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PubMed1976

Kinetics of hydrogen-deuterium exchange of tryptophan and tryptophan peptides in deutero-trifluoroacetic acid using proton magenetic resonance spectroscopy.

The methods which have been used for the observation and assignment of resonances in the NMR spectra of proteins are reviewed. One such method, the selective deuteration of the aromatic protons of tryptophyl residues, is studied by NMR spectroscopy in model compounds in this paper, and in proteins in the following paper. On the basis of a reassignment of the PMR spectrum of the aromatic protons of L-tryptophan, the relative rates of H-D exchange in deutero-trifluoracetic acid (d-TFA) are H-2 greater than H-5 greater than H-6 greater than H-4 approximately H-7. The energies of activation for the first order exchange of both the H-2 and H-5 protons is 12 k.cal.mol-1. The rate constant for exchange of the H-2 protons of tryptophyl residues in peptides is much greater than in the amino acid itself and 5-10 times that for exchange of the H-5 protons. This suggests that the method can be used to label tryptophyl residues in proteins rapidly and specifically.

Deuterium↗

PubMed1996

Effects on protein structure and function of replacing tryptophan with 5-hydroxytryptophan: single-tryptophan mutants of the N-terminal domain of the bacteriophage lambda repressor.

Conformational energy computations have been carried out on the N-acetyl-N'-methylamide of 5-hydroxytryptophan (5OH-Trp) using ECEPP/3. As observed with tryptophan (Trp), the most preferred conformation about the C alpha-C beta bond of the side chain is g+ or t. This preference is reduced to only the t conformational state when 5-hydroxyTrp is in the middle of a right-handed poly(L-alanine) alpha-helix. A similar result has been obtained with Trp [Piela et al. (1987), Biopolymers 1987, 1273-1286]. These results suggest that replacement of Trp by its analog 5-hydroxyTrp may be tolerated in an alpha-helix. To test this hypothesis, we have replaced Trp by 5OH-Trp in the fifth helices of two functionally active mutants of the N-terminal domain of the bacteriophage lambda repressor. Computations on the packing of these helices have shown that no significant structural changes results from the replacement of Trp by 5OH-Trp. The DNA-binding activity of these mutants, as assessed indirectly through geometrical parameters, is also unaltered.

5-Hydroxytryptophan↗

PubMed1990

Variation of tryptophan-5-hydroxylase concentration in the rat raphe dorsalis nucleus after p-chlorophenylalanine administration. II. Anatomical distribution of the tryptophan-5-hydroxylase protein and regional variation of its turnover rate.

Distribution of tryptophan-5-hydroxylase (TpOH)-containing cells and TpOH protein tissue concentrations were evaluated in the nucleus raphe dorsalis (NRD) of rat brain by immunocytochemistry and direct transfer onto nitrocellulose filters of unfixed adjacent brain sections. This work has demonstrated that: (1) the direct transfer onto nitrocellulose filters could be easily used for the quantitative analysis of TpOH protein distribution; (2) the origin of the TpOH in this brain nucleus was preferentially cellular; (3) classical subdivisions, qualitatively defined from morphometric and topographic observations could be precisely described in terms of cellular density, tissue and cellular concentrations and turnover of TpOH protein. Such differences could imply a physiological control of TpOH gene expression in the serotoninergic neurons.

Animals↗

PubMed1991

Cycloheximide blocks the fall of plasma and tissue tryptophan levels after tryptophan-free amino acid mixtures.

The hypothesis that incorporation of tryptophan (TRY) into proteins is the mechanism underlying the decrease in plasma and tissue TRY levels after a TRY-free amino acid mixture was investigated. Rats fasted 15 hours were pretreated with saline or with the protein synthesis inhibitor cycloheximide (CHEX) and treated with saline or a TRY-free amino acid mixture. In a first experiment, in saline pretreated rats the TRY-free mixture caused a decrease of 49% in total plasma TRY, of 64% in free plasma TRY, of 66% in brain TRY and of 42% in liver TRY. After 5 mg/kg of CHEX the same TRY-free diet caused a decrease of 5% in total plasma TRY, 14% in free plasma TRY, 18% in brain TRY and 9% in liver TRY. In a second experiment, the TRY-free diet caused a 43% decrease of total plasma TRY in saline pretreated animals and a decrease of 15%, 6% and 2% respectively after the pretreatment with 0.3, 1.0 and 5.0 mg/kg of CHEX. In brain TRY, the TRY-free diet caused a 62% decrease in saline pretreated rats and a decrease of 38%, 20% and 19% respectively after the pretreatment with 0.3, 1.0 and 5.0 mg/kg of CHEX. Since 5.0 mg/kg of CHEX almost completely block protein synthesis and since doses of CHEX from 0.3 to 5.0 mg/kg cause a dose-dependent inhibition of protein synthesis, our data support the hypothesis that protein synthesis is the mechanism through which TRY-free mixtures decrease TRY levels.

Amino Acids↗

PubMed1993

Large changes in serum free tryptophan levels do not alter brain tryptophan levels: studies in streptozotocin-diabetic rats.

The effect of meal-induced changes in serum free tryptophan (TRP) levels on brain TRP levels was examined in streptozotocin-diabetic rats. Diabetic rats, fasted overnight, were given free access to a non-protein food containing either no fat or large amounts of fat (45% by weight), and were killed 1, 2 or 3 hr thereafter. Ingestion of the high-fat meal produced large increases in both serum non-esterified fatty acid (NEFA; 2-fold) and free TRP levels (2.5-fold), but no increments in cerebral cortical or hypothalamic TRP levels or in the rate of serotonin synthesis in these brain regions. Because the rats were diabetic, serum levels of the other large neutral amino acids (which compete with TRP for transport into brain) did not vary from fasting values in any of the treatment groups. There thus was no uncontrolled variation in the competitive transport of TRP into brain that might have obscured potential effects due to the alterations in serum free TRP levels. The results add further evidence to the notion that TRP transport into the central nervous system is not influenced by the size of the free TRP pool in blood.

Amino Acids↗

PubMed1998

The neurobiology of tryptophan depletion in depression: effects of intravenous tryptophan infusion.

BACKGROUND: Previous work has suggested that acute depletion of the serotonin (5-HT) precursor tryptophan (TRP) causes transient compensatory changes in the 5-HT system that might be exploited for their antidepressant effects. In this study, neuroendocrine and mood responses to intravenous (i.v.) infusion of TRP were examined in order to evaluate central 5-HT function in depressed patients undergoing acute TRP depletion. METHODS: Thirty-eight drug-free patients with DSM-III-R major depression participated. Each patient underwent two randomized, double-blind TRP depletion tests, one sham and one active. At the estimated time of maximum TRP depletion, each patient received an i.v. infusion of TRP 100 mg/kg. Blood was obtained for serum cortisol, prolactin, and growth hormone. Mood was assessed using standardized rating scales. RESULTS: The cortisol response to i.v. TRP was significantly greater during TRP depletion than during sham depletion. Depressive symptoms showed a tendency to decrease after i.v. TRP following active, but not sham, TRP depletion. CONCLUSIONS: These findings are consistent with the present hypothesis and previous evidence that acute TRP depletion in drug-free depressed patients induces compensatory upregulation of postsynaptic 5-HT receptors. These changes are insufficient to serve as a means of effecting clinical improvement, but suggest that the antidepressant properties of rapid, marked manipulations of 5-HT function warrant further study.

Adult↗

PubMed1991

Resolution of fluorescence intensity decays of the two tryptophan residues in glutamine-binding protein from Escherichia coli using single tryptophan mutants.

Time correlated single photon counting measurements of tryptophan (Trp) fluorescence intensity decay and other spectroscopic studies were performed on glutamine-binding protein (GlnBP) from Escherichia coli. Using site-specifically mutated forms of the protein in which tyrosine (Tyr) and phenylalanine (Phe) substitute for the Trp residues at positions 32 and 220, we have examined whether wild-type (Wtyp) intensity decay components may be assigned to specific Trp residues. Results indicate that: (a) two exponential intensity decay components are recovered from the Wtyp protein (6.16 ns, 0.46 ns); (b) the long decay component arises from Trp-220 and comprises greater than 90% of the total fluorescence emission; (c) the short component arises from Trp-32 and is highly quenched; (d) all four single-Trp mutants exhibit multiexponential intensity decays, yet equimolar mixtures of two single-Trp mutants yield only two decay components which are virtually indistinguishable from the Wtyp protein; (e) the recovery of additional components in protein mixtures is obscured by statistical noise inherent in the technique of photon counting; (f) various spectroscopic measurements suggest that Trp-Trp interactions occur in the Wtyp protein, but the Wtyp intensity decay may be closely approximated by a linear combination of intensity decays from single-Trp mutants; and (g) inferences derived independently from fluorescence and NMR spectroscopy which pertain to the presence of Trp-Trp interactions and the relative solvent exposure of the two Trp residues are in agreement.

Amino Acid Sequence↗

PubMed1998

Study of complexes of a tryptophan-free mutant of E. coli trp aporepressor with tryptophan analogues using optically detected magnetic resonance (ODMR).

Phosphorescence and optically detected magnetic resonance (ODMR) spectra of tryptophan (W) and several of its analogues (4-, 5-, 6-methyltryptophan (MeW); 4-, 5-, 6-fluorotryptophan (FW); 5-bromotryptophan) are compared with those of complexes formed with the W-free trp aporepressor from Escherichia coli (W19,99F). W19,99F binds W and each analogue except 4-FW with an estimated KD < or = 30 microM; triplet state spectroscopic and kinetic effects that accompany binding at the corepressor site are reported. ODMR data for the MeW isomers are presented for the first time. No binding of 7-azaW is observed, in agreement with the low affinity found by previous workers.

Apoproteins↗

PubMed2004

Acute tryptophan and serotonin depletion using an optimized tryptophan-free protein-carbohydrate mixture in the adult rat.

In contrast to humans, a tryptophan (TRP)-free amino acid (AA) mixture only leads to moderate depletion in plasma TRP levels in adult rats. In this study we evaluated the effects of an acute administration of a TRP-free protein-carbohydrate nutritional mixture in adult male Wistar rats. Plasma amino acid levels were examined at 2 and 4h starting after the first administration. Furthermore, the concentrations of amino acid, serotonin (5-HT), dopamine (DA) and their metabolite (5-hydroxyindolacetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC), respectively) were measured within the striatum, hippocampus and cortex. In the TRP depleted animals, the TRP/sigmaLNAA ratio (LNAA: large neutral amino acids) was substantial decreased at 2 and 4h after the first administration of the oral administration (by 71 and 78%, respectively). Four hours after treatment central TRP and 5-HT concentrations were decreased by 50%. Both peripheral and central TRP levels returned to basal values in the group treated with the nutritional mixture supplemented with TRP. Surprisingly, tyrosine levels were also reduced after oral administration of the protein-carbohydrate mixture without affecting central DA concentrations. In conclusion, the TRP-free protein-carbohydrate nutritional mixture appears to be an efficient tool to substantially reduce plasma and central TRP levels in adult rat.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2002

Formation in vitro of hybrid dimers of H463F and Y74F mutant Escherichia coli tryptophan indole-lyase rescues activity with L-tryptophan.

Y74F and H463F mutant forms of Escherichia coli tryptophan indole-lyase (Trpase) have been prepared. These mutant proteins have very low activity with L-Trp as substrate (kcat and kcat/Km values less than 0.1% of wild-type Trpase). In contrast, these mutant enzymes exhibit much higher activity with S-(o-nitrophenyl)-L-cysteine and S-ethyl-L-cysteine (kcat/Km values about 1-50% of wild-type Trpase). Thus, Tyr-74 and His-463 are important for the substrate specificity of Trpase for L-Trp. H463F Trpase is not inhibited by a potent inhibitor of wild-type Trpase, oxindolyl-L-alanine, and does not exhibit the pK(a) of 6.0 seen in previous pH dependence studies [Kiick, D. M., and Phillips, R. S. (1988) Biochemistry 27, 7333]. These results suggest that His-463 may be the catalytic base with a pK(a) of 6.0 and Tyr-74 may be a general acid catalyst for the elimination step, as we found previously with tyrosine phenol-lyase [Chen, H., Demidkina, T. V., and Phillips, R. S. (1995) Biochemistry 34, 12776]. H463F Trpase reacts with L-Trp and S-ethyl-L-cysteine in rapid-scanning stopped-flow experiments to form equilibrating mixtures of external aldimine and quinonoid intermediates, similar to those observed with wild-type Trpase. In contrast to the results with wild-type Trpase, the addition of benzimidazole to reactions of H463F Trpase with L-Trp does not result in the formation of an aminoacrylate intermediate. However, addition of benzimidazole with S-ethyl-L-cysteine results in the formation of an aminoacrylate intermediate, with lambda(max) at 345 nm, as was seen previously with wild-type Trpase [Phillips, R. S. (1991) Biochemistry 30, 5927]. This suggests that His-463 plays a specific role in the elimination step of the reaction of L-Trp. Refolding of equimolar mixtures of H463F and Y74F Trpase after unfolding in 4 M guanidine hydrochloride results in a dramatic increase in activity with L-Trp, indicating the formation of a hybrid H463F/Y74F dimer with one normal active site.

Dimerization↗

PubMed2005

Tryptophan side chain electrostatic interactions determine edge-to-face vs parallel-displaced tryptophan side chain geometries in the designed beta-hairpin "trpzip2".

The interaction geometries of the four tryptophan (Trp) side chains in the 12-residue designed beta-hairpin trpzip2 are investigated using all-atom explicit-solvent molecular dynamics simulations. The experimentally observed edge-to-face (EtF) pairwise interaction geometries are stable on a time scale of 10 ns. However, removing the electrostatic multipoles of the Trp side chains while retaining the dipoles of the side chains' NH moieties induces a conformational change to a geometry in which three of the four side chains interact in a parallel-displaced (PD) manner. Free energy simulations of the Etf to PD conformational change reveal that, with the side chain multipole moments intact (+MP), the EtF conformation is preferred by 5.79 kcal/mol. Conversely, with only the dipole moments of the side chain NH moieties intact (-MP), the PD conformation's free energy is more favorable by 1.71 kcal/mol. In contrast to energetic similarities for Trp side chain-water electrostatic and Trp side chain-Trp side chain and Trp side chain-water van der Waals, +MP Trp side chain-Trp side chain electrostatic interactions are more favorable by 4.21 kcal/mol in the EtF conformation, while in the -MP case the EtF and PD conformations' Trp side chain-Trp side chain electrostatic energies are nearly identical. The results highlight the importance of electrostatic multipole moments in determining aromatic-aromatic interaction geometries in aqueous biomolecular systems and argue for the inclusion of this physics in simplified models used for protein-ligand docking and protein structure prediction, possibly through a truncated Coulomb term between aromatic moieties.

Computer Simulation↗

PubMed2001

Determination of free and conjugated indole-3-acetic acid, tryptophan, and tryptophan metabolites in grape must and wine.

Tryptophan (Trp) and its metabolites, especially indole-3-acetic acid (IAA), are considered to be potential precursors of 2-aminoacetophenone (AAP), an aroma compound that causes an "untypical aging off-flavor" (UTA) in Vitis vinifera wines. In this study, RP-HPLC with fluorescence detection was used for the qualitative and quantitative analysis of Trp and Trp metabolites in grape musts and wines to which different viticultural measures had been applied (time of harvest, soil treatment, leaf plucking, vine prune). An alkaline hydrolysis was developed to release bound IAA and Trp. A sensitive and selective determination of different Trp metabolites was achieved after solid phase extraction using a strong anion exchange material. In the examined grape musts, more than 95% of the total IAA was bound either as ester conjugate or as amide conjugate. Free IAA and other Trp metabolites were below the detection limit (<3 microg/L) or could be determined only in traces. Their amounts increased significantly during fermentation, whereas the amount of Trp decreased. It could be shown that the different viticultural measures applied (except the vine prune) as well as the climatic conditions of the vintage exhibited significant influences on the amounts of Trp and Trp metabolites in grape musts or wines.

Chromatography, High Pressure Liquid↗

PubMed1999

Effects of acute tryptophan depletion on plasma and cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers.

Brain serotonin synthesis and metabolism (turnover), as indicated by CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), may depend on plasma concentrations of the essential amino acid L-tryptophan (TRP). We investigated the biochemical effects of acute plasma TRP depletion (ATD) in normal volunteers undergoing a 36-h CSF collection via lumbar drain. Six subjects who were in good health were put on a low-TRP diet (160 mg/day) 24 h before lumbar puncture; this diet was continued for the first 22 h of the CSF collection. At hour 22, subjects ingested a TRP-deficient 15-amino acid drink shown previously to deplete plasma TRP. Total plasma TRP, free plasma TRP, and CSF TRP subsequently decreased 86.3, 86.5, and 92.3%, respectively. CSF 5-HIAA decreased by 32.8%. Plasma total and free TRP concentrations were both decreased at approximately 2 h following ingestion of the TRP-free amino acid drink and were lowest approximately 6 h after ATD; CSF TRP and 5-HIAA were decreased at 2.5 h and approximately 4 h after ATD, respectively. CSF TRP was lowest 8.0 h later. CSF 5-HIAA continued to decrease 14 h after the TRP-deficient amino acid drink was given.

Adult↗

PubMed1979

Attenuation in the Escherichia coli tryptophan operon: role of RNA secondary structure involving the tryptophan codon region.

The secondary structure of the terminated trp leader transcript from Escherichia coli was analyzed by RNase T1 partial digestion. Base-paired regions were recovered by nondenaturing gel electrophoresis and identified by denaturing gel electrophoresis and fingerprinting. The tandem tryptophan codons in the leader peptide coding region were found to be base paired with a more distal region of the transcript. This and other secondary structures that the trp leader RNA can form help explain the physiological response of the operon as well as the behavior of regulatory mutants.

Codon↗

PubMedDate not supplied

Tryptophan metabolism in alcoholism. Tryptophan but not excitatory amino acid availability to the brain is increased before the appearance of the alcohol-withdrawal syndrome in men.

Tryptophan (Trp) metabolism and disposition and excitatory and other amino acid concentrations were determined in alcohol-dependent subjects in relation to the alcohol-withdrawal syndrome (AWS). Parameters were examined in 12 alcohol-dependent male subjects, undergoing elective upper digestive tract tumour resection, and 12 age-, gender-, and medication-matched controls on three occasions: pre-operatively, post-operatively, and immediately before (i.e. within 24 h of) the appearance of the AWS. No significant differences were observed between controls and alcoholic subjects on the first or second of these occasions. On the third occasion, within 24 h of the appearance of the AWS, alcoholics showed a dramatic elevation (117%) in free serum Trp concentration and a consequent increase (111%) in the ratio of [free Trp]/[competing amino acids], which is an accurate predictor of Trp entry into the brain. Increases were also observed on this third occasion in concentrations of total Trp (49%), cortisol (123%), and norharman (137%). Concentrations of glutamate, glycine, aspartate, serine, and taurine did not differ significantly within or between the control and alcohol-dependent groups of subjects on any of the three occasions. The possible significance of the Trp and related metabolic changes in relation to the behavioural features of the AWS is discussed.

Alcoholism↗

PubMed2006

Studies on the tryptophan requirement of lactating sows. Part 1: Estimation of the tryptophan requirement by performance.

Mature sows were evenly assigned to six dietary treatments, which differed only in the concentration of total (apparent ileal digestible, AID) tryptophan (Trp) amounting per kg feed to 1.2 g (0.8 g) to 4.2 g (3.8 g) in diets 1-6. For a total of 72 lactations (28 days) sows' feed intake was measured daily and body weight was measured on day 110 of pregnancy and on days 1 and 28 of lactation. Litter size was standardized to 10-12 piglets within 1 week after farrowing. The piglets were weighed at days 1, 21 and 28. Milk yield was recorded by the weigh-suckle-weigh method on days 20 and 21. Concentrations of milk fat and protein were measured in manually drawn samples (days 20 and 21) by infrared spectroscopy. Average daily feed intake of the sows was 3.4, 4.7, 4.7, 6.1, 5.1 and 4.7 kg (diets 1-6 respectively, p < 0.001). Body weight losses of the sows during lactation were 30.8, 16.9, 19.2, 9.5, 14.1 and 13.1 kg (diets 1-6 respectively, p < 0.05). Milk output in the average of days 20 and 21 was 6840, 8192, 8362, 9035, 8618 and 8140 g/day, respectively (p < 0.01). There were no differences in milk fat or protein contents. Daily weight gain of the piglets in the average of lactation was 157, 184, 184, 187, 185 and 177 g, respectively (p < 0.10). Based on the results of this study the estimated Trp requirement of lactating sows for optimal performance was calculated with 1.9 g AID Trp/kg in the lactation diet (according to 2.0 g true ileal digestible Trp and approximately 2.6 g Trp on total basis).

Animal Nutritional Physiological Phenomena↗

PubMed2006

Studies on the tryptophan requirement of lactating sows. Part 2: Estimation of the tryptophan requirement by physiological criteria.

Mature sows were fed for a total of 72 lactations with diets which provided an adequate supply of energy and nutrients except for tryptophan (Trp). By supplementing a basal diet [native 1.2 g Trp/kg, equivalent to 0.8 g apparent ileal digestible (AID) Trp or 0.9 g true ileal digestible (TID) Trp] with L-Trp, five further diets (2-6) containing 1.5-4.2 g Trp/kg were formulated. The dietary Trp content had no effect on amino acid contents in milk on days 20 and 21 of lactation, but Trp in blood plasma on day 28 of lactation reflected the alimentary Trp supply with an increase from 2.74 +/- 1.14 mg/l (diet 1) to 23.91 +/- 7.53 mg/l (diet 6; p < 0.001). There were no directional differences between the diets with regard to the other amino acids. Concentrations of urea in milk and blood were higher with diet 1 (211 and 272 mg/l, respectively) than with diets 3-6 (183 and 227 mg/l, respectively). Serotonin levels in the blood serum were lower with diet 1 (304 ng/ml) than the average of diets 4-6 (540 ng/ml). This study confirms previously given recommendations for the Trp content in the diet of lactating sows, estimated by means of performance, of 1.9 g AID Trp (equivalent to 2.0 g TID Trp; approximately 2.6 g gross Trp) per kg diet.

Amino Acids↗

PubMed1986

Amino acid analysis demonstrates that increased plasma free tryptophan causes the increase of brain tryptophan during exercise in the rat.

Rats were trained to run on a horizontal treadmill for 2 h at 20 m/min. This activity considerably increased plasma free tryptophan (TRP) (+70%) but did not alter plasma total TRP levels and had little or no effect on plasma concentrations of the other large neutral amino acids (LNAAs) that compete with TRP for entry into the brain. Brain TRP levels increased by 80%. The only other brain LNAA to be affected by exercise was threonine, which rose moderately. The results indicate that increased plasma free TRP was specifically responsible for the increase of brain TRP after 2 h of exercise. Brain lysine was also increased whereas glycine, alanine, and gamma-aminobutyric acid were decreased. The differences between the present findings and those previously obtained following 2 h immobilization stress are discussed.

Alanine↗