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Tryptophan is an amino acid essential 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, however the D-stereoisomer is occasionally found in natural materials (for example, the marine venom peptide contryphan.[1] A distinquishing structural characteristic of tryptophan is that it contains an indole functional group. </p><br />
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 serotonin (a neurotransmitter), melatonin (a neurohormone), and niacin.
In organisms which 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 which codes for 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.
Tryptophan, found as a component of dietary protein, is particularly plentiful[2] 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 [2].
For some time, tryptophan was available in health food stores as a dietary supplement. Since 2002, L-Tryptophan has been sold again in its original form. 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).[3]
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. (Particularly work by Dr. Richard Wurtman at MIT). In particular, tryptophan showed considerable promise as an antidepressant alone, and as an "augmenter" of antidepressant drugs. Other promising indications included relief of chronic pain and reduction of impulsive, violent, manic, addictive, anxiety-related, obsessive, and compulsive behaviours and disorders.
In 1989, a large outbreak of a new, disabling, and in some cases deadly autoimmune illness called eosinophilia-myalgia syndrome (EMS) was traced to one source of L-tryptophan. The bacterial culture used to synthesize tryptophan by a major Japanese manufacturer, Showa Denko KK, had been genetically modified several times to increase tryptophan production during the 1980s.[4]
Along with the higher tryptophan concentrations in the modified culture media, the purification process had also been streamlined to reduce costs, and a purification step that used charcoal absorption to remove some impurities had been omitted.[5] The manufacturer maintained that this process modification allowed another bacterial metabolite through the purification, resulting in the presence of an end-product contaminant responsible for the toxic effects. As of 1996, Showa Denko had destroyed all modified organisms without FDA receipt of culture samples.[6][7] The FDA was unable to publicly establish with certainty what contaminant was the cause of the outbreak.
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.”[8]
At the time of the ban the FDA did not know, or did not indicate, that EMS was caused by a contaminated batch,[9][10] 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."[11]
According to popular belief, eating tryptophan in turkey meat causes drowsiness. Turkey does contain tryptophan, which does have a documented sleep-inducing effect as it is readily converted into serotonin by the body. However, ingestion of turkey alone has not been proven to have this effect. An additional hypothetical mechanism is as follows: A large quantity of any food, such as a Thanksgiving feast, introduces large quantities of both carbohydrates and branched-chain amino acids releasing insulin. Insulin stimulates the uptake of large neutral branched-chain amino acids (and not tryptophan) by muscle cells through the myocyte membranes. The result is an increase in the ratio of tryptophan to large neutral amino acids in the blood. This 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. Once inside the central nervous system, tryptophan is converted into serotonin by the raphe nuclei, and serotonin is further metabolised into melatonin by the pineal gland.
Alcoholic beverage consumption at holiday feasts is likely to compound the effect.
5-Hydroxytryptophan (5-HTP), a metabolite of tryptophan, has been suggested as a treatment for epilepsy[12] and depression though clinical trials are inconclusive and lacking.[13]
5-HTP readily crosses the blood brain barrier and in addition is rapidly decarboxylated to serotonin (5-hydroxytryptamine or 5-HT)[14] 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.
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.
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 psychiatrists continue to prescribe, particularly as an augmenting agent for people who are unresponsive to antidepressant drugs. 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 (SAD).
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.[15] Hence protein fluorescence may be used as a diagnostic of the conformational state a protein.[16]
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. Hence tryptophan fluorescence is may be a very sensitive measurement of the conformational state of individual tryptophan residues.