Plants and microorganisms commonly synthesize tryptophan from shikimic acid or anthranilate. 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.
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):
In bacteria that synthesize tryptophan, high cellular levels of this amino acid activate a repressor protein, which binds to the trp operon. 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.
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. 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. The safety of these medications has not been well studied. 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.
There is evidence that blood tryptophan levels are unlikely to be altered by changing the diet, but tryptophan is available in health food stores as a dietary supplement. Consuming purified tryptophan increases brain serotonin whereas eating foods containing tryptophan does not. 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. High plasma levels of other large neutral amino acids prevent the plasma concentration of tryptophan from increasing brain concentration levels.
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.
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.
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.
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.
Subsequent epidemiological studies 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. 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. Against this backdrop, the FDA rescinded its restriction on sales and marketing of tryptophan in February 2001, but continued to ban importation.
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." 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.
Tryptophan affects brain serotonin synthesis when given orally in a purified form and is used to modify serotonin levels for research in psychology. Low brain serotonin is induced by administration of tryptophan-poor protein in a technique called 'acute tryptophan depletion'. Studies using this method have evaluated the effect of serotonin on mood and social behavior, finding that serotonin reduces aggression and increases agreeableness.
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.
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