Tryptophan

Tryptophan is an amino acid required by all forms of life for protein synthesis and other important metabolic functions (Moffett and Namboodiri, 2003) and accounts for the major fluorophore contributing to protein in tissue.

From: Biophotonics for Medical Applications , 2015

Tryptophan

Wendy Marsh , in xPharm: The Comprehensive Pharmacology Reference, 2007

Tryptophan; alpha amino 3 indolepropionic acid; alphaaminoindole 3 propionic acid; 2 amino 3 indolepropionic acid; 2 amino 3indolylpropanoic acid; amiphan; ardeydorm; ardeytropin; beta 3indolylalanine; biotonin; dextro levo tryptophan; dextrolevotryptophan; dltryptophan; dorphan; eltrip; kalma; l alpha amino 3 indolepropionic acid; lalpha aminoindole 3 propionic acid; l beta 3 indolylalanine; levo tryptophan; levotryptophan; levo tryptophane; l tryptophan; l tryptophane; pacitron; somnidor; triptum; trofan; tryptacin; tryptan; trypto; tryptocal; tryptocalm; 1 tryptophan; tryptophanate; tryptophane; tryptophan residue; tryptophanylgroup; tryptophanyl residue; tryptophyl residue; 2 amino 3 indolylpropanoic acid; alpha aminoindole 3 propionic acid; beta 3 indolylalanine; dl tryptophan; l alpha aminoindole 3 propionic acid; tryptophanyl group

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Tryptophan

In Meyler's Side Effects of Drugs (Sixteenth Edition), 2016

General information

Tryptophan is a naturally-occurring essential amino acid, which has been advocated as an innocuous health food for the treatment of depression, insomnia, stress, behavioral disorders, and premenstrual syndrome. The availability of amino acids in health food stores and a contemporary interest in natural remedies led to reported widespread use of tryptophan to treat depression. It was estimated in 1976 that up to that time several hundred patients with affective disorders had been studied, with results reported in at least 21 papers [ 1]. However, the results of clinical trials with l-tryptophan in the treatment of depressive disorders are inconsistent [2,3].

It has been suggested that there may be some benefit of using tryptophan in selected patients, particularly those with psychomotor retardation [4]. Unfortunately, most of these reports have appeared as letters to the editors of journals [5–7] or as preliminary communications [8]. In addition to the possible absence of any consistent effect, there are many plausible reasons to explain the variability in response. Tryptophan has been given in both the racemic and monomeric (levorotatory) forms, both alone and together with a number of substances intended to increase the synthesis or availability of serotonin, including monoamine oxidase (MAO) inhibitors [9], potassium or carbohydrate supplements [10], and co-enzymes such as pyridoxine or ascorbic acid [11]. It has also been suggested that tryptophan plasma concentrations have a therapeutic window [5], and that repeated administration induces hepatic tryptophan pyrrolase, resulting in lowered plasma concentrations and loss of therapeutic effect after 2 weeks of treatment [9]. Attempts have been made to ameliorate this problem by co-administration of nicotinamide [5].

In addition to the difficulty of interpreting possible benefits due to tryptophan, there is a paucity of information on adverse reactions. This may be partly accounted for by the assumed safety of a natural substance, but it is also contributed to by the preliminary nature of many communications. In at least two studies [6,8], in which tryptophan was compared with a tricyclic antidepressant, inquiry about adverse reactions was deliberately avoided, in order to protect the double-blind integrity of the study. Two studies have reported the lack of any consistent or definite changes in hematological values, serum electrolytes, plasma proteins, or liver function tests after 4 weeks of treatment with l-tryptophan up to 8   g/day [8,11]. Nausea early in treatment [12], light-headedness, which does not appear to be related to postural hypotension [13], and deterioration in mental status [14,15] have been reported. Hypomania on combining tryptophan with a MAO inhibitor has been reported [15] and adverse reactions, including muscle tremor, hypomanic mood, hyper-reflexia, and bilateral Babinski signs, were seen in a patient taking phenelzine and tryptophan.

Although L-tryptophan was withdrawn in many countries, in 1994 it became available again in the UK for combination treatment of patients with long-standing refractory depression, on the strict condition that it should only be prescribed by hospital specialists for patients with long-standing resistant depression [16]. It is also still in use in other countries, such as Germany and Canada, but not in the USA.

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Tryptophan

Martin Kohlmeier , in Nutrient Metabolism, 2003

Transport and cellular uptake

Blood circulation: The plasma concentration of Trp (typically around 50 μmol/l) decreases in response to low dietary intake (Kaye et al., 2000). Uptake from blood into uses various transporters, including system T (TAT1), LAT1, and LAT2, whose expression patterns vary considerably between specific tissues.

Blood-brain barrier: The sodium-independent transporter TAT1 and the glycoprotein-anchored complex LAT1 are expressed in brain capillary endothelial cells and certainly contribute to Trp transport, but their relative importance, location, and the role of other transporters is not completely understood. Trp competes with the branched-chain amino acids (valine, leucine, isoleucine) and other large neutral amino acids (methionine, tyrosine, tryptophan, and histidine) for the transport into brain. This may mean that increased blood concentrations of phenylalanine (especially in patients with phenylketonuria, an inborn error of metabolism with defective phenylalanine utilization) or branched-chain amino acids (due to a high-carbohydrate diet) limit Trp availability in brain.

Materno-fetal transfer: The exchanger LAT1 appears to be the major route for Trp travelling from maternal blood into the syncytiotrophoblast (Ritchie and Taylor, 2001). Transfer across the basolateral membrane may proceed predominantly via LAT1 and LAT2 (Ritchie and Taylor, 2001); a contribution by TAT1, which is strongly expressed in placenta (Kim et al., 2001), has been disputed (Ritchie and Taylor, 2001).

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Sleep

George M. Kapalka , in Nutritional and Herbal Therapies for Children and Adolescents, 2010

Adverse Effects

Tryptophan is usually well tolerated, although some patients may exhibit daytime drowsiness, dizziness, and dry mouth. At higher doses, additional problems with nausea, lack of appetite, and headaches may become evident ( Medical Economics, 2007). Because tryptophan is a sedative, concurrent use of other compounds that exert similar effects (for example, alcohol) should be avoided.

Tryptophan is associated with a small risk of cardiac dysfunctions. Because tryptophan is converted into serotonin in the brain as well as peripherally, increases in serotonin may become evident in tissues and muscles, including the heart. For this reason, some recommend that tryptophan supplements should only be taken with carbidopa, which blocks the conversion of tryptophan into serotonin until it crosses the blood–brain barrier (Xu et al., 2002).

Tryptophan needs to be used cautiously with patients who have been diagnosed with diabetes or exhibit family history of diabetes. One of tryptophan's metabolites, xanthurenic acid, has been found to have a diabetogenic effect in animals. Although no cases in humans have been reported, caution should be exercised.

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Amino acids: Metabolism

P.W. Emery , in Encyclopedia of Human Nutrition (Third Edition), 2013

Tryptophan

Tryptophan is oxidized by the hormone-sensitive enzyme tryptophan oxygenase to N-formyl kynurenine, which then follows a series of steps to yield amino-carboxymuconic semialdehyde. Most of this undergoes enzymic decarboxylation, leading ultimately to acetyl CoA. However, a small proportion undergoes nonenzymatic cyclization to quinolic acid, which leads to the formation of NAD. This is why excess dietary tryptophan can meet the requirement for the vitamin niacin (see Figure 9).

Figure 9. Metabolism of tryptophan.

One of the steps in the catabolism of tryptophan is catalyzed by the vitamin B6-dependent enzyme kynureninase. If vitamin B6 status is inadequate and a large dose of tryptophan is administered much of the tryptophan will be metabolized by an alternative pathway to kynurenic and xanthurenic acids, which will be excreted in the urine. This is the basis of the tryptophan load test for vitamin B6 status.

A small amount of tryptophan undergoes hydroxylation to 5-hydroxytryptophan, which is then decarboxylated to the physiologically active amine 5-hydroxytryptamine (serotonin).

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Substances Involved in Neurotransmission

George M. Kapalka , in Nutritional and Herbal Therapies for Children and Adolescents, 2010

Tryptophan

Tryptophan is also one of the 20 standard amino acids present in the body and used by cells to synthesize proteins. This is an essential amino acid, meaning that it is only ingested from diet. Tryptophan is found in a wide variety of protein-containing foods, including eggs, cheese, meat (especially turkey), fish, wheat, rice, potatoes, and bananas. Since tryptophan must be ingested in food, the WHO has set a typical recommended daily intake for tryptophan at 4  mg/kg of body weight (WHO, 2007).

When food is ingested that contains tryptophan, the molecule is extracted during metabolic processes that take place in the small intestine, and absorbed into circulation. There, it travels through the body, crosses the blood–brain barrier, and enters neurons, where it gets metabolized into indolamine neurotransmitters, as well as niacin. Because the body does not produce tryptophan, it has limited abilities to regulate the amount of tryptophan in cells. When too much tryptophan is ingested, it is broken down through various metabolic processes, and can sometimes be retroconverted if needed. However, when limited amounts are ingested, tryptophan deficiency may be apparent, resulting in suppressed amounts of serotonin, melatonin, niacin, and other important molecules. Depression and sleep disorders may partially be caused by limited amounts of tryptophan in the body.

For this reason, supplementation with tryptophan has been attempted, and was popular until the late 1980s, when over 30 deaths were caused by contaminated batches of tryptophan. The supplement was then banned in the United States (and many other countries), but, more recently, it was revealed that problems in manufacture were responsible for these deaths and the supplement is potentially safe. Consequently, sales of tryptophan as a supplement were allowed to resume in 2001, and the FDA ban on tryptophan supplement importation was lifted in 2005.

Clinicians are advised to carefully consider whether supplementation with tryptophan is indicated. First, the WHO recommendations about dietary intake should be observed. In cases where it is apparent that the dietary intake falls significantly below recommended levels, supplementation may be attempted. Otherwise, supplementation with tryptophan may be helpful in addressing sleep problems (as discussed in Chapter 9), and supplementation with 5-HTP, a transformed form of tryptophan, may be effective in treating symptoms of depression (discussed in Chapter 6) and anxiety (covered in Chapter 8).

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AMINO ACIDS | Determination

A.P. Williams , in Encyclopedia of Food Sciences and Nutrition (Second Edition), 2003

Tryptophan

Tryptophan is also present in low concentrations and extensively degraded during acid hydrolysis. However, there is no measurable end product, and so it is normal to use alkaline hydrolysis specifically for tryptophan analysis. Sodium, barium, or lithium hydroxides may be used at concentrations ranging from 4 to 6  M, with additives such as maltodextrin, starch, or thiodigycol often recommended to reduce tryptophan losses. Hydrolysis may be for 8   h at 145   °C or 20   h at 110   °C using polypropylene vessels. Ideally, the tryptophan should be separated from interfering compounds, e.g., lysinoalanine (LAL) by IEC or RPC. The latter takes only a few minutes, and precolumn derivatization is unnecessary, since tryptophan can be detected by its native fluorescence.

Tryptophan has also been estimated by acid hydrolysis of intact proteins in the presence of ninhydrin with which it reacts before it can be degraded. Corrections must be made for tyrosine.

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Valerian and Other CAM Botanicals in Treatment of Sleep Disturbances

Diana M. Taibi , Carol A. Landis , in Complementary and Alternative Therapies and the Aging Population, 2009

l-tryptophan and 5-HTP

l -tryptophan is an essential amino acid that may be taken as a supplement or consumed in dietary protein both from animal and plant sources. l-tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), the immediate precursor of serotonin, have been used for improving sleep because serotonin is known to have multiple functions in the regulation of wake and sleep states [128]. Because serotonin is a precursor of melatonin, sleep promotion through l-tryptophan administration may also result from increased melatonin levels. Whereas the conversion of l-tryptophan to serotonin is limited by the availability of the metabolizing enzyme tryptophan hydroxylase and protein transporters that are shared with other amino acids, 5-HTP conversion is not limited by these factors and may be more efficiently converted to serotonin [129], although more research is needed on the clinical effects of this difference.

Early studies on l-tryptophan generally used small samples and produced mixed results. Some research showed that l-tryptophan or 5-HTP supplementation reduced sleep latency [129]. Additionally, some evidence suggests that consumption on foods rich in l-tryptophan along with carbohydrates (which promotes l-tryptophan uptake) also reduces sleep latency [130], and CBT strategies include a bedtime snack with foods high in this amino acid. After the occurrence of a 1989 epidemic of the life-threatening condition eosinophilia-myalgia syndrome (EMS) associated with l-tryptophan, research on l-tryptophan for sleep ceased, and only recently have investigators begun to study its effects on sleep. One double-blind, placebo controlled RCT showed improvement in self-reported total sleep time, sleep efficiency, total wake time, and sleep quality with both pharmaceutical grade l-tryptophan and specifically formulated l-tryptophan/carbohydrate food bars [131]. Another study showed that REM sleep suppression caused by use of a serotonin-reuptake inhibiting antidepressant was reversed by concurrent l-tryptophan supplementation [132]. At present, insufficient evidence exists to determine the clinical efficacy of l-tryptophan and 5-HTP for sleep disturbance.

Safety concerns regarding l-tryptophan were raised in 1989 following an epidemic of EMS that resulted in at least 37 reported deaths [133]. In most cases, EMS was linked to a contaminated product from Japan, but individual susceptibility could not be excluded as a contributing factor. The US Food and Drug Administration (FDA) issued an advisory and banned the sale of most tryptophan products. Only recently has marketing of l-tryptophan been allowed in the United States again, but an advisory remains in effect and restrictions remain on imported l-tryptophan products [133]. Other than the rare but serious risk of EMS, l-tryptophan and 5-HTP supplements have few reported side effects and are not associated with residual sedation. Nausea is a common side effect of l-tryptophan doses above 5   mg [103].Although some evidence suggests that concurrent use of serotonin precursors (l-tryptophan or 5-HTP) with antidepressants may be beneficial, such use should be avoided until more is known about potential product interactions due to risk of serotonin syndrome, a dangerous condition associated with hyperthermia, hyperreflexia, and risk of death.

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Eosinophilia–Myalgia Syndrome

J.A. Allen , J Varga , in Encyclopedia of Toxicology (Third Edition), 2014

Prevalence and Reasons for l-Tryptophan Usage

l- Tryptophan usage was widespread in the United States in 1989. In Oregon and Minnesota, approximately 2% of surveyed household members used tryptophan at some time between 1980 and 1989. The most common reasons for tryptophan use were insomnia, premenstrual syndrome, and depression; other reasons included anxiety, headaches, behavioral disorders, obesity, and smoking cessation. Although most consumers purchased tryptophan for therapeutic use, it was marketed as a food supplement and widely available in the United States without a prescription. This product was not approved or regulated by the FDA.

l-Tryptophan is an essential amino acid; however, sufficient quantities are present in the diet of most North Americans without the need for supplements. The typical daily US diet contains 1–3   g of tryptophan, which satisfies the recommended daily dose of 3   mg   kg−1 body weight (or 210   mg (70   kg)−1 individual). It is metabolized to serotonin and therefore theoretically might have sedative and antidepressant properties.

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Chemical bases and biological relevance of protein oxidation

Oren Tirosh , Abraham Z. Reznick , in Handbook of Oxidants and Antioxidants in Exercise, 2000

1.2 Tryptophan oxidation

Tryptophan has a unique chemical structure, the tryptophenyl residue has no similarity to any other amino acid and therefore its function cannot be replaced by any other amino acid by site-directed mutagenesis [ 5]. However, tryptophan residues can be easily altered by oxidation. The indole residue in tryptophan can undergo oxidation by several pathways. The end result as well as the oxidative products distribution, depends on the oxidizing species and the conditions under which the reaction was performed.

Oxidation of proteins by ozone is one way to achieve high yield of tryptophan oxidation without damaging other amino acids [5–7]. The main oxidation product of tryptophan by ozone is cleavage of the pyrrole ring which results in formation of. N'-formylkynurenine (NFK) which is also a metabolite of tryptophan, Freezing and thawing of NFK in acidified solution converts it to kynurenine (Fig. 1). Circular dichroic and fluorescence spectra of γ-immunoglobulin light chains, ribonuclease, and hen egg-white lysozyme treated by ozone for tryptophan oxidation, demonstrated that the tertiary structure of protein is maintained. However, the slight modification of even a single tryptophan residue produced a large decrease in the stability of these proteins when treated with guanidine hydrochloride and heat [5]. Stability studies have shown that the lower the mobility or solvent accessibility of tryptophan residue, the greater is the extent of the decrease in the stability upon modification [8]. Studies of the changes in stability of Staphylococcus nuclease with amino acid substitutions of a buried hydrophobic residue with a bulkier and more polar residue showed that the enthalpy and the entropy changes for thermal unfolding of the protein are both larger, and that the free energy change is smaller for the mutant protein compared with values for the wild protein. These findings may be explained by a greater disruption of interchain interactions in the unfolded state of the mutant protein. The same explanation can be valid for the oxidative modification of tryptophans [9].

Fig. 1. Oxidation pathways of tryptophan, N'-formylkynurenine (NFK), kynurenine (kyn).

Hydroxyl radical, which is the most potent oxidant in biology, can trigger two types of reaction: hydroxylation (especially on aromatic rings), and hydrogen abstraction (especially with electron donors) [1]. The complex chemical integrity of tryptophan makes it subject to both type of reaction cited above [10, 11]. Pulse radiolysis experiments have shown that hydroxyl radicals react with tryptophan to form two kinds of species [11]: a hydroxycyclohexadienyl radical or hydroxyl radical adduct, and a tryptophenyl radical in equilibrium with its cation radicals (Fig. 1). Radiolysis of a nitrous oxide-saturated, unbuffered tryptophan solution at neutral pH produces six primary products: 4-OHtrp, 5-OHtrp, 6-OHtrp, 7-OHtrp, NFK, and oxindole-3-alanine. Also a yellow polymeric product is formed, as result of radical-radical interactions. The main product during γ-radiation of tryptophan solutions saturated with nitrous oxide is a yellow product with a maximum absorbance at 425 nm. This is a product of dimerization and polymerization of the hydroxyl-radical-tryptophan-adduct intermediate which is also a radical [11]. In this situation, the yield of stable hydroxylation products is very low (4%) [11]. However, in the presence of iron the radical intermediate can undergo a disproportional reaction that generate back the tryptophan molecule and a stable hydroxylation adduct. The maximum yield achieved at high concentrations of Fe(III)-ethylenediaminetetraacetic acid (EDTA) (0.5 mM) is 27 hydroxylation products for every 100 hydroxyl radicals [11].

The second type of products that originate as a result of hydrogen abstraction, specially from the pyrrole ring, provide the tryptophenyl radical itself as an intermediate. Further oxidation, spontaneous or enhanced, in the presence of dioxan facilitates the transformation of ring cleavage rearrangement and the formation of NFK.

Treatment of peptides containing tryptophans as well as N-teri-butyloxycarbonyl (BOC)-l-tryptophan with superoxide in the presence of iron-EDTA or H2O2/horseradish peroxidase selectively transform tryptophan into NFK, and oxygenation of the pyrrole ring of the indole nucleus (3-(3-oxindolyl) propionic acid) without any formation of hydroxylation products [12]. This suggests that in these systems hydroxyl radical was not involved and that higher valent iron oxygen complexes served as the oxidizing species. Thus, iron oxygen species may play a central role in tryptophan oxidation. When tryptophan reacts with oxidants generated by Fenton reaction (reduce iron and hydrogen peroxide) or Udenfriend reaction (vitamin C, oxidized metal, and oxygen), NFK is predominantly produced and the yield of hydroxylation product is low. This product distribution may also indicate a lower involvement of hydroxyl radicals or higher scavenging of hydroxyl radicals by the vitamin C which is used in the Udenfriend reaction [11].

An interesting aspect of tryptophan oxidation by metal ions such as Cu+2 is the possible ability of intermediate tryptophan radicals to initiate lipid peroxidation. This type of chemistry (Fig. 1) which include, tryptophan oxidation in the formation of a tryptophan radical, and in the presence of oxygen, formation of trypto-phanperoxy radical can initiate lipid peroxidation chain reaction [13, 14]. In low density lipoprotein (LDL) five tryptophan residues are lost within few minutes of exposure to copper. This implies that LDL oxidation is initiated through oxidative modification of proteins rather than that of lipids [13, 14].

Another powerful oxidant that possesses a significant biological relevancy is peroxynitrite. This oxidizing species can be formed by the combination of superoxide and NO• radical in biological systems. Alternatively peroxynitrite can be prepared synthetically by reaction between hydrogen peroxide and nitrite. Hydrogen peroxide by itself cannot induce tryptophan oxidation. The mechanism by which peroxynitrite degrades tryptophan residues remain obscure. Using (Boc)-tryptophan (trp) as a model for tryptophan oxidation in proteins and by reverse phase-HPLC, NMR and FAB/MS analysis it has been identified that peroxynitrite does not cause nitration of tryptophan residues. Another explanation for the lack of nitration is that the nitration products were not identified by HPLC [15]. The oxidized product that were identified were Boc-NFK, Boc-oxindole, and Boc-hydropyrroloindole (Fig. 1). Using different techniques such as liquid chromatography-MS other groups have reported that peroxynitrite can induce tryptophan nitration [16, 17].

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