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PubMed2007

Crystal structure and mechanism of tryptophan 2,3-dioxygenase, a heme enzyme involved in tryptophan catabolism and in quinolinate biosynthesis.

The structure of tryptophan 2,3-dioxygenase (TDO) from Ralstonia metallidurans was determined at 2.4 A. TDO catalyzes the irreversible oxidation of l-tryptophan to N-formyl kynurenine, which is the initial step in tryptophan catabolism. TDO is a heme-containing enzyme and is highly specific for its substrate l-tryptophan. The structure is a tetramer with a heme cofactor bound at each active site. The monomeric fold, as well as the heme binding site, is similar to that of the large domain of indoleamine 2,3-dioxygenase, an enzyme that catalyzes the same reaction except with a broader substrate tolerance. Modeling of the putative (S)-tryptophan hydroperoxide intermediate into the active site, as well as substrate analogue and mutagenesis studies, are consistent with a Criegee mechanism for the reaction.

Binding Sites↗

PubMed1987

Inhibition of rat liver tryptophan pyrrolase activity and elevation of brain tryptophan concentration by administration of DL-alpha-amino-beta-pyridinepropanoic acid (pyridylalanine) analogs.

Single doses of DL-alpha-amino-beta-(2-pyridine)propanoic acid (2-PA, 100 mg/kg) significantly decreased the holoenzyme and apoenzyme activities of rat liver tryptophan pyrrolase (TP) and increased brain tryptophan, serotonin (5-HT) and 5-hydroxyindole-3-ylacetic acid concentrations. 2-PA had no inhibitory effect on either of the enzyme activities in vitro, but its expected metabolites were effective. Single doses of DL-alpha-amino-beta-(3-pyridine)propanoic acid (3-PA, 100 mg/kg) decreased only the holoenzyme activity and elevated brain tryptophan and its metabolites levels in rats. 3-PA and its metabolite, 3-pyridylpyruvate, inhibited only the holoenzyme activity in vitro. DL-alpha-Amino-beta-(4-pyridine)propanoic acid (4-PA) caused significant changes in liver TP (holo- and apoenzyme forms) activity and brain tryptophan concentration only after repeated administration (100 mg/kg/day). 4-PA was a weak inhibitor of the holoenzyme, but its metabolites apparently inhibited the holo- and apoenzyme activities in vitro. These findings suggest that PA analogs (and/or their metabolites) increased brain tryptophan (and hence 5-HT synthesis) by directly inhibiting liver TP activity.

Alanine↗

PubMed1982

The differences in growth and activity of the tryptophan-NAD pathway between Wistar and Sprague Dawley strains of rats fed on tryptophan-limited diet.

Three-week-old weanling rats of Wistar and Sprague Dawley strains were fed on tryptophan-limited and nicotinic acid-free diets for 46 days and the following was observed. (1) Gain in body weight of the Sprague Dawley strain was significantly higher than that of the Wistar strain from the 10th day of feeding. (2) Tryptophan oxygenase [EC 1.13.11.11]activity in the Wistar strain was constant but was significantly increased in the Sprague Dawley strain during the latter period of this experiment. (3) The total amount of nicotinic acid, quinolinic acid, N1-methylnicotinamide and tryptophan in liver and kidney of the Sprague Dawley strain was significantly higher than that of the Wistar strain. (4) Total urinary nicotinic acid, quinolinic acid and N1-methylnicotinamide levels were not very different between the two strains, but it was observed that at the 38th day the levels in the Sprague Dawley strain were significantly higher than those in the Wistar strain. From the above result, it was presumed that the Sprague Dawley strain of rat was more resistant to deficiency of nicotinic acid than the Wistar strain fed on a low tryptophan and nicotinic acid-free diet. Aminocarboxymuconate-semialdehyde decarboxylase [EC 4.1.1.45] activities in livers of both strains dropped to half the original value at the end of the experiment. This change may indicate metabolic control of increase in flow from tryptophan to NAD.

Animals↗

PubMedDate not supplied

Effects of two different loading doses of L-tryptophan on the urinary excretion of tryptophan metabolites in rats, mice and guinea pigs. Correlation with the enzyme activities.

The effect of two different loading doses of L-tryptophan (0.5 and 1.0 g/Kg b.w.) on excretion of tryptophan metabolites and the relation to the enzyme activities were studied in rats, mice and guinea pigs. In rats there is no ratio between the dosage used and the levels of the metabolites excreted. Doubling the amount of tryptophan administered, a 5-fold increase in the elimination of the metabolites along the kynurenine pathway is obtained. The 1.0 g/Kg load provides a more complete pattern of the metabolites than with the 0.5 g/Kg b.w. load. Kynurenic acid, kynurenine and xanthurenic acid are the chief metabolites excreted. In mice, the urinary excretion of the metabolites is very low with both loads. In guinea pigs, xanthurenic acid is excreted in the highest amount and kynurenic acid and kynurenine also constitute the large fractions with both loadings. The load of 0.5 g/Kg b.w. is preferable to that of 1.0 g/Kg b.w. for not causing B6-deficiency. Liver tryptophan pyrrolase exists in two forms in rats, while in mice and in guinea pigs it is present only as holoenzyme. This enzyme is more active in rats than in the other two species of animals. Kynureninase activity is lower in guinea pigs, but it apparently correlated to the low levels of excretion of the metabolites following this step. Kynurenine aminotransferase is very active in rats and in mice, while it is apparently depressed in guinea pigs, in contrast with the high excretion of xanthurenic and kynurenic acids, that puts in evidence a B6-deficiency. The excretion of tryptophan metabolites and enzyme activities are better correlated in rats.

Animals↗

PubMed1985

Differential inhibition of tryptophan synthase and of tryptophanase by the two diastereoisomers of 2,3-dihydro-L-tryptophan. Implications for the stereochemistry of the reaction intermediates.

Oxindolyl-L-alanine and 2,3-dihydro-L-tryptophan, which are analogs of a proposed reaction intermediate, are potent competitive inhibitors of both tryptophanase and the alpha 2 beta 2 complex of tryptophan synthase (Phillips, R. S., Miles, E. W., and Cohen, L. A. (1984) Biochemistry 23, 6228-6234). Since these inhibitors can exist in two diastereoisomeric forms, which we expected to differ in inhibitory potency, we have separated the diastereoisomers of 2,3-dihydro-L-tryptophan by preparative high performance liquid chromatography. These diastereoisomers were designated "A" and "B" in order of elution from the high performance liquid chromatography column. Diastereoisomer B is a potent competitive inhibitor of the alpha 2 beta 2 complex of tryptophan synthase with KI = 6 microM at pH 7.8 and 25 degrees C. In contrast, diastereoisomer A is a weak competitive inhibitor, with KI = 940 microM under these conditions. With tryptophanase, the situation is reversed; diastereoisomer A is a potent slow-binding competitive inhibitor of tryptophanase with KI = 2 microM at pH 8.0 and 25 degrees C, while diastereoisomer B is much weaker with KI = 1600 microM under these conditions. These results not only provide additional support for the proposal that the indolenine tautomer of tryptophan is an intermediate in the reactions catalyzed by both enzymes but also suggest that these enzymes catalyze their respective reactions via enantiomeric indolenine intermediates.

Chromatography, High Pressure Liquid↗

PubMed1985

[Tryptophan of facultative methylotrophic bacteria Pseudomonas sp. M. II. Regulation of tryptophan biosynthesis].

Regulation of tryptophan biosynthesis of facultative methylotrophic Pseudomonas sp. M was studied. Repression of the trpE, trpD and trpC genes by tryptophan was demonstrated. It was also shown that the trpE and trpDC genes are derepressed noncoordinately. No regulation of the trpF gene product could be demonstrated, indicating that its synthesis is constitutive. The trpA and trpB genes are inducible by indol-3-glycerophosphate. Anthranilate synthase and tryptophan synthase were sensitive to the feedback inhibition. The tryptophan concentrations giving 50% inhibition were estimated to be 9 microM and 1 microM, respectively. Experimental evidence for activation of the N-5-phosphoribosyl anthranilate isomerase and for inhibition of the indol-3-glycerophosphate synthase by some tryptophan intermediates was obtained.

Anthranilate Synthase↗

PubMed1992

Brain kinetics of 11 C-labelled L-tryptophan and 5-hydroxy-L-tryptophan in the rhesus monkey. A study using positron emission tomography.

5-Hydroxy-L-tryptophan labelled with 11 C is introduced as a tracer for the in vivo assessment of brain serotonin synthesis in the Rhesus monkey using positron emission tomography, PET. Increasing radioactivities were seen in the striatal area in contrast to that seen in other brain regions. Following 11 C-labelled L-tryptophan an even spread of brain radioactivity was seen. This selective increase most probably results from the decarboxylation of tracer and retention of formed products since no striatal increase of radioactivity was seen when 5-hydroxy-L-tryptophan labelled with 11 C in the carboxy-position was administered. Furthermore, pretreatment of the monkey with a centrally active decarboxylase inhibitor (NSD 1015, 10 mg/kg) did not lead to increased striatal radioactivities after the administration of 5-hydroxy-(beta-11 C)-L-tryptophan. The selective utilization of the radiotracer in the striatal area increased with a rate constant calculated to be 0.0055 +/- 0.0015 min-1 (n = 5) using the surrounding brain as reference area. A non-significant influence of radiolabelled metabolites to the rate constants measured was shown after pretreatment of the monkeys with selective and non-selective monoamine oxidase inhibitors, respectively. These results may give a basis for the use of the new tracer 5-hydroxy-(beta-11 C)-L-tryptophan in PET-studies of brain serotonin metabolism in health and disease.

5-Hydroxytryptophan↗

PubMedDate not supplied

Effects of age on serum tryptophan and urine indican in adults given a tryptophan load test.

An oral load of L-tryptophan (490 mumol/kg) was administered to 25 men and 25 women between the ages of 30 and 80 years. Blood samples were drawn before the load and at 2-h intervals for 6 h after the load. Urine samples were collected for 5 days. Fasting serum tryptophan levels averaged 79.5 mumol/l (+/- 12.9 s.d.). Peak serum tryptophan levels (911-1002 mumol/l) occurred 2 h after the load. Urinary indican excretion on the day of the load averaged 6.4 mumol/24h/kg of body weight (+/- 2.8 s.d.). The concentration of tryptophan in serum, the amount of indican excreted in urine, and the indican:creatinine ratio in urine depended on the age of the subjects. The findings are discussed in relation to previous reports on effects of age on tryptophan pharmacokinetics.

Adult↗

PubMed1992

Selective photochemical modification by trichloroethanol of tryptophan residues in proteins with a high tyrosine-to-tryptophan ratio.

We present an improved procedure for the selective modification of tryptophan residues in proteins. A simple, low-cost set-up allows rapid tryptophan photoreaction upon ultraviolet irradiation in the presence of 2,2,2-trichloroethanol. This photochemical reaction is carried out under native conditions, occurs only in the excited state of tryptophan, and yields a single, as yet unidentified, photoproduct. Except for tyrosine, no reaction with other amino acid side chains are known. Stringent photoselection of tryptophan, ensuring that tyrosine residues are not affected, is achieved in situ without the need for an elaborate system of optical filters or lenses. Illumination with a medium-wave uv lamp of samples placed in disposable, dual pathlength, polystyrene fluorescence cuvettes allows treatment of small sample volumes (greater than or equal to 100 microliters) of various optical density. Chromophore accessibility in oligomeric assemblies or protein-nucleic acid complexes can be assessed by this reaction since the integrity of these structures is preserved. Moreover, this technique can be used to evaluate the involvement of tryptophan residues in catalytic or ligand binding processes.

Animals↗

PubMed1999

Tryptophan metabolism in pregnant sheep: increased fetal kynurenine production in response to maternal tryptophan loading.

OBJECTIVE: The effects of a tryptophan load on the plasma concentration of kynurenine, the precursor for the production in the brain of the neuroactive products kynurenic acid and quinolinic acid, were determined in pregnant sheep at midgestation and late gestation and in nonpregnant sheep. STUDY DESIGN: Pregnant ewes were given an intravenous infusion of 100 mg/kg L-tryptophan during 2 hours at 95 to 98 days' gestation (n = 4) or 135 to 138 days' gestation (n = 10). Nonpregnant ewes (n = 6) were studied in late estrus. Arterial blood samples taken from 2 hours before to 48 hours after the start of the infusion were used for analysis of plasma tryptophan, kynurenine, and cortisol concentrations. RESULTS: Tryptophan loading at both gestational ages resulted in significantly greater increases in kynurenine concentrations in fetal plasma (at 95-98 days' gestation, from 5.7 +/- 1.2 micromol/L [baseline] to 247.9 +/- 86.7 micromol/L (peak); at 135-138 days' gestation, from 9.0 +/- 2.3 micromol/L [baseline] to 289.0 +/- 194.0 micromol/L [peak]) than in maternal plasma [at 95-98 days' gestation, from 4.6 +/- 0.8 micromol/L [baseline] to 118.0 +/- 79.7 micromol/L [peak]; at 135-138 days' gestation, from 4.8 +/- 2.9 micromol/L [baseline] to 98.3 +/- 67.8 micromol/L [peak]). It took longer for kynurenine concentrations to return to basal values in the fetus (24-30 hours) than in the ewe (8-12 hours). The kynurenine responses in pregnant and nonpregnant ewes were not different from each other. CONCLUSION: The production of kynurenine from tryptophan is significantly greater in the fetal lamb than in the pregnant or nonpregnant adult ewe.

Animals↗

PubMed2000

Tryptophan depletion and risk of depression relapse: a prospective study of tryptophan depletion as a potential predictor of depressive episodes.

BACKGROUND: This study investigated the relationship between depressive symptom response during tryptophan depletion and future depressive episodes. METHODS: Twelve subjects with prior major depressive episodes in remission and medication-free for > or =3 months (patients), and 12 matched healthy (control) subjects received two tryptophan depletion tests 1 week apart. During follow-up the Hamilton Depression Rating Scale was administered weekly for 1 month, monthly for 3 months, and once at 6 and 12 months. RESULTS: With results from both tests, tryptophan depletion has a sensitivity of 78%, specificity of 80%, positive predictive value of 70%, and negative predictive value of 86% to identify future depressive episodes. Survival analysis shows that mood response to tryptophan depletion reliably predicts major depressive episodes during the follow-up year (r =.2725, p =.014). CONCLUSIONS: Tryptophan depletion may be clinically useful in identifying individuals at risk for future major depressive episodes.

Adult↗

PubMed2001

Decomposition of protein tryptophan fluorescence spectra into log-normal components. II. The statistical proof of discreteness of tryptophan classes in proteins.

The physical causes for wide variation of Stokes shift values in emission spectra of tryptophan fluorophores in proteins have been proposed in the model of discrete states (Burstein, E. A., N. S. Vedenkina, and M. N. Ivkova. 1973. Photochem. Photobiol. 18:263-279; Burstein, E. A. 1977a. Intrinsic Protein Luminescence (The Nature and Application). In Advances in Science and Technology (Itogi Nauki i Tekhniki), Biophysics Vol. 7. VINITI, Moscow [In Russian]; Burstein, E. A. 1983. Molecular Biology (Moscow) 17:455-467 [In Russian; English translation]). It was assumed that the existence of the five most probable spectral classes of emitting tryptophan residues and differences among the classes were analyzed in terms of various combinations of specific and universal interactions of excited fluorophores with their environment. The development of stable algorithms of decomposition of tryptophan fluorescence spectra into log-normal components gave us an opportunity to apply two mathematically different algorithms, SImple fitting with Mean-Square criterion (SIMS) and PHase-plot-based REsolving with Quenchers (PHREQ) for the decomposition of a representative set of emission spectra of proteins. Here we present the results of decomposition of tryptophan emission spectra of >100 different proteins, some in various structural states (native and denatured, in complexes with ions or organic ligands, in various pH-induced conformations, etc.). Analysis of the histograms of occurrence of >300 spectral log-normal components with various maximum positions confirmed the statistical discreteness of several states of emitting tryptophan fluorophores in proteins.

Algorithms↗

PubMed1984

The influence of starvation and tryptophan administration on the metabolism of phenylalanine, tyrosine and tryptophan in isolated rat liver cells.

Liver cells from fed Sprague-Dawley rats metabolized phenylalanine, tyrosine and tryptophan at rates consistent with the known kinetic properties of the first enzymes of each pathway. Starvation of rats for 48 h did not increase the maximal activities of phenylalanine hydroxylase, tryptophan 2,3-dioxygenase and tyrosine aminotransferase in liver cell extracts, when results were expressed in terms of cellular DNA. Catabolic flux through the first two enzymes was unchanged; that through the aminotransferase was elevated relatively to enzyme activity. This is interpreted in terms of changes in the concentrations of 2-oxoglutarate and glutamate. Cells from tryptophan-treated animals exhibited significant increases in the catabolism of tyrosine and tryptophan, but not of phenylalanine. The activities of tyrosine aminotransferase and tryptophan 2,3-dioxygenase were also increased, although the changes in flux and enzyme activity did not correspond exactly. These results are discussed with reference to the control of aromatic amino acid catabolism in liver; the role of substrate concentration is emphasized.

Amino Acids↗

PubMed1981

Effect of L-tryptophan injection in rats on some enzymes of amino acid metabolism in liver. I. In vitro studies of the effect of L-tryptophan and its metabolites on the extramitochondrial L-alanine: 2-ketoglutaric aminotransferase.

Fed and fasted rats were injected with L-tryptophan (12.5 mg/100 g body weight) and the specific activities of L-glutamic: NAD oxidoreductase (deaminating) (EC 1.4.1.2) (GDH), L-aspartic-2-ketoglutaric aminotransferase (EC 2.6.1.1) (GOT) and L-alanine-2-ketoglutaric aminotransferase (EC 2.6.1.2) (GPT) from hepatic mitochondria and cytosol were compared. L-tryptophan results in a decrease of mitochondrial GDH activity by 22% and of cytosolic GPT and GOT by 42% and 38% respectively in the liver of fasted rats. Xanthurenate is a potent inhibitor of purified extramitochondrial GPT, whereas anthranilate and quinolinate are less potent inhibitors. L-tryptophan, 5-OH-tryptophan and indole exert a slight inhibition. Kynurenine, 5-OH-tryptamine, tryptamine, picolinic acid, nicotinic acid and indoloacetic acid do not show any inhibition of GPT. It is suggested that L-tryptophan injection inhibits extramitochondrial GPT by its transformation to xanthurenate and anthranilate.

Alanine Transaminase↗

PubMed1985

Stability of tryptophan during food processing and storage. 2. A comparison of methods used for the measurement of tryptophan losses in processed foods.

Tryptophan losses in stored milk powders and in different model systems representing the major reactions of food proteins during processing and storage were determined using four different chemical methods and in a rat assay. Similar tryptophan values were obtained by the three chemical methods which included high pressure liquid chromatography (HPLC) after sodium hydroxide hydrolysis, colorimetric reaction with p-dimethylamino-benzaldehyde (p-DAB) after barium hydroxide hydrolysis, and fluorescence of the Norharman derivative after NaOH hydrolysis. Tryptophan losses in the treated proteins as measured by the alkaline-hydrolysis methods were generally smaller than those determined by the rat assay. Good agreement however was obtained when the chemical value was multiplied by the true nitrogen digestibility. Determination of tryptophan by reaction with p-DAB after papain (EC 3.4.22.2) digestion gave lower values in the processed proteins than the other chemical methods or the rat assay. A method using alkaline-hydrolysis is recommended, preferably combined with HPLC-measurement of the liberated tryptophan.

Animals↗

PubMed1978

Tryptophan residues of saccharifying alpha-amylase from Bacillus subtilis. A kinetic discrimination of states of tryptophan residues using N-bromosuccinimide.

Four tryptophan residues of saccharifying alpha-amylase from B. subtilis out of eleven in total are reactive towards N-bromosuccinimide (NBS), suggesting that they are on the surface of the enzyme. This is consistent with the results of solvent perturbation difference spectrophotometry with ethylene glycol. One of four tryptophan residues was clearly distinguished from the other three in reactivity with NBS by the stopped-flow method. This most reactive tryptophan residue was not protected from modification by substrates of analogs, indicating that the tryptophan is not located in the substrate binding site. One of the other three tryptophan residues, probably the second most reactive one, is considered to be related in some way to the glycosyl transfer in the reaction of the enzyme with maltose as a substrate.

Amylases↗

PubMed1973

Tryptophan metabolism and kynureninase induction in mutants of Neurospora crassa resistant to 4-methyl-tryptophan.

Mutants of Neurospora crassa that are resistant to 4-methyl-tryptophan were found to differ in ability to synthesize kynureninase in the presence of the inducers kynurenine, 3-OH-kynurenine, N-formyl-kynurenine, tryptophan, and indole. One strain (mtr26), although incapable of accumulating intracellular pools of these compounds, showed induced synthesis of kynureninase, whereas the second (mtr21) could neither accumulate nor be induced by them. Strain mtr21, with the suppressor su(mtr), could not be induced by indole but was induced by tryptophan and kynurenine derivatives. These results suggest that the mtr mutation, in addition to altering the ability of these strains to concentrate tryptophan and its metabolites, may have some effect on either the intracellular distribution of tryptophan or directly on the synthesis of kynureninase.

Biological Transport, Active↗

PubMed2001

Effects of dietary pyrazinamide, an antituberculosis agent, on the metabolism of tryptophan to niacin and of tryptophan to serotonin in rats.

The effects of pyrazinamide on the metabolism of tryptophan to niacin and of tryptophan to serotonin were investigated to elucidate the mechanism for pyrazinamide action against tuberculosis. Weanling rats were fed with a diet with or without 0.25% pyrazinamide for 61 days. Urine samples were periodically collected for measuring the tryptophan metabolites. The administration of pyrazinamide significantly increased the metabolites, 3-hydroxyanthranilic acid and beyond, especially quinolinic acid, nicotinamide, N'-methylnicotinamide, and N1-methyl-4-pyridone-3-carboxamide, and therefore significantly increased the conversion ratio of tryptophan to niacin and the blood NAD level . However, no difference in the upper metabolites of the tryptophan to niacin pathway such as anthranilic acid, kynurenic acid and xanthurenic acid was apparent between the two groups. No difference in the concentrations of trytptophan and serotonin in the blood were apparent either. It is suggested from these results that the action of pyrazinamide against tuberculosis is linked to the increase in turnover of NAD and to the increased content of NAD in the host cells.

Animals↗