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PubMed1990

Intrinsic fluorescence of succinyl-CoA synthetase and four tryptophan mutants. Tryptophan 76 and tryptophan 248 of the beta-subunit are responsive to CoA binding.

Previous studies showed that modification of an average of one of the three tryptophan residues of succinyl-CoA synthetase of Escherichia coli abolished enzyme activity, but did not prevent phosphorylation of the enzyme by ATP [Ybarra, J., Prasad, A. R. S., & Nishimura, J.S. (1986) Biochemistry 25, 7174-7178]. In the present study, single mutations in which each of the three tryptophans (beta-Trp43, beta-Trp76, and beta-Trp248) has been changed to phenylalanine (designated W43F, W76F, and W248F) have been accomplished by the technique of site-directed mutagenesis and the mutant proteins isolated. In addition, a double mutant in which beta-Trp43 and beta-Trp248 were changed to phenylalanines (W43,248F) has also been isolated. Each of the mutant enzymes was practically as active as wild type. Since the emission spectrum of beta-Trp76 reflected a low fluorescence intensity for this residue, it was possible to obtain the emission spectrum of each tryptophan residue by using W43F, W248F, and W43,248F. From the positions of the emission maxima and the results of iodide quenching of fluorescence, it was deduced that beta-Trp248 is a surface residue, beta-Trp43 is buried, and beta-Trp76 is intermediate in location. Coenzyme A, but no other substrate, protected the fluorescence of beta-Trp76 and beta-Trp248, but not of beta-Trp43, against quenching by acrylamide. These results are consistent with an interaction between beta-Trp76 and beta-Trp248 and the binding site for CoA.

Adenosine Diphosphate↗

PubMed2000

Brain net unidirectional uptake of alpha-[14c]methyl-L-tryptophan (alpha-MTrp) and its correlation with regional serotonin synthesis, tryptophan incorporation into proteins, and permeability surface area products of tryptophan and alpha-MTrp.

The uptake and trapping constants for labeled tryptophan (Trp) via the serotonin (5-hydroxytryptamine; 5-HT) metabolic pathway and for the incorporation of Trp into proteins, and alpha-[14C]methyl-L-tryptophan (alpha-MTrp) were measured. Measurements were done in rats treated with either saline or probenecid (200 mg/kg). In addition, the blood-brain barrier (BBB) permeability surface area products for Trp (PS(T)) and alpha-MTrp (PSalpha) were measured in normal rats. The results suggest that, in both groups of rats, there is a highly significant correlation (p < 0.05; Pearson Product Moment Correlation (PPMC) between the brain uptake and trapping constants for alpha-MTrp and those of Trp via the 5-HT metabolic pathway, but there is no significant correlation (p > 0.05; PPMC) between either of these constants and the PS products of either compound. There is also no significant correlation (p > 0.05; PPMC) between the constant for the Trp incorporation into proteins with any of the other parameters. For all parameters, except Trp incorporation into proteins (alpha-MTrp is not incorporated into proteins), there was a highly significant correlation (p < 0.001) between the quantities measured for Trp and alpha-MTrp. The data presented here strongly suggests that the brain uptake and trapping of alpha-MTrp relates to brain 5-HT synthesis, and does not relate to the BBB transport or protein incorporation of Trp. On the basis of these results, as well as those previously reported, we concluded that trapping (unidirectional uptake) of alpha-MTrp can be converted to the 5-HT synthesis rates in the brain. From this also follows that labeled alpha-MTrp is a good tracer for in vivo evaluation of the brain 5-HT synthesis.

Animals↗

PubMed1992

The metabolic fate of infused L-tryptophan in men: possible clinical implications of the accumulation of circulating tryptophan and tryptophan metabolites.

L-Tryptophan (Trp) was widely used as a natural tool for the support of serotonin-mediated brain functions and as a challenge probe for the assessment of serotonin-mediated neuroendocrine responses. The metabolic fate of the administered Trp and the kinetics of the accumulation of Trp metabolites in the circulation, however, have never thoroughly been investigated. This study describes the time- and dose-dependent alterations in the plasma levels of various Trp metabolites and large neutral amino acids after the infusion of Trp to healthy young men (1, 3 and 5 g; placebo-controlled, double-blind, cross-over study during day- and night-time). The major Trp metabolites (kynurenine, indole acetic acid and indole lactic acid) in plasma increased dose-dependently but rather slowly after Trp administration to reach their maximal plasma levels (up to 10-fold after the 5 g dose) at about 3 h p.i., and remained at an elevated level (about 5-fold) for up to 8 h. N-acetyl-Trp and 5-hydroxy-Trp rose rapidly and massively after Trp infusions, at the 5 g dose more than 200- and 20-fold, respectively, and declined rapidly to about 5-fold baseline levels within 2 h. Whole blood serotonin levels were almost unaffected by the Trp infusions. A rather slow increase of 5-hydroxyindole acetic acid was seen, reaching maximum values (3-fold at the 5 g dose) at about 2 h after the infusion of Trp. Additionally, a dose-dependent rise of circulating melatonin was observed after L-Trp infusions. The administration of L-Trp caused a depletion of the concentrations of the other large neutral amino acids and a dose dependent decrease of the ratio between plasma tyrosine and the sum of the plasma concentrations of the other large neutral amino acids. Apparently, none of the existing pathways of peripheral Trp metabolism is saturated by its substrate, Trp in men. At least some of the central effects reported after L-Trp administration may be mediated by the Trp-stimulated formation of neuroactive metabolites or by the decreased availability of tyrosine for catecholamine synthesis.

Adult↗

PubMed2005

Estimates of individual factors of the tryptophan requirement based on protein and tryptophan accretion responses to increasing tryptophan supply in broiler chickens 8-21 days of age.

Ten diets (196 g CP and 13.0 MJ ME(N)/kg) with graded levels of tryptophan (Trp) between 0.9 and 2.7 g/kg were offered ad libitum to Ross broilers from day 8-21 post-hatch. Each diet was allocated to three pens of ten birds each. In addition to growth and feed conversion, the accretions of protein, Trp, fat, and energy were determined by comparative whole body analyses. A sigmoidal function was fitted to the data. Responses to Trp supply were nonlinear and attained plateau values (y(max)) within the studied range of Trp supply. The Y(max) values estimated for BW gain, whole body protein gain, and Trp gain during the 14 days under study were 615, 104, and 0.87 g/bird, respectively. Based on the response in whole body protein gain, the estimated requirement was 1.9 g Trp/kg of diet or 0.15 g Trp/MJ of MEN. Estimates made from the other response criteria were similar to this value. While the protein concentration in gained BW was unaffected by Trp intake (169 g of protein per kg of gained BW), fat and energy concentrations of gained BW increased with increasing Trp supply, approaching plateau values of 146 g fat and 9.8 MJ energy per kg of gained BW. This is supposed to result from feed intake increasing with Trp supplementation. The Trp concentration in gained whole body protein (0.84 g Trp/ 16 g of gained N) was not significantly affected by Trp intake. As long as Trp intake was the limiting factor, 59% of supplemented Trp was transferred to gained whole body protein. During the 14 days of the study, broilers inevitably lost 87 mg Trp. This is equivalent to a daily loss of 30 mg/kg BW or a maintenance requirement of 52 mg/kg BW per day. Data determined for the individual factors may be used for future modelling of broilers' Trp requirement.

Animal Feed↗

PubMed1981

Mechanism of decline in rat brain 5-hydroxytryptamine after induction of liver tryptophan pyrrolase by hydrocortisone: roles of tryptophan catabolism and kynurenine synthesis.

1 Two mechanisms have been proposed to explain the decline in brain tryptophan and 5-hydroxytryptamine (5-HT) after administration of hydrocortisone and the subsequent induction of liver pyrrolase. These are depletion of tryptophan by high rates of tryptophan catabolism and inhibition of tryptophan uptake by elevated levels of the tryptophan catabolite, kynurenine.2 The increase in plasma kynurenine after hydrocortisone injection (25 mg/kg) was small, and kynurenine, at a concentration ten fold greater, did not inhibit tryptophan uptake by brain as measured by the Oldendorf technique. Thus, inhibition of tryptophan uptake by kynurenine is not an important mechanism in the control of brain tryptophan and 5-HT.3 The decline in brain tryptophan after hydrocortisone was comparable to that seen in other tissues, which comprise more than half of the body weight of a rat.4 The total decline in free tryptophan stores in whole animals treated with hydrocortisone was estimated to be about 450 mug. This amount of tryptophan would be catabolized by tryptophan pyrrolase in about 20 min, when the enzyme is induced, according to an earlier estimate of the rate of tryptophan catabolism in vivo.5 Tryptophan pyrrolase activity remains high for much longer than 20 min, suggesting that there is net protein catabolism, which releases tryptophan and prevents non-protein tryptophan levels falling very far.6 These results demonstrate that the decline in brain tryptophan and 5-HT after hydrocortisone is caused by depletion of tryptophan stores due to the high activity of tryptophan pyrrolase. However, our data suggest that this effect is diminished by release of tryptophan from proteins. Thus, peripheral protein metabolism may be an important factor in the control of brain tryptophan levels and 5-HT synthesis.

Animals↗

PubMed2006

Effects of tryptophan supplementation on plasma tryptophan and related hormone levels in heifers and dairy cows.

This study was conducted to investigate the effects of rumen-protected tryptophan (125 g tryptophan per day) in heifers and dairy cows. Blood samples from dairy cows and heifers were collected for 24h in 3-h intervals on the day before tryptophan supplementation, on day 2, 5 and 7 of tryptophan supplementation, and in heifers additionally on d 14 after tryptophan supplementation was ceased. Plasma tryptophan, melatonin, serotonin, and prolactin concentrations were determined. Tryptophan plasma concentrations on d 5 were augmented at day (11:00 h) and nighttime (02:00 h), (P<0.05) in response to tryptophan supplementation in heifers by 119% and in dairy cows by 47%, respectively, as compared with d 0. Melatonin increased (P<0.05) in response to tryptophan supplementation in heifers, but not in cows. The effect of tryptophan supplementation on plasma tryptophan and melatonin was reversible as demonstrated in heifers on d 14 after cessation of tryptophan supplementation. Serotonin and prolactin in plasma did not respond to tryptophan supplementation. However, milk yield during morning milking increased significantly in tryptophan supplemented cows on d 1, 3 and 4 as compared to the day before tryptophan supplementation. Additional blood samples were taken during afternoon milking in cows at 1-min intervals for the analyses of oxytocin and prolactin on the day before the start and on d 7 of tryptophan supplementation. Milk flow curves were recorded during milking. No effect of tryptophan supplementation on the milking related release of oxytocin and prolactin and on any characteristic of milk flow was observed. In conclusion, tryptophan supplementation caused increased plasma tryptophan in cows and heifers and plasma melatonin in heifers. However, plasma serotonin, prolactin and oxytocin release in cows remained unchanged by tryptophan supplementation. Milk yield at morning milking increased slightly and transiently in response to tryptophan supplementation.

Animals↗

PubMed1980

Metabolism of an oral tryptophan load. I: Effects of dose and pretreatment with tryptophan.

1 The metabolism of three oral doses of L-tryptophan (50, 25 and 10 mg/kg) in healthy young males has been investigated. 2 There was a linear relationship between both peak and area under curve of the total plasma tryptophan concentrations whilst the relationship between these parameters and plasma free tryptophan was hyperbolic. 3 Before the tryptophan load about 85% of plasma tryptophan was bound to albumin. As plasma tryptophan concentrations increased there was a hyperbolic increase in free tryptophan. Scatchard analysis revealed 1.4 binding sites/molecule albumin with a dissociation constant (Kd) of 57.9 microM. Following administration of L-tryptophan (50 mg/kg) twice daily for 7 days there was no alteration in the number of binding sites but the dissociation constant (Kd) had decreased to 30.9 microM. 4 L-Tryptophan (50 mg/kg twice daily for 7 days) markedly increased both basal plasma total and free tryptophan. However following a further load the total tryptophan curve was comparable to that seen after acute administration. The plasma free tryptophan curve was lowered relative to that seen after an acute dose. 5 Increasing the tryptophan dose shortened the plasma half-life and decreased the volume of distribution and the rate of clearance. Longer term tryptophan administration had no significant effect on plasma half-life or volume of distribution but did decrease the rate of plasma clearance. 6 The plasma kynurenine concentration increased with increasing tryptophan dose and basal concentrations increased markedly after longer term tryptophan administration. 7 Tryptophan administration either acutely or chronically produced little change in urinary tryptophan or 5-hydroxyindole acetic acid excretion. Urinary kynurenine and indole acetic acid excretion increased with increasing doses of tryptophan. 8 Data are discussed in relation to the administration of L-tryptophan for the treatment of depression.

Administration, Oral↗

PubMed1984

Ethanol-induced increase in liver tryptophan oxygenase activity in the starved rat: evidence against tryptophan mediation.

A single oral dose of ethanol (4.0 g/kg) increased the activity of liver tryptophan oxygenase in starved male rats. The peak increase of 340% for the total activity and 400% for the holoenzyme activity occurred 6 hr after ethanol administration. At or after these peaks, the levels of tryptophan in plasma and brain but not in liver, decreased significantly. Plasma total tryptophan and brain tryptophan started to decrease significantly as early as 0.5-1.0 hr after the ethanol treatment, while the activity of liver tryptophan oxygenase was still at the control level. These findings suggest that not all the changes in tissue tryptophan concentrations seen after acute ethanol treatment are caused by increased liver tryptophan oxygenase activity. Prior to the increase in liver tryptophan oxygenase activity, an increase of 104 and 50% in plasma corticosterone and free tryptophan, respectively, were seen 15 min after ethanol treatment. However, the increase in liver tryptophan at this time appeared to be small (13%) and statistically insignificant. With tryptophan treatment, the initial peak levels of liver tryptophan and plasma free tryptophan required to stimulate an increase in tryptophan oxygenase activity were 170 times higher than those caused by ethanol. It was therefore concluded that increases in plasma and liver tryptophan after acute ethanol ingestion, probably mediated by the lipolytic action of ethanol, are too small to cause the increase in liver tryptophan oxygenase activity seen after ethanol administration. However, experiments with different corticosterone doses showed that ethanol-induced increases in plasma corticosterone concentrations are high enough to cause an increase in liver tryptophan oxygenase activity.

Animals↗

PubMed1980

The metabolism of L-tryptophan by isolated rat liver cells. Quantification of the relative importance of, and the effect of nutritional status on, the individual pathways of tryptophan metabolism.

1. The metabolism of L-tryptophan by liver cells prepared from fed and 48 h-starved rats was studied. Methods are described, with the use of L-[ring-2-(14)C], L-[carboxy-14C]-and L-[benzene-ring-U-14C]-tryptophan, for the simultaneous determination of tryptophan 2,3-dioxygenase and kynureninase activities and of the oxidation of tryptophan to CO2 and non-aromatic intermediates of the kynurenine-glutarate pathway. 2. At physiological concentrations (0.1 mM), tryptophan was oxidized by tryptophan 2,3-dioxygenase at comparable rates in liver cells from both fed and starved rats. Kynureninase activity of hepatocytes from starved rats was 50% greater than that of cells from fed rats. About 10% of the tryptophan metabolized by tryptophan 2,3-dioxygenase was degraded completely to CO2. 3. In the presence of 0.5 mM-L-tryptophan, tryptophan 2,3-dioxygenase and kynureninase activities increased 5--6-fold. Liver cells from starved rats oxidized tryptophan at about twice the rate of these from fed rats. Degradation of tryptophan to non-aromatic intermediates of the glutarate pathway and CO2 was increased only 3-fold, suggesting an accumulation of aromatic intermediates of the kynurenine pathway. 4. Rates of metabolism with 2.5 mM-L-tryptophan were not significantly different from those obtained with 0.5 mM-tryptophan. 5. Rates of synthesis of quinolinic acid from 0.5 mM-L-tryptophan, determined either by direct quantification or indirectly from rates of radioisotope release from L-[carboxy-(14)C]- and [benzene-ring-U-14C]tryptophan, were essentially similar. 6. At all three concentrations examined, tryptophan was degraded exclusively through kynurenine; there was no evidence of formation of either indol-3-ylacetic acid or 5-hydroxyindol-3-ylacetic acid.

Animals↗

PubMed2003

Injected tryptophan increases brain but not plasma tryptophan levels more in restrained rats.

Immobilization stress given for one hour decreased cumulative food intake and growth rate in rats. Activity in an open field scored next day was also smaller in the restrained animals. Stress is known to enhance brain serotonin (5-hydroxytryptamine; 5-HT) metabolism. It is however not clear, whether this enhancement is caused by an increase in the activity of tryptophan hydroxylase, the rate limiting enzyme of 5-HT biosynthesis or availability of the precursor tryptophan to the brain. In order to determine the utilization of tryptophan via serotonin path way in brain during stress; rats were injected with saline or tryptophan (50 mg/kg, i.p.). A group of both saline and tryptophan injected animals was restrained for one hour, while another group left unrestrained. The animals were killed immediately after the termination of stress period to collect plasma and brain samples. Injected tryptophan resulted in 3-4 fold rise of plasma tryptophan in both unstressed and stressed animals in one hour. Stress alone however had no effect on plasma total tryptophan concentration. Free tryptophan in plasma, brain tryptophan, 5-HT and 5-hydroxyindole acetic acid (5-HIAA) all increased by both stress and tryptophan injection. The increases of brain tryptophan, 5-HT and 5-HIAA but not of free tryptophan in plasma were considerably greater in restrained animals given tryptophan load. The results suggest that enhancement of brain serotonin metabolism during stress is caused by an increase in the availability of tryptophan to the brain as well as an increase in the activity of the enzyme tryptophan hydroxylase. Factors affecting the availability of tryptophan to the brain are discussed.

Journal Article↗

PubMed1985

Disturbances of tryptophan metabolism in mice acutely deprived of tryptophan.

The effect of a dietary tryptophan deficiency on tissue serotonin (5-hydroxytryptamine) synthesis rates, systemic tryptophan metabolism and its response to steroid or cycloheximide treatment was investigated. Brain serotonin synthesis was depressed in tryptophan-deprived (TD) mice while duodenal serotonin synthesis was enhanced following a tryptophan load. Liver total protein content was initially depressed in TD mice but increased following a tryptophan load. Blood tryptophan and albumin were depressed in TD mice while the percentage of albumin-bound tryptophan significantly increased in TD mice. Serum-free fatty acids were not significantly altered. Furthermore, enzyme kinetics studies indicated that in TD mice, tryptophan-5-hydroxylase has a reduced Vmax, while the Km for both tryptophan and the pteridine cofactor was significantly lowered. The tryptophan hydroxylase response to tryptophan or hydrocortisone injection was accentuated in TD mice while the tryptophan-2,3-dioxygenase response to tryptophan or hydrocortisone injection was blunted in TD mice. Finally, injection of tryptophan and cycloheximide blocked the tryptophan-2,3-dioxygenase response while the tryptophan hydroxylase response was unaltered in both control and TD diet mice.

Animals↗

PubMed1994

Studies with 1,1'-ethylidenebis(tryptophan), a contaminant associated with L-tryptophan implicated in the eosinophilia-myalgia syndrome.

L-Tryptophan binds to a rat liver nuclear envelope protein, and this binding is saturable, stereospecific, and of high affinity. Utilizing an in vitro assay of [3H]tryptophan binding to rat hepatic nuclear envelopes, we have previously determined that the L-tryptophan obtained from Showa Denko and which was implicated in cases of the eosinophilia-myalgia syndrome (EMS) inhibited [3H]tryptophan binding differently than did control L-tryptophan (not implicated in EMS). Therefore, in this study we investigated whether the addition of 1,1'-ethylidenebis(tryptophan) (EBT), a contaminant or impurity in L-tryptophan implicated in EMS, would have an effect. Our results indicate that EBT alone has little inhibitory binding effect compared with that of control L-tryptophan and that when EBT was added to control L-tryptophan the inhibitory binding effort was similar to that of control L-tryptophan alone. On the other hand, in vitro addition of EBT plus L-tryptophan to nuclei of cultured murine macrophages (WLG5) results in less inhibition of [3H]-tryptophan binding than does addition of L-tryptophan alone. Similar in vitro additions to nuclei of rat brain reveal little effect on binding, as was also the case for hepatic nuclear envelopes. Adding EBT to an in vitro hepatic protein synthesis system and measuring [3H]tryptophan incorporation into acid-precipitable proteins reveal that it competes similarly to that found with equimolar concentrations of unlabeled L-tryptophan. It does not affect [14C]leucine incorporation into proteins. [14C]EBT becomes incorporated in vitro into proteins (acid-precipitable), and this incorporation is diminished in the presence of equimolar concentrations of unlabeled EBT or L-tryptophan. This suggests that EBT or possibly a breakdown product becomes incorporated into proteins. Speculation as to how EBT may affect tissues in experimental animals is presented.

Animals↗

PubMed1995

The effects of a novel and selective inhibitor of tryptophan 2,3-dioxygenase on tryptophan and serotonin metabolism in the rat.

The effects of a novel inhibitor 680C91 ((E)-6-fluoro-3-[2-(3- pyridyl)vinyl]-1H-indole) of the key enzyme of tryptophan catabolism tryptophan 2,3-dioxygenase (TDO) (EC 1.13.11.11), were examined on tryptophan catabolism in vitro and in vivo and on brain levels of tryptophan, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). 680C91 was a potent (Ki = 51 nM) and selective TDO inhibitor with no inhibitory activity against indoleamine 2,3-dioxygenase (EC 1.13.11.17), monoamine oxidase A and B, 5-HT uptake and 5-HT1A,1D,2A and 2C receptors at a concentration of 10 microM. 680C91 had no effect on the binding of tryptophan to serum albumin in plasma and inhibited TDO competitively with respect to its substrate tryptophan. 680C91 inhibited the catabolism of tryptophan by rat liver cells and rat liver perfused in situ. The catabolism of L-[ring-2-14C]-tryptophan and a load dose of tryptophan (100 mg/kg) in vivo were inhibited by prior administration of 680C91. Administration of 680C91 alone produced marked increases in brain tryptophan, 5-HT and 5-HIAA. A load dose of tryptophan (100 mg/kg), producing increases in brain tryptophan 4-fold greater than that seen with 680C91, did not increase brain 5-HT and 5-HIAA to levels greater than those seen with 680C91 and produced a shorter-lasting increase in these parameters. These data therefore demonstrate the importance of TDO as a regulator of whole-body tryptophan catabolism and brain levels of tryptophan and 5-HT and suggest that a greater antidepressant efficacy might be achieved with inhibitors of TDO than tryptophan administration alone.

Animals↗

PubMed1996

Effects of alpha-deuteration and of aza and thia analogs of L-tryptophan on formation of intermediates in the reaction of Escherichia coli tryptophan indole-lyase.

Tryptophan indole-lyase catalyzes the hydrolytic cleavage of L-tryptophan to indole and ammonium pyruvate. After the enzyme is mixed with L-tryptophan in the rapid-scanning stopped-flow spectrophotometer, there is an absorbance increase at 505 nm in the pre-steady state attributed to formation of a quinonoid intermediate, which occurs in at least three consecutive first-order phases. Reaction with [alpha-2H]-L-tryptophan results in significant primary kinetic isotope effects on the first two phases, and there is a significant isotope effect on the amplitude of the absorbance increase in the second phase. This result suggests that proton transfer to carbon to form the indolenine intermediate is relatively slow and is probably at least partially rate-determining. Reaction of L-tryptophan in the presence of benzimidazole results in a rapid increase in absorbance in the first phase, followed by a decrease in absorbance in the second phase, with rate constants very similar to those observed without benzimidazole. We have also examined aza and thia analogs of L-tryptophan, with the benzene ring of the indole replaced by pyridine or thiophene. Both 4,5-thiatryptophan and 6,7-thiatryptophan form quinonoid intermediates in the reaction with tryptophan indole-lyase; however, 6,7-thiatryptophan is a better substrate (kcat/K(m) = 32% of L-trp) for tryptophan indole-lyase than is 4,5-thiatryptophan (kcat/K(m) = 4% of L-trp). Benzimidazole affects the pre-steady-state reaction of 6,7-thiatryptophan in a way similar to L-tryptophan, while benzimidazole does not affect the pre-steady-state reaction of 4,5-thiatryptophan. 4-Aza-, 5-aza-, 6-aza-, and 7-aza-L-tryptophan are all very slow substrates (kcat < 1% of L-trp) for Escherichia coli tryptophan indole-lyase. beta-Indazolyl-L-alanine is a relatively good substrate and exhibits a quinonoid intermediate in its reaction with tryptophan indole-lyase. 6-Aza- and 7-azatryptophan accumulate quinonoid intermediates in the reaction with tryptophan indole-lyase, whereas 4-aza- and 5-azatryptophans do not significantly accumulate quinonoid intermediates, and these latter compounds exhibit very high K(m) values. Addition of benzimidazole does not change the rapid-scanning stopped-flow spectra of 6-aza- and 7-azatryptophan. This suggests that the rate-determining step in the reaction changes depending on the position and type of heteroatom substitution. For 6-aza- and 7-azatryptophan, the very slow rates of elimination may be due to slow C-protonation of the azaindole, while for 4,5-thiatryptophan, the elimination of thienopyrrole is probably slow. Of all analogs examined, 6,7-thiatryptophan is most similar to tryptophan in its reaction with E. coli tryptophan indole-lyase.

Aza Compounds↗

PubMed1982

Effect of tryptophan intake on oxidation of [7a-14C]tryptophan and urinary excretion on N1-methylnicotinamide in the rat.

Oxidation of tryptophan and urinary excretion of niacin metabolites were studied in weanling rats fed ad libitum for 12 to 16 days niacin-free and nicotinamide-supplemented (20 mg/kg of diet) diets containing 15% of crystalline amino acids and from 0.04 to 1.0% of L-tryptophan. N1-methylnicotinamide was measured in urine collected during the last 3 days of the feeding period. After the feeding period, rats were placed in metabolic cages, and each rat was given 4 g (dry weight) of diet containing a tracer dose of DL-[7a-14C]tryptophan. Expired CO2 was collected hourly for 10 hours. In both the niacin-free and nicotinamide-supplemented groups, weight gains increased with increasing increments of tryptophan up to about 0.16% L-tryptophan. With more than 0.16% of L-tryptophan, the amount of N1-methylnicotinamide excreted per day by both groups of rats increased linearly with increasing tryptophan intake, but proportionately less N1-methylnicotinamide was excreted when the dietary tryptophan level was 1.0%. The amount of tryptophan oxidized per 10 hours increased linearly with increasing dietary tryptophan levels between 0.16 and 1.0%. Therefore, the decline in excretion of N1-methylnicotinamide with the 1.0% tryptophan level could not be accounted for by increased oxidation. These results suggest that after the tryptophan requirement for growth is met, the amount of tryptophan oxidized and converted to nicotinamide is directly proportional to the level of tryptophan intake up to about 3 times the requirement for growth. The tryptophan requirement of the growing rat fed niacin-free and nicotinamide-supplemented diets estimated from the inflection points of N1-methylnicotinamide excretion curves was in good agreement with the requirement of about 100 mumoles/day determined from the growth curve.

Animals↗

PubMed1999

Efficiency of a lysine-tryptophan blend as a tryptophan source in animal nutrition.

The use of L-tryptophan for balancing tryptophan deficient diets in animal feeding is currently impeded by the cost of feed-grade product. Recently ADM CORP. (Decatur, IL, USA) developed a method whereby liquid L-tryptophan and liquid L-lysine-HCl could be blended before drying. The final product contains at least 15% L-tryptophan and 70% L-lysine-HCl (Trademark Tryptosine). Experiments have been conducted with pigs and broilers to evaluate the efficiency of tryptophan from Tryptosine in comparison with feed grade L-tryptophan. Results indicated a clear tryptophan deficiency of the basal diet. Graded doses of tryptophan to the basal diet resulted in improvements in weight gain, daily feed intake and feed conversion rate. In pigs the differences in weight gain, feed intake and feed conversion rate between both tryptophan sources were not significant. In broilers feed intake with commercial L-tryptophan was higher than with Tryptosine. Weight gain, feed conversion rate and health state did not differ significantly between both sources. Protein deposition in broilers was significantly improved with dietary supplementation of 0.3 g/kg tryptophan, whereas the addition with 0.6 g/kg showed no further response. No differences were observed between both tryptophan sources. From the results of the two studies it was concluded that the biological activity of tryptophan from Tryptosine is equal to that of L-tryptophan for pigs and broilers.

Animal Feed↗

PubMed1980

Tryptophan and indolic tryptophan metabolites in chronic renal failure.

Tryptophan and indolic tryptophan metabolites were measured in the serum of normal subjects and chronic renal failure patients. The tryptophan free/total ratio was 0.07 in the normal serum, but the other tryptophan metabolite values were below detectable levels. The free/total ratio was 0.66 in patients with chronic renal failure, and both increase of free tryptophan and decrease of total tryptophan were observed. At the same time, 5-hydroxyindoleacetic acid, indole acetic acid, 5-hydroxytryptophol, and N-acetyltryptophan also increased in the serum of chronic renal failure patients, existing not only in free form but in protein-bound form. In the serum samples, following hemodialysis the indolic tryptophan metabolites showed a tendency to decrease, and the tryptophan free/total ratio of 0.42 a approached the normal value. When indolic tryptophan metabolites were added to normal serum in vitro, the free tryptophan level rose, and competition for binding to albumin between tryptophan and indolic tryptophan metabolites was observed. These findings suggested that the cause of the decrease in protein-bound tryptophan in uremic serum may be an accumulation of indolic tryptophan metabolites which complete for binding to albumin in uremia.

Humans↗

PubMed1985

The role of tryptophan 2,3-dioxygenase in the hormonal control of tryptophan metabolism in isolated rat liver cells. Effects of glucocorticoids and experimental diabetes.

The metabolism of L-tryptophan by isolated liver cells prepared from control, adrenalectomized, glucocorticoid-treated, acute-diabetic, chronic-diabetic and insulin-treated chronic-diabetic rats was studied. Liver cells from adrenalectomized rats metabolized tryptophan at rates comparable with the minimum diurnal rates of controls, but different from rates determined for cells from control rats 4h later. Administration of dexamethasone phosphate increased the activity of tryptophan 2,3-dioxygenase (EC 1.13.11.11) 7-8-fold, and the flux through the kynurenine pathway 3-4-fold, in cells from both control and adrenalectomized rats. Increases in flux through kynureninase (EC 3.7.1.3) and to acetyl-CoA can be explained in terms of increased substrate supply from tryptophan 2,3-dioxygenase. The metabolism of tryptophan was increased 3-fold in liver cells isolated from acutely (3 days) diabetic rats, with a 7-8-fold increase in the maximal activity of tryptophan 2,3-dioxygenase. The oxidation of tryptophan to CO2 and metabolites of the glutarate pathway increased 4-5-fold, consistent with an increase in picolinate carboxylase (EC 4.1.1.45) activity. Liver cells isolated from chronic (10 days) diabetic rats metabolized tryptophan at rates comparable with those of cells from acutely diabetic rats, but with a 50% decrease in the activity of tryptophan 2,3-dioxygenase. The proportion of flux from tryptophan 2,3-dioxygenase to acetyl-CoA, however, was increased by 50%; this was indicative of further increases in the activity of picolinate carboxylase. Administration of insulin partially reversed the effects of chronic diabetes on the activity of tryptophan 2,3-dioxygenase and flux through the kynurenine pathway, but had no effect on the increased activity of picolinate carboxylase. The role of tryptophan 2,3-dioxygenase in regulating the blood tryptophan concentration is discussed with reference to its sensitivity to the above conditions.

Adrenalectomy↗