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PubMed1983

[Effect of para-chlorophenylalanine and 5-hydroxytryptophan on the tryptophan content of the blood serum and its ability to stimulate tryptophan capture by the cells].

Intraperitoneal injection of parachlorphenylalanine to guinea-pigs leads to an increase in the blood tryptophan content and a reduction of blood serum activity that determines tryptophan cell uptake. Administration of 5-hydroxytryptophan brings about opposing changes in the parameters indicated. The presence of a reverse correlation between variations of tryptophan content and blood serum activity responsible for tryptophan cell uptake, which occur under the effect of substances that change the rate of serotonin synthesis indicates that these factors belong to the united system controlling tryptophan metabolism.

5-Hydroxytryptophan↗
PubMed1971

The Conversion of d-Tryptophan to l-Tryptophan in Cell Cultures of Tobacco.

d-Tryptophan was converted to l-tryptophan in tissue cultures of tobacco, in whole cells treated with dimethylsulfoxide, and in cell-free extracts treated by Sephadex G-25 filtration. Evidence was obtained that tryptophanase, tryptophan pyrrolase, and transaminase activities were not involved. The data were best explained by the presence of a tryptophan racemase as the enzyme catalyzing the reaction. The possible role of d-tryptophan in the biosynthesis of indoleacetic acid is discussed.

Journal Article↗
PubMed1984

Activation of liver tryptophan oxygenase by hydrocortisone, hematin and tryptophan in streptozotocin-diabetic rats.

This study compared changes in liver tryptophan oxygenase (TPO) activity in response to hydrocortisone, hematin and tryptophan administration to non-diabetic and diabetic (streptozotocin) rats. Hydrocortisone caused similar increases in apoenzyme (inactive), holoenzyme (heme-saturated) and total (holoenzyme + apoenzyme) TPO activities in non-diabetic and diabetic rats. The ability of hematin to increase total TPO activity was significantly less in diabetic rats. The largest differences between diabetic and non-diabetic rats were found with tryptophan which increased total TPO and holoenzyme activities 300% and 650% respectively in non-diabetic rats. However, tryptophan increased both apoenzyme (unchanged in non-diabetic rats) and holoenzyme activities by 300% in diabetic rats. These results indicate that in the diabetic state, the TPO-heme conjugation process is impaired, especially substrate mediated TPO-heme saturation.

Animals↗
PubMed1986

Spectroscopic and equilibrium properties of the indoleamine 2,3-dioxygenase-tryptophan-O2 ternary complex and of analogous enzyme derivatives. Tryptophan binding to ferrous enzyme adducts with dioxygen, nitric oxide, and carbon monoxide.

The dioxygen adduct of the heme protein indoleamine 2,3-dioxygenase has been generated at -30 degrees C in mixed solvents, and spectroscopic and equilibrium studies of its L-tryptophan (substrate) binding properties have been carried out for the first time. Comparative studies have also been performed with the NO and CO adducts of the ferrous enzyme. Under the conditions employed (-30 degrees C), both autoxidation and turnover (L-tryptophan + O2----formylkynurenine) of the ternary complex are effectively suppressed. Structural identification of the ternary complex is based on the 1:1 molar stoichiometry for the substrate-oxygenated enzyme adduct formation (Kd approximately 10(-4) M), the time-dependent linear product formation (turnover) at -20 degrees C, and the quantitative conversion of the complex to the ferrous CO derivative by bubbling with CO. Binding of L-tryptophan to the oxygenated enzyme leads to decreases in the intensities of its major absorption bands (lambda max 415, 541, 576 nm) and to a blue shift of its Soret peak. Interestingly, among the ferrous enzyme derivatives examined, only the substrate-bound oxygenated enzyme exhibits solvent-dependent Soret absorption peak positions, e.g., lambda max 411.5 and 413.5 nm in 65% (v/v) aqueous glycerol and ethylene glycol, respectively. In addition, indole binds to the oxygenated enzyme, causing a red shift of its Soret peak in these solvents only in the presence of substrate (411.5----414 nm and 413.5----414.5 nm, respectively), while similar effects of indole are independent of tryptophan for the other ferrous enzyme derivatives.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1973

Effect of high- and low-protein diets on the regulation of rat liver tyrosine aminotransferase and tryptophan oxygenase activities by L-tyrosine and L-tryptophan.

Induction of rat liver tyrosine aminotransferase by l-tyrosine and tryptophan oxygenase by l-tryptophan was studied in groups of rats fed on diets containing 18 or 5% protein. The basal activity of hepatic tyrosine aminotransferase of rats receiving 5% protein gradually increased with the age of the animals but that of rats receiving 18% protein did not. l-Tyrosine induced hepatic tyrosine aminotransferase in rats receiving 18% protein when tested at ages from 4 to 20 weeks. When induction by l-tyrosine was carried out in rats receiving the 5% protein diet, significant induction of tyrosine aminotransferase occurred only in 4- or 6-week-old rats. Induction by l-tryptophan of tryptophan oxygenase in liver or the basal activity of this enzyme in liver did not differ between the groups fed on 5 and 18% protein. On changing the diet from 0 to 18% protein, the above-mentioned effects on the induction of hepatic tyrosine aminotransferase were reversed.

Animals↗
PubMed1976

Animal liver tryptophan pyrrolases: Absence of apoenzyme and of hormonal induction mechanism from species sensitive to tryptophan toxicity.

1. Liver tryptophan pyrrolase exists as holoenzyme and apoenzyme in rat, mouse, pig, turkey, chicken and possibly man. 2. The apoenzyme is absent from cat, frog, gerbil, guinea pig, hamster, ox, sheep and rabbit. 3. The hormonal mechanism of induction of the pyrrolase is absent from species lacking the apoenzyme. 4. The concentrations of tryptophan in livers and sera of these species are lower than in species possessing the apoenzyme. 5. Species lacking the apoenzyme or the hormonal induction mechanism have a deficient kynurenine pathway and are sensitive to the toxicity of tryptophan. 6. It is suggested that these species are not suitable as models for studying human tryptophan metabolism. 7. The possible significance of these findings in relation to veterinary and human neonatal care is discussed.

Allopurinol↗
PubMed2003

Detection of open and closed conformations of tryptophan synthase by 15N-heteronuclear single-quantum coherence nuclear magnetic resonance of bound 1-15N-L-tryptophan.

1-15N-L-Tryptophan (1-15N-L-Trp) was synthesized from 15N-aniline by a Sandmeyer reaction, followed by cyclization to isatin, reduction to indole with LiAlH4, and condensation of the 15N-indole with L-serine, catalyzed by tryptophan synthase. 1-15N-L-Trp was complexed with wild-type tryptophan synthase and beta-subunit mutants, betaK87T, betaD305A, and betaE109D, in the absence or presence of the allosteric ligands sodium chloride and disodium alpha-glycerophosphate. The enzyme complexes were observed by 15N-heteronuclear single-quantum coherence nuclear magnetic resonance (15N-HSQC NMR) spectroscopy for the presence of 1-15N-L-Trp bound to the beta-active site. No 15N-HSQC signal was detected for 1-15N-L-Trp in 10 mm triethanolamine hydrochloride buffer at pH 8. 1-15N-L-Trp in the presence of wild-type tryptophan synthase in the absence or presence of 50 mm sodium chloride showed a cross peak at 10.25 ppm on the 1H axis and 129 ppm on the 15N axis as a result of reduced solvent exchange for the bound 1-15N-L-Trp, consistent with formation of a closed conformation of the active site. The addition of disodium alpha-glycerophosphate produced a signal twice as intense, suggesting that the equilibrium favors the closed conformation. 15N-HSQC NMR spectra of betaK87T and betaE109D mutant Trp synthase with 1-15N-L-Trp showed a similar cross peak either in the presence or absence of disodium alpha-glycerophosphate, indicating the preference for a closed conformation for these mutant proteins. In contrast, the betaD305A Trp synthase mutant only showed a 15N-HSQC signal in the presence of disodium alpha-glycerophosphate. Thus, this mutant Trp synthase favored an open conformation in the absence of disodium alpha-glycerophosphate but was able to form a closed conformation in the presence of disodium alpha-glycerophosphate. Our results demonstrate that the 15N-HSQC NMR spectra of 1-15N-L-Trp bound to Trp synthase can be used to determine the conformational state of mutant forms in solution rapidly. In contrast, UV-visible spectra of wild-type and mutant Trp synthase in the presence of L-Trp with NaCl and/or disodium alpha-glycerophosphate are more difficult to interpret in terms of altered conformational equilibria.

Escherichia coli↗
PubMed1982

Inhibition of rat liver tryptophan pyrrolase activity and elevation of brain tryptophan concentration by acute administration of small doses of antidepressants.

1 Administration to rats of a 0.5 mg/kg dose of any of 19 antidepressants, but not that of many other drugs, causes a significant inhibition of the total enzyme and apoenzyme activities of liver tryptophan pyrrolase (of 24-48% and 37-65% respectively) and elevates brain tryptophan concentration by 13-66%. 2 When liver tryptophan pyrrolase activity is enhanced by pretreatment with cortisol or haematin, subsequent administration of a 0.5 mg/kg dose of some, but not other, antidepressants causes inhibition, which is weak (up to 38%). 3 This weak inhibition of the enhanced pyrrolase activity together with other pharmacological and physiological factors could explain the time lag between the start of antidepressant medication and the occurrence of a therapeutic response. 4 The cortisol-induced and haematin-activated pyrrolases respond differentially to inhibition by imipramine and amitriptyline, and this may explain the differential response to these two drugs of depressed patients in relation to urinary excretion of the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol. 5 The results are discussed in relation to the mechanism of action of antidepressants and the possible involvement of disturbed hepatic tryptophan metabolism in depressive illness.

Animals↗
PubMed1979

Hyperproduction of tryptophan by Escherichia coli: genetic manipulation of the pathways leading to tryptophan formation.

Conversion of glucose and ammonium salts into tryptophan by mutants of Escherichia coli was examined as part of a feasibility study on the manufacture of tryptophan. This involved construction, largely by transduction, or a variety of multiple-mutation strains with defined genotypes. By comparing the properties of these strains, we were able to define in biochemical terms several changes that significantly enhance process productivity, namely (i) release of the first enzyme of the common pathway of aromatic biosynthesis and the first enzyme of the tryptophan pathway (3-deoxy-D-arabino-heptulosonate 7-phosphate synthase and the anthranilate aggregate, respectively) from inhibition by end products, (ii) blockage of the diversion of chorismate to phenylalanine and tyrosine biosynthesis, and (iii) presence of highly elevated tryptophan pathway enzyme levels, such as result from interference with both repression and attenuation, combined with gene amplification. By using strains carrying appropriate mutations to effect all of these changes, high values of specific productivity were obtained in bath culture (approximately 80 mg/g [dry weight] per h). Furthermore, a pronounced decay in the level of 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase activity was implicated as a cause of declining process producitivity during stationary phase, emphasizing the value of having derepressed levels of this enzyme.

3-Deoxy-7-Phosphoheptulonate Synthase↗
PubMed1994

High-performance liquid chromatographic determination of 1,1'-ethylidenebis(L-tryptophan) in L-tryptophan preparations.

In studies to determine the cause or causes of the eosinophilia myalgic syndrome (EMS) and to monitor the purity of L-tryptophan preparations, an HPLC method has been developed for determining 1,1'-ethylidenebis(L-tryptophan) (EBT) in L-tryptophan (W) preparations. The W preparations are extracted with 0.1% trifluoroacetic acid (TFA) and filtered, and the EBT is purified by passage through a Sep-Pak C18 cartridge. The cartridge is washed with water and 6% acetonitrile in water, and EBT is eluted with methanol. The water-diluted eluate is then chromatographed on a silica-based, reversed-phase HPLC column with a gradient of water and 80% acetonitrile, both solvents containing 0.1% TFA. EBT absorbance is measured at 280 nm. The average recovery of EBT from L-tryptophan powder, spiked over the range 1.2-4.8 micrograms/g, was 91%. The limit of determination was approximately 0.6 micrograms/g. Sixteen test samples of W products manufactured by the company to which most of the cases of EMS have been traced contained > 70 micrograms of EBT/g. Three nonpatient-related test samples either did not contain EBT or contained < 2 micrograms of EBT/g.

Buffers↗
PubMed1993

Characterization of two fluorescent tryptophans in recombinant human granulocyte-colony stimulating factor: comparison of native sequence protein and tryptophan-deficient mutants.

In order to probe the role of the individual tryptophans of granulocyte-colony stimulating factor (G-CSF) in pH and guanidine HCl-induced fluorescence changes, site-directed mutagenesis was used to generate mutants replacing Trp118,Trp58, or both with phenylalanine. Neither Trp to Phe mutation affected the folding or activity of the recombinant G-CSF, and the material expressed in yeast behaved identically to that expressed in Escherichia coli. All of the G-CSF species responded to pH and guanidine HCl in qualitatively the same manner. Trp58 has a fluorescence maximum at 350 nm and is quenched to a greater extent by the addition of guanidine HCl, indicating that it is fully solvent-exposed. Trp118 has a fluorescence maximum at 344 nm, and is less solvent-accessible than Trp58. The analog in which both tryptophans have been replaced with phenylalanine shows only tyrosine fluorescence, with a peak at 304 nm which decreases with increasing pH. The intensity of the tyrosine fluorescence in this analog is much greater than that of the native sequence protein or single tryptophan mutants, indicating that energy transfer is taking place from tyrosine to tryptophan in these molecules. Below neutral pH the tyrosine fluorescence is much greater in the [Phe58]G-CSF than in the [Phe118]G-CSF, indicating that Trp58 might be a more efficient recipient of energy transfer from the tyrosine(s).

Cloning, Molecular↗
PubMed1989

Neuroactive metabolites of L-tryptophan, serotonin and quinolinic acid, in striatal extracellular fluid. Effect of tryptophan loading.

Extracellular fluid levels of the neurotoxin quinolinic acid in the corpus striatum of rats, measured by in vivo microdialysis, were increased in a dose-dependent manner following the intraperitoneal administration of tryptophan. The lowest dose of tryptophan (12.5 mg/kg), equivalent to about 5% of the normal daily intake, increased peak quinolinic acid levels nearly 3-fold. At higher doses of tryptophan (up to 250 mg/kg), concentrations of quinolinic acid increased over 200-fold and exceeded potentially neurotoxic levels (10 microM). In contrast, the increase in extracellular serotonin following even the highest tryptophan dose was small (less than 2-fold). These data indicate that quinolinic acid is present in the extracellular fluid where it may function as a neuromodulator and that it is very responsive to physiological changes in precursor availability.

Animals↗
PubMed1993

Effect of disulfiram administration on brain tryptophan, serotonin and peripheral tryptophan content.

The prophylactic deterrent effect of disulfiram (DS) has been attributed to its ability to exacerbate sympathetic function. Though there are reports to indicate that DS administration could as well affect the neurotransmitter metabolism, few reports implicate the possibility of central nervous system (CNS) mediated anticraving effect of the drug. The present study involving the oral administration of DS to rats for 45 days has clearly shown a significant increase in 5-HT (815.4 +/- 74.7 ng/g, P < 0.01) and 5-HIAA (506.1 +/- 86.3 ng/g, P < 0.02) contents in brain when compared to control rats. The observed increase in 5-HT and 5-HIAA content was found to correlate (zeta = 0.89) with the concomitant increase in brain tryptophan content (4.15 +/- 1.05 nmol/g, P < 0.001) following DS administration. Further, the study on peripheral tryptophan content has shown an increase in both total and free fraction (ultrafiltrate) of plasma, which in turn was found to have an inverse relationship (zeta = -0.94, P < 0.05) with the decrease in liver tryptophan content following DS administration. Thus the observed increase in brain 5-HT level is attributed to the ability of DS to mobilise peripheral tryptophan for 5-HT synthesis in CNS. As there are reports to imply the hyposerotonergic function as responsible for craving, the present findings, that DS could enhance the 5-HT metabolism in brain, may partially explain the CNS mediated anticraving effect of DS.

Animals↗
PubMed2005

The tryptophan hydroxylase activation inhibitor, AGN-2979, decreases regional 5-HT synthesis in the rat brain measured with alpha-[14C]methyl-L-tryptophan: an autoradiographic study.

Many experimental conditions are stressful for animals. It is well known that stress induces tryptophan hydroxylase (TPH) activation, resulting in increased serotonin (5-HT) synthesis. In our experimental procedure to measure 5-HT synthesis using alpha-[(14)C]methyl-L-tryptophan (alpha-MTrp) autoradiographic method, the hind limbs of animals are restrained using a loose-fitted plaster cast such that the forelimbs of the animal remain free. The objective of the present investigation was to evaluate the changes, if any, in 5-HT synthesis, after injecting these restrained rats with the TPH activation inhibitor AGN-2979. The effect on regional 5-HT synthesis was studied using the alpha-MTrp autoradiographic method. The hypothesis was that the TPH activation inhibitor would reduce 5-HT synthesis, if TPH activation was induced by this restraint. The rats received injection of AGN-2979 (10 mg/kg, i.p.) or distilled water vehicle (1 mL/kg, i.p.) 1 h prior to tracer administration. The free- and total tryptophan concentrations were not significantly different between the treatment and control groups. The results demonstrate that 5-HT synthesis in AGN-2979 treated rats is significantly decreased (-12 to -35%) in both the raphe nuclei and their terminal areas when compared to the control rats. These findings suggest that restrained conditions, such as those used in our experimental protocol, induce TPH activation resulting in an increased 5-HT synthesis throughout the brain. The reduction in 5-HT synthesis in the AGN-2979 group is not related to a change in the plasma tryptophan. Because there was no activation in the pineal body, the structure having a different isoform of TPH, we can propose that it is only the brain TPH that becomes activated with this specific restraint.

Analysis of Variance↗
PubMed2003

Role of the vancomycin-ristocetin heterodimerization on the enantioselectivity of D,L-tryptophan and D,L-dansyl tryptophan.

In this paper, a chromatographic system using immobilized ristocetin as chiral stationary phase and vancomycin as chiral mobile phase additive (CMPA) was described in order to investigate the role of the glycopeptide heterodimerization on the retention and enantioselectivity of D,L-tryptophan and D,L-dansyl tryptophan. A simplified interaction model was derived considering the formation of heterodimers between immobilized ristocetin and vancomycin. This theoretical approach was convenient to describe adequately the retention behavior. When the CMPA concentration increased, the solute retention factor increased for all the solute enantiomers studied indicating that the vancomycin adsorbed on the immobilized ristocetin played a preponderant role in the retention. The D,L-tryptophan enantioselectivity on the dynamically modified stationary phase was improved by a factor of 1.3, probably due to a glycopeptide conformational change upon heterodimerization. On the other hand, a decrease in the chiral discrimination of D,L-dansyl tryptophan was observed. Such a behavior seems to result from the antagonist enantioselective properties of the two glycopeptides for the dansyl amino acids.

Chromatography, High Pressure Liquid↗
PubMed1979

Triplet state of tryptophan in proteins. 2. Differentiation between tryptophan residues 62 and 108 in lysozyme.

We have used optically detected magnetic resonance (ODMR) to characterize the degree of solvent availability of the tryptophan residues in lysozyme that are likely to be responsible for the observed phosphorescence. From the phosphorescence spectra, ODMR zero-field splittings (zfs), and ODMR line widths, we concur with the X-ray structure [Blake, C. C., Mair, G. A., North, A. C. T., Phillips, D. C., & Sarma, V. R. (1967) Proc. R. Soc. London, ser. B 167, 365-377] that Trp-62 behaves as an exposed residue and Trp-108 is buried. In addition, we present evidence that ODMR can be used in conjunction with conventional phosphorescence to evaluate the degree of order in the microenvironments of tryptophan in a protein containing several tryptophans. By the specific modification of residues Trp-62 and Trp-108, we have identified those portions of the ODMR lines in the native enzyme that are due to those specific residues. Barring major enzyme conformational changes in the vicinity of unmodified tryptophan residues when Trp-62 or Trp-108 are selectively modified, we find that Trp-108 dominates both the phosphorescence and the ODMR signals in native lysozyme. The results are discussed in view of previous fluorescence findings.

Luminescent Measurements↗
PubMed1998

Tryptophan fluorescence of the lux-specific Vibrio harveyi acyl-ACP thioesterase and its tryptophan mutants: structural properties and ligand-induced conformational change.

The lux-specific myristoyl-ACP thioesterase from Vibrio harveyi contains four tryptophan residues, Trp23, Trp99, Trp186, and Trp213. Replacement of each of these residues with tyrosine by site-directed mutagenesis coupled with fluorescence and quenching studies of the purified mutant and wild type thioesterases during catalysis has been used to probe ligand-induced conformational changes. Mutant W99Y retained high enzyme activity (80%) with W213Y and W23Y retaining intermediate activity and W186Y having the lowest activity (20%). The sum of the differential fluorescence spectra of the individual tryptophans was identical to the fluorescence spectrum of the wild type thioesterase, showing that mutation had not caused a major conformational change and energy transfer did not occur between the tryptophans. Fluorescence emission maxima and quenching by acrylamide revealed that Trp213 and Trp23 are in a polar environment and/or exposed to solvent while Trp186 appeared to be buried inside the molecule, consistent with the crystal structure of the thioesterase. The fluorescence intensities of the wild type, W23Y, W99Y, and W186Y thioesterases increased in direct correlation to their degree of acylation with myristoyl-CoA, while the fluorescence of the acylated W213Y mutant remained constant, showing that the enhancement of fluorescence was entirely due to interaction of the acyl group with Trp213. Acrylamide quenching of the acylated mutants showed that the accessibility of the tryptophans to solvent was differentially altered and that the quenching of W23Y was enhanced in contrast to the quenching of the other mutants, supporting a ligand-induced conformational change during enzyme turnover.

Acrylamide↗
PubMed1980

Oxidation of tryptophan to oxindolylalanine by dimethyl sulfoxide-hydrochloric acid. Selective modification of tryptophan containing peptides.

Tryptophan is readily oxidized to oxindolylalanine (2-hydroxytryptophan) in good yield on treatment in acetic acid solution with a mixture of dimethyl sulfoxide (DMSO) and concentrated aqueous HCl at room temperature. Other sulfoxides can be used in combination with HCl; for example, methionine sulfoxide reacts with an equimolar amount of tryptophan to give high yields of methionine and oxindolylalanine. Methionine and cysteine are quantitatively oxidized by DMSO/HCl to methionine sulfoxide and cystine, respectively. The tryptophan containing peptides LRF (luteinizing hormone-releasing factor), somatostatin, valine-gramicidin A and ACTH 1-24 were each treated with the DMSO/HCl reagent in acetic acid solution and the corresponding oxindolylalanine-derivatives isolated in over 90% yield after chromatography. The identity and purity of the derivatives were established on the basis of ultraviolet spectral characteristics and quantitative amino acid analysis of the oxindolylalanine content of acid hydrolyzates of the oxidized peptides with 3N-p-toluenesulfonic acid at 110 degrees for 24 h. The results indicate that modification of tryptophan peptides with DMSO/HCl provides a useful procedure, which seems superior to previously used reagents. In addition, the method could be well applied to other indoles of biological and pharmacological interest.

5-Hydroxytryptophan↗