
*[http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/AminoAcid/TrpCat2.html Tryptophan catabolism (later stages)]
 
*[http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/AminoAcid/TrpCat2.html Tryptophan catabolism (later stages)]
Line 107: Line 106:
 
*[http://www.ceri.com/trypto.htm The FDA Ban of L-Tryptophan: Politics, Profits and Prozac]
 
*[http://www.ceri.com/trypto.htm The FDA Ban of L-Tryptophan: Politics, Profits and Prozac]
 
*[http://www.nature.com/npp/journal/v31/n5/full/1300932a.html Effects of Tryptophan Depletion on the Performance of an Iterated Prisoner's Dilemma Game in Healthy Adults] - Nature Neuropsychopharmacology
 
*[http://www.nature.com/npp/journal/v31/n5/full/1300932a.html Effects of Tryptophan Depletion on the Performance of an Iterated Prisoner's Dilemma Game in Healthy Adults] - Nature Neuropsychopharmacology
* {{McGrawHillAnimation|genetics|Tryptophan%20Repressor}}
+
{{ChemicalSources}}
 
 
{{AminoAcids}}
 
{{AminoAcids}}
 
{{Tryptamines}}
 
{{Tryptamines}}
   
[[Category:Proteinogenic amino acids]]
+
[[Category:Amino acids]]
[[Category:Glucogenic amino acids]]
+
[[Category:Serotonin precursors]
[[Category:Ketogenic amino acids]]
 
[[Category:Aromatic amino acids]]
 
[[Category:Essential amino acids]]
 
 
[[Category:Tryptamines]]
 
[[Category:Tryptamines]]
 
[[Category:Natural tryptamine alkaloids]]
 
[[Category:Natural tryptamine alkaloids]]
[[Category:Serotonin]]
 
   
 
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  +
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-->
 
-->
 
 
 
 
 
{{Psych-stub}}
 
{{enWP|Tryptophan}}
 
 
== See also ==
 
* [[5-HTP]] (5-Hydroxytryptophan)
 
* [[Tryptamines]]
 
 
== External links ==
 
*[http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/AminoAcid/trytophan.html Tryptophan biosynthesis]
 
*[http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/AminoAcid/TrpCat1.html Tryptophan catabolism (early stages)]
 
*[http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/AminoAcid/TrpCat2.html Tryptophan catabolism (later stages)]
 
*[http://www.compchemwiki.org/index.php?title=Tryptophan Computational Chemistry Wiki]
 
* [http://www.chemistry.org/portal/a/c/s/1/feature_ent.html?DOC=enthusiasts%5Cent_tryptophan.html Thanksgiving, Turkey, and Tryptophan]
 
* [http://www.cfsan.fda.gov/~dms/ds-tryp1.html FDA Information Paper on L-tryptophan and 5-hydroxy-L-tryptophan]
 
* [http://www.snopes.com/food/ingredient/turkey.asp Snopes article debunking the turkey–drowsiness connection]
 
 
{{Tryptamines}}
 
{{AminoAcids}}
 
 
[[Category:Tryptamines]]
 
 
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[[zh:色氨酸]]
 
 
{{enWP|Tryptophan}}
 
{{enWP|Tryptophan}}

Latest revision as of 08:15, January 13, 2008

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Tryptophan
Systematic name (S)-2-Amino-3-(1H-indol-3-yl)-propanoic acid
Abbreviations Trp
W
Chemical formula C11H12N2O2
Molecular mass 204.23 g mol−1
Melting point 289 °C
Density  ? g cm-3
Isoelectric point 5.89
pKa 2.38
9.34
CAS number [73-22-3]
EINECS number 200-795-6
SMILES N/A
L-TryptophanTryptophan3d
Disclaimer and references

Tryptophan (abbreviated as Trp or W)[1] is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in genetic code as the codon UGG. Only the L-stereoisomer of tryptophan is used in structural or enzyme proteins, but the D-stereoisomer is occasionally found in naturally produced peptides (for example, the marine venom peptide contryphan).[2] The distinguishing structural characteristic of tryptophan is that it contains an indole functional group.

IsolationEdit

The isolation of tryptophan was first reported by Sir Frederick Hopkins in 1901 [3] through hydrolysis of casein. From 600 grams of crude casein one obtains 4-8 grams of tryptophan.[4]

Biosynthesis and industrial production Edit

Plants and microorganisms commonly synthesize tryptophan from shikimic acid or anthranilate.[5] 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 E. coli. The conversion is catalyzed by the enzyme tryptophan synthase.[6]

FunctionEdit

File:Tryptophan metabolism.png

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 principal function of amino acids including tryptophan are 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[11] and depression.[12]

In bacteria that synthesize tryptophan, high cellular levels of this amino acid activate a repressor protein, which binds to the trp operon. [How to reference and link to summary or text] 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 organization of the trp operon thus permits tightly regulated and rapid responses to changes in the cell's internal and external tryptophan levels.

Dietary sourcesEdit

Tryptophan is a routine constituent of most protein-based foods or dietary proteins. It is particularly plentiful in chocolate, oats, bananas, mangoes, dried dates, milk, yogurt, cottage cheese, red meat, eggs, fish, poultry, sesame, chickpeas, sunflower seeds, pumpkin seeds, spirulina, and peanuts.[13] It is also found in turkey at a level typical of poultry in general.[14]

Tryptophan (Trp) Content of Various Foods[14][15]</center>
Food Protein
[g/100 g of food]
Tryptophan
[g/100 g of food]
Tryptophan/Protein [%]
turkey
21.89
0.24
1.11
cheese, cheddar
24.90
0.32
1.29
chicken
20.85
0.24
1.14
beef
20.13
0.23
1.12
lamb, chop
18.33
0.21
1.17
pork, chop
19.27
0.25
1.27
salmon
19.84
0.22
1.12
perch, Atlantic
18.62
0.21
1.12
milk
3.22
0.08
2.34
egg
12.58
0.17
1.33
wheat flour, white
10.33
0.13
1.23
potatoes, russet
2.14
0.02
0.84
rice, white
7.13
0.08
1.16

Use as a dietary supplementEdit

For some time, tryptophan was available in health food stores as a dietary supplement, although it is common in dietary protein. 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)[16] and/or melatonin (a sleep-inducing hormone secreted by the pineal gland in response to darkness or low light levels).[17][18]

Clinical research tends to confirm tryptophan's effectiveness as a sleep aid[19][20][21] and for a growing variety of other conditions typically associated with low serotonin levels or activity in the brain[22] such as premenstrual dysphoric disorder [23] and seasonal affective disorder.[24][25] In particular, tryptophan has been showing considerable promise as an antidepressant alone,[26] and as an "augmenter" of antidepressant drugs.[26][27] However others have questioned the reliability of these clinical trials.[28][29]

MetabolitesEdit

5-Hydroxytryptophan (5-HTP), a metabolite of tryptophan, has been suggested as a treatment for epilepsy[30] and depression, although clinical trials are regarded inconclusive and lacking.[31]

5-HTP readily crosses the blood-brain barrier and in addition is rapidly decarboxylated to serotonin (5-hydroxytryptamine or 5-HT)[32] 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, and therefore is likely to have limited efficacy. It 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. However, since the quality of dietary supplements is 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.

Tryptophan supplements and EMS Edit

Although currently available for purchase, in 1989 a large outbreak (1500 cases of permanent disability including at least 37 deaths) of a disabling autoimmune illness called eosinophilia-myalgia syndrome (EMS) was traced by some epidemiological studies[33][34][35] to L-tryptophan supplied by a Japanese manufacturer, Showa Denko KK.[36] It was further hypothesized that one or more trace impurities produced during the manufacture of tryptophan may have been responsible for the EMS outbreak.[37][38] 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.[39][40] 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.[41]

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."[42]

At the time of the ban, the FDA did not know, or did not indicate, that EMS was caused by a contaminated batch,[43][44] 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."[36]

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.[How to reference and link to summary or text]

Turkey meat and drowsinessEdit

One widely-held belief is that heavy consumption of turkey meat (as for example in a Thanksgiving feast) results in drowsiness, which has been attributed to high levels of tryptophan contained in turkey.[45][46][47] While turkey does contain high levels of tryptophan, the amount is comparable to that contained in most other meats.[14] Furthermore, postprandial Thanksgiving sedation may have more to do with what is consumed along with the turkey, in particular carbohydrates, rather than the turkey itself.

It has been demonstrated in both animal models[48] and in 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 (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).[52][53] Once inside the CNS, 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.[9] Hence, these data suggest that "feast-induced drowsiness," and in particular, 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.[48][49][50][51]


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[[Category:Serotonin precursors]
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