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PubMed1991

Dynamics of L-valine in relation to the production of cyclosporin A by Tolypocladium inflatum.

We report the kinetics of endogenous L-valine in the fungus Tolypocladium inflatum, in an effort to understand the enhancing effect of externally supplemented L-valine on the production of the immunosuppressant cyclosporin A (CyA) in chemically defined medium. In a batch laboratory stirred reactor cultivation, the concentration of intracellular L-valine increased by up to four times between the end of the exponential phase and the beginning of the stationary phase when the medium was supplemented externally with 4 g/l L-valine. The final CyA titre under these conditions was 710 mg/l compared to only 130 mg/l attained without L-valine supplementation. In contrast to substantial growth-associated production of CyA in unsupplemented culture, the formation of the immunosuppressant was prolonged during the stationary phase in L-valine-supplemented medium. As a result, the conversion yield of CyA on L-valine remained constant during the stationary phase at 0.27 g CyA/g L-valine.

Cyclosporins↗

PubMed1984

Effect of D-valine and cytosine arabinoside on [3H]thymidine incorporation in rat and rabbit epididymal epithelial cell cultures.

Epithelial cell enriched primary cultures were established from the rat and the rabbit epididymis. Epithelial cell aggregates, obtained after pronase digestion of minced epididymis, attached to the culture dish and after 72 h in vitro spread out to form discrete patches of cells. These cells have an epithelioid morphology and form a monolayer of closely apposed polygonal cells where DNA synthesis, as judged by [3H]thymidine uptake, is very low. In L-valine medium the nonepithelial cell contamination was no more than 10% in rat and rabbit epididymal primary cultures. The labeling index of rat epididymal cells cultured in D-valine medium was significantly lower than that of cells cultured in L-valine medium. In contrast, the labeling index of rabbit epididymal cells cultured in D-valine medium was significantly higher than that of cells cultured in L-valine medium. Cytosine arabinoside decreased the number of labeled cells in both L-valine and D-valine cultures. From these results, it appears that D-valine is a selective agent for rat epididymal epithelial cells, but not for rabbit epithelial cells, and that cytosine arabinoside is a simple and effective means to control the proliferation of fibroblast-like cells in both rat and rabbit epididymal cell cultures.

Animals↗

PubMed1998

Effects of L-valine on growth and polyamine metabolism in human colon carcinoma cells.

HT-29 cells, originating from a human colon carcinoma, can proliferate in standard culture conditions with an absolute requirement for polyamines. The major precursor provided in the culture medium for polyamine biosynthesis is L-arginine. L-Arginine conversion to L-ornithine by arginase is followed by stepwise conversion of this latter amino acid to putrescine, spermidine and spermine. The aim of the present work was to document the consequences of a total inhibition of L-arginine flux through arginase, resulting in a decreased L-ornithine availability, on HT-29 cell proliferation and polyamine metabolism. L-Valine, a known arginase inhibitor, when used at a high concentration, i.e., 100 mM, inhibits L-arginine flux through arginase almost totally. The addition in the culture medium of 100 mM L-valine or 50 mM NaCl used to mimic the L-valine induced increase in medium osmolality both reduced equally cellular growth. Cell viability, protein synthesis or oxidative metabolism measured in isolated cells were unaffected by the L-valine treatment, suggesting that decreased proliferation was not associated with an acute toxic effect of this aminoacid, but was rather due to the increase in the medium osmolality. L-Valine treated cells displayed an altered polyamine metabolism when compared with control cells grown in the absence of the amino acid. After 4 days of treatment with 100 mM L-valine, L-ornithine flux through ornithine decarboxylase was significantly higher as well as putrescine and spermidine cellular uptakes in treated cells. However, the changes in polyamine metabolism led to similar polyamine cell contents in untreated and L-valine treated cells. In conclusion, we propose that the observed alterations of polyamine metabolism may reflect an adaptative response of HT-29 cells to the presence of L-valine which contribute together with the low amount of L-ornithine present in the culture medium to polyamine homeostasis.

Arginine↗

PubMed1977

Valine requirement of the growing kitten.

The valine requirement of the kitten was studied using a crossover design with two groups of three weanling kittens. The kittens were fed a semipurified diet containing only free amino acids as a source of nitrogen containing 0.0%, 0.6%, or 1.8% valine. The mean +/- SE of the linear components of growth (g/day) of the six kittens were respectively:-13.8 +/- 1.7, 17.3 +/- 4.8, and 15.3 +/- 2.6. Corresponding food intakes were 26.0 +/- 3.9, 50.4 +/- 2.5, and 44.0 +/- 1.5. Nitrogen balance was positive with the same amount retained for the two valine-containing diets while nitrogen balance was negative for the kittens fed the valine-free diet. Plasms valine dropped markedly when the dietary valine was decreased from 1.8% to 0.6% (363 +/- 59 versus 66 +/- 13 nmole/ml), and was further decreased (33 +/- 13) when the valine-free diet was fed. It does not appear that the valine requirement of the kitten exceeds 0.6% of a diet containing 25% fat. These results support the hypothesis that the high protein requirement of the kitten is not a result of a high requirement for all the essential amino acids, but a result of a high "nitrogen" requirement.

Amino Acids↗

PubMed1967

Induced phenotypic resistance to valine in Mycobacterium pellegrino.

Valine coordinately increases the levels of three of the enzymes participating in the biosynthesis of isoleucine and valine in Mycobacterium pellegrino. The amount of valine required for end-product induction depends on the condition of the cells. Isoleucine inhibits the effect of valine. Acetohydroxy acid synthetase, the enzyme catalyzing the first common step in the biosynthesis of valine and isoleucine, is inhibited by valine. The induction effect of valine appears to be due to its ability to inhibit the activity of this enzyme, thus causing isoleucine deficiency, which in turn leads to derepression. This conclusion is supported by the fact that valine, under certain conditions, inhibits growth.

Enzyme Repression↗

PubMed1987

Valine entry into rat brain after diet-induced changes in plasma amino acids.

Passage of amino acids across the blood-brain barrier is assumed to be modified by amino acid composition of the blood. To gain a better understanding of the effects of protein intake on brain amino acid uptake, we examined associations among diet, plasma amino acid patterns, and the rate of entry of valine into the brain. Rats were fed (8 h/day for 7-10 days) diets containing 6, 18, or 50% casein before receiving one meal of a diet containing 0, 6, 18, or 50% casein. After 4-7 h, they were anesthetized and infused intravenously with [14C]valine for 5 min before plasma and brain samples were taken for determination of radioactivity and content of individual amino acids. As protein content of the meal was increased from 0 to 50% casein, plasma and brain concentrations of valine and most other large neutral amino acids (LNAA) increased severalfold; also the ratio of [14C]valine in brain to that in plasma decreased by greater than 50%, and the rate of valine entry into the brain increased 3.5-fold. The increase in valine flux slowed as plasma levels of LNAA, competitors for valine transport, increased. The results were far more dependent on protein content of the final meal than on that of the adaptation diet; thus changes in protein intake, as reflected in altered plasma amino acid patterns, markedly altered valine entry into the brain.

Amino Acids↗

PubMed1997

The effect of dietary lysine and valine fed during lactation on sow and litter performance.

Sows (98 first parity and 104 second parity) were used to determine the effects of dietary lysine and valine on lactation performance. Treatments were arranged in a 2 x 3 factorial with two levels of lysine (.80 or 1.20%) and three valine:lysine ratios (80, 100, or 120% of lysine). For all sows, increasing dietary lysine increased litter weaning weight (P < .001) and litter weight gain (P < .002) and reduced sow weight loss (P < .001). Litter weight gain tended (P = .22) to increase with increasing dietary valine, but the increase was not significant. Data were separated into two groups: sows that weaned 10 or more pigs and sows that weaned fewer than 10 pigs. For sows that weaned 10 or more pigs, litter weaning weight (P < .001) and litter weight gain (P < .001) increased and sow BW loss decreased (P < .001) when dietary lysine increased from .80 to 1.20%. For sows that weaned fewer than 10 pigs, increasing lysine had no effect (P < .77) on litter growth rate. For sows weaning 10 or more pigs, litter weaning weights (linear, P < .04; quadratic, P < .06) and litter weight gain increased (linear, P < .04; quadratic, P < .02) as dietary valine increased. For sows that weaned fewer than 10 pigs, maximum litter weight gain was observed at a valine:lysine ratio of 100% (quadratic, P < .13). These results demonstrate the need to increase dietary lysine and valine as litter weaning weights increase. High-producing sows that wean 10 or more pigs require increased dietary lysine and valine to maximize litter growth rate and minimize sow weight loss compared with sows weaning fewer than 10 pigs. The independent increases in litter weaning weights from adding lysine and valine suggest separate modes of action for these amino acids in high-producing sows.

Animals↗

PubMed1994

Cooperative binding of the feedback modifiers isoleucine and valine to biosynthetic threonine deaminase from Escherichia coli.

Control of the regulatory enzyme threonine deaminase from Escherichia coli is achieved by isoleucine inhibition and valine activation. The mechanism by which these heterotropic effectors regulate the enzyme was investigated by measuring the binding of isoleucine and valine by spectroscopic, kinetic, calorimetric and equilibrium dialysis techniques. The addition of isoleucine or valine to threonine deaminase resulted in large changes in the intrinsic fluorescence of the two tryptophans per polypeptide chain. Slightly cooperative binding isotherms for isoleucine were obtained in potassium phosphate, pH 7.5, yielding an average dissociation constant of 4.91 microM, which was confirmed by equilibrium dialysis measurements. Valine binding was much more cooperative, and yielded an average dissociation constant of 122 microM. Titration calorimetry experiments indicated that cooperative heterotropic ligand binding was exothermic, and yielded a stoichiometry of four isoleucine bound per tetrameric enzyme, with an average enthalpy of -10.70 kcal/mol. Valine also bound to four sites per tetramer, with an average enthalpy of -7.45 kcal/mol. The effect of ligands on the fluorescence and circular dichroism spectra of the essential pyridoxal phosphate cofactor indicates that isoleucine and valine bind to effector sites that are distinct from the active sites in threonine deaminase. Shifts in the kinetic properties of threonine deaminase promoted by isoleucine and valine binding are to a first approximation consistent with analyses of effector binding isotherms in terms of a simple two-state model, and suggest that isoleucine regulates threonine deaminase by preferentially binding to the low activity T state, whereas valine binds preferentially to the high activity R state. Finally, analyses of heterotropic effector binding isotherms suggest that active site ligands may have significant affinity for the regulatory sites, which gives rise to underestimates for the allosteric equilibrium constants determined from substrate analog binding isotherms.

Binding Sites↗

PubMed1998

Transport of L-valine-acyclovir via the oligopeptide transporter in the human intestinal cell line, Caco-2.

It has been reported that conjugating acyclovir, a potent antiviral with low oral bioavailability, to L-valine increases its urinary excretion in rats. However, it was also reported that this increase is not found for the D-valine ester, suggesting that a carrier-mediated mechanism is involved in its intestinal absorption. Therefore, mechanisms involved in the transepithelial transport of L-valine-acyclovir were investigated using the intestinal cell line, Caco-2, as a model system for the intestinal epithelium. Only the mucosal-to-serosal transport of acyclovir was increased by conjugation with L-valine (approximately 7-fold), suggesting the involvement of a carrier-mediated mechanism. This conclusion was supported by the finding that this increase was saturable. The mucosal-to-serosal transport of L-valine-acyclovir could be inhibited by L-glycylsarcosine, but not by L-valine, suggesting the involvement of the dipeptide carrier. Also it was found that L-valine-acyclovir inhibits the uptake of cephalexin, a substrate for the oligopeptide transporter. Stability of the esters in either the mucosal or serosal bathing solution is more than 90% after completion of the transport study. However, after transport, the receiver solution contained approximately 90% of acyclovir. Based on these findings it was concluded that absorption of the L-valine ester of acyclovir occurs as a result of uptake by the oligopeptide transporter at the apical cell membrane followed by intracellular hydrolysis of the ester and efflux of acyclovir.

Acyclovir↗

PubMed1992

Incorporation of [h]leucine and [h]valine into protein of freshwater bacteria: uptake kinetics and intracellular isotope dilution.

Incorporation of [H]leucine and [H]valine into proteins of freshwater bacteria was studied in two eutrophic lakes. Incorporation of both amino acids had a saturation level of about 50 nM external concentration. Only a fraction of the two amino acids taken up was used in protein synthesis. At 100 nM, the bacteria respired 91 and 78% of leucine and valine taken up, respectively. Respiration of H and C isotopes of leucine gave similar results. Most of the nonrespired leucine was recovered in bacterial proteins, while only up to one-half of the nonrespired valine occurred in proteins. In intracellular pools of the bacteria, [H]leucine reached an isotope saturation of 88 to 100% at concentrations of >40 nM. For [H]valine, an isotope equilibrium of about 90% was obtained at concentrations of >80 nM. Within an incubation period of typically 1 h, tritiated leucine and valine incorporated into proteins of the bacteria reached an isotope saturation of 2 to 6%. In a 99-h batch experiment, bacterial protein synthesis calculated from incorporation of leucine and valine corresponded to 31 and 51% (10 nM) and 89 and 97% (100 nM), respectively, of the chemically determined protein production. Measured conversion factors of 100 nM leucine and valine were 6.4 x 10 and 6.6 x 10 cells per mol, respectively, and fell within the expected theoretical values. The present study demonstrates that incorporation of both valine and leucine produces realistic measurements of protein synthesis in freshwater bacteria and that the incorporation can be used as a measure of bacterial production.

Journal Article↗

PubMed2006

Effect of valine on the efficiency and precision at S4 cleavage of the Notch-1 transmembrane domain.

Presenilin-dependent intramembranous proteolysis mediates the dual cleavage of the Notch-1 protein (S4 and S3) as well as the beta amyloid precursor protein (betaAPP) (gamma40 and epsilon-site). betaAPP has a valine residue just before the gamma40 (amyloid beta [Abeta] numbering) site and after the epsilon-site. Both gamma40 and epsilon have multiple cleavage sites, and the varieties of gamma40 cleavage are associated with Alzheimer's disease (AD). These lines of evidence suggest that valine plays a role in the intramembranous proteolysis. S4 cleavage in the middle of the Notch-1 transmembrane domain (TMD) corresponds to the gamma40 cleavage of betaAPP. The cleavage site is in the center of four sequential alanine residues between Ala1731 and Ala1732, neither of which has a valine residue. To investigate the effects of valine on presenilin-dependent intramembranous proteolysis, we replaced the transmembrane domain residue of Notch-1 with valine and analyzed the efficiency and precision at S4 and S3. We observed that all valine-mutated Notch-1 proteins have a dominant cleavage site (S4) between Ala1731 and Ala1732 with some variations of cleavage precision, suggesting that valine is not indispensable for determining the cleavage site of the Notch-1 transmembrane domain, but affects the efficiency and precision at S4 cleavage of the Notch-1 transmembrane domain.

Amino Acid Sequence↗

PubMed1984

Effects of perfusate leucine concentration on the metabolism of valine by the isolated rat hindquarter.

Rates of oxidation of valine and release of alpha-ketoisovaleric acid by hindquarters from rats fed a 9% casein diet were measured at intervals over 90 minutes. The hindquarters were perfused with medium containing between 0.03 and 10 mmol/L L-leucine; concentrations of valine and isoleucine were kept constant at 0.2 and 0.1 mmol/L, respectively. The rate of oxidation of [1-14C]valine increased two to threefold when the perfusate contained 0.8 or 1.0 mmol/L leucine but was depressed by 50% when the leucine concentration was 10 mmol/L. The rate of release of alpha-ketoisovaleric acid from the hindquarter was affected little by perfusate leucine concentrations up to 1.0 mmol/L, but release was depressed when perfusate leucine concentration was increased to 10 mmol/L. The rate of release of alpha-ketoisocaproic acid increased with increasing perfusate leucine concentration, as did intracellular alpha-ketoisocaproic acid and leucine concentrations. These results indicate that valine oxidation by the isolated perfused hindquarter is stimulated by a high perfusate leucine concentration (1.0 mmol/L), suggesting that this response contributes to the depressed plasma and tissue valine pools of rats fed a high-leucine diet. An excessively high concentration of leucine (10 mmol/L) suppresses valine oxidation, presumably by competing with valine for transmination or transport.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗

PubMed1986

Assessment of in vivo protein synthesis in lamb tissues with [3H]valine flooding doses.

Week-old lambs received an intravenous injection of 4.3, 8.5, 12.8 or 17.1 mmol [3H]valine/5 kg body weight, i.e., 3.6-14.4-times the whole-body free valine content. To ensure that protein synthesis measurements in lambs are reliable within a 30-min period, these large amounts of valine must account for at least around 11-times the total free pool of valine. This amounted to 12.8 mmol valine/5 kg body weight. There were no significant variations in plasma insulin and plasma glucagon levels 5, 13 and 30 min after the injection of so much valine. The fractional rates of protein synthesis were determined in tissues of animals receiving either 12.8 or 17.1 mmol valine/5 kg body weight. The rates of protein synthesis in the jejunum (87.5%/day), liver (106.6%/day) and tensor fasciae latae muscle (18.8%/day) of lambs injected with the 12.8 mmol [3H]valine flooding dose, were in the range of data obtained in immature rats. Increasing the flooding amount of valine up to 17.1 mmol/5 kg body weight did not significantly alter protein synthesis rates in the jejunum, liver or skeletal muscle. This suggested that both the flooding-dose method in itself and valine had no effect on in vivo protein synthesis.

Animals↗

PubMed1988

Culture of bovine mammary epithelial cells in D-valine modified medium: selective removal of contaminating fibroblasts.

Bovine mammary epithelial cells were cultured in nutrient medium containing D-valine substituted for L-valine in an attempt to control fibroblast overgrowth. Contamination of epithelial cell cultures with fibroblasts was prevented in cultures maintained in D-valine but not in control cultures containing L-valine. Microscopic examination of cells cultured in the D-valine medium demonstrated similar morphology as controls after 27 days in culture. Concentration of alpha-lactalbumin in the D-valine medium was similar to levels found in control medium. Results suggest D-valine modified medium controls fibroblast overgrowth of cell cultures, but doesn't impair epithelial cell morphology or function.

Animals↗

PubMed1977

Direct evidence for synthesis of valine in man.

Plasma valine and 13C-valine concentrations were measured in 2 healthy volunteers and 2 uraemic patients during and after a 3-hour intravenous infusion of the 13-c-labelled alpha-keto-acid analogue of valine. Plasma-valine increased by 23-43%. 13C-valine accounted for most of the early increase, but for less than 30% of the increase 1 hour after infusion. It was concluded that valine had increased by 2 mechanisms with different time courses. Initially, transamination of the infused ketoacid predominated, confirming directly for the first time that the essential aminoacid valine can be synthesised in-vivo both in health and uraemia. The previously unsuspected second mechanism was quantitatively more important but slower in ooperation; it may prove to be the key to understanding the metabolic effects of essential aminoacid precursors.

Adult↗

PubMed2000

Valine transport and biodiversity of Leuconostoc wild strains from French raw milk cheeses.

The rate of L-valine transport in whole cells of Leuconostoc was at the maximum at 30 degrees C, pH 6.0 in the presence of an energy source. Transport was inhibited by 40-55%, in the presence of the ionophores (valinomycin, nigericin or monensin), and uncouplers (carbonyl cyanide-m-chloro-phenylhydrazone or 2,4-dinitrophenol) confirming the previously described delta p-driven branched-chain amino acid transport system described in cytoplasmic membranes (Winters et al., 1991, Appl. Environ. Microbiol., 57, 3350-3354). Sulfhydryl group reagents (p-chloro-mercuribenzoate, iodoacetate and N-ethyl maleimide) all inhibited valine transport by 60-70%, indicating that valine is actively transported at high valine concentration. Three kinetically distinguishable transport systems were identified for each strain using whole cells, confirming results obtained with membranes. L-valine transport Kt and Vmax could be an additional tool to estimate the biodiversity of 18 Leuconostoc strains belonging to the dominant flora of French raw milk cheeses. Kt values varied from 20 to 510 nmol/l for the very high affinity system, from 26 to 427 pmol/l for the high affinity system and from 0.65 to 4.40 mmol/l for the low affinity system. No correlation existed between valine transport rates and a particular strain's ability to acidify milk or complex media, suggesting that valine transport is not a growth-limiting function in species of the genus Leuconostoc.

Biological Transport, Active↗

PubMed1979

Metabolism of [U-14C; 2,3-3H]-L-valine by the isolated perfused goat udder.

Two lactating mammary glands excised from 2 goats were perfused for several hours in the presence of [U-14C; 2,3-3H]-L-valine and received adequate quantities of glucose, acetate and amino acids. In the synthesized milk 96 and 89% respectively of the casein valine was derived from free plasma valine. Valine was extensively catabolized by mammary tissue, resulting in a considerable 14CO2 production and in the incorporation of 14C into milk citric acid and to a lesser extent into casein aspartic acid and glutamic acid. About 30% of the valine molecules which were taken up by the mammary gland were oxidized to CO2 and 70% were incorporated in casein as valine residues. About 10% of the plasma valine molecules were reversibly transaminated during one passage through the udder. An important amount of radioactivity of plasma was present in unknown metabolites. Only 7% of this activity was localized in isobutyrate. The radioactivity of total milk fat was very low. Mainly iso-14:0, iso-16:0 and 15:0 were labelled.

Animals↗

PubMed1999

Characterization of the reactivity, regioselectivity, and stereoselectivity of the reactions of butadiene monoxide with valinamide and the N-terminal valine of mouse and rat hemoglobin.

Occupational exposure to 1,3-butadiene (BD) has been monitored by measuring the level of hemoglobin N-terminal valine adduct formation with the primary reactive metabolite, butadiene monoxide (BMO). However, mechanistic details concerning the relative reactivity, regioselectivity, and stereospecificity of BMO with the N-terminal valine of hemoglobin are lacking. In the studies presented here, L-valinamide was used as a model for the N-terminal valine of hemoglobin to compare the nucleophilic reactivity, regioselectivity, and stereoselectivity of the reaction both in aqueous solution and within a protein microenvironment. Four products produced by the reaction of L-valinamide with racemic BMO (two pairs of diastereomers produced by reactions at C-1 and C-2 of the epoxide moiety) were synthesized, purified, and characterized by (1)H NMR and GC/MS. These four reaction products were used as analytical standards for kinetic studies of the reaction of valinamide with BMO at physiological pH (7.4) and temperature (37 degrees C). The results show that the adducts formed by reaction at C-2 were formed at a ratio of approximately 2:1 compared to the adducts formed by reaction at C-1. The stereoisomers of each respective regioisomer were produced with similar rates of formation. The reaction of BMO with the N-terminal valine of hemoglobin was also studied in vitro using intact erythrocytes from Sprague-Dawley rats and B6C3F1 mice. After cleavage of the N-modified valine by the N-alkyl Edman degradation procedure using pentafluorophenylisothiocyanate (PFPITC), a novel procedure was developed that allowed GC/MS detection and quantitation of the four expected products by silylation of the PFPTH-valine-BMO derivatives. The hemoglobin results contrast with the valinamide results in that the reaction of BMO with the N-terminal valine residue in both rat and mouse hemoglobin produced mostly C-1 adducts. The rates obtained with rat hemoglobin were much slower than the rates obtained with mouse hemoglobin or with valinamide. These results, and the finding that the reaction with rat hemoglobin produced a higher ratio of C1:C2 adducts in comparison with the reaction with mouse hemoglobin, indicate the importance of measuring all four adducts when comparing the relative rates of adduct formation both with model compounds and among different species.

Animals↗