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PubMed1995

Glycerol effect on spiramycin production and valine catabolism in Streptomyces ambofaciens.

Spiramycin production by Streptomyces ambofaciens in a chemically defined medium, with valine as nitrogen source, was controlled by the nature and the concentration of the carbon source. The production of this antibiotic was better in dextrins than in glycerol-containing medium. The negative effect of glycerol could be attributed in part to an excess of energy and a high specific growth rate. The intracellular ATP content, at the start of spiramycin production, was twofold higher in glycerol than in dextrin-containing medium. Increasing the initial concentrations of glycerol led to an increase in the specific growth rate and a drop in spiramycin production. Comparison between glycerol and a protein synthesis inhibitor effects and the use of resting cell systems (RCS) proved that glycerol exerted both inhibitory and repressive actions on spiramycin production independently from the growth. At the enzymatic level, glycerol interfered with valine catabolism by repressing partially valine dehydrogenase (VDH) and alpha-ketoisovalerate dehydrogenase (KIVDH), generator of spiramycin aglycone precursors.

Amino Acid Oxidoreductases↗
PubMed1988

Regulation of isoleucine-valine biosynthesis in Saccharomyces cerevisiae.

The threonine deaminase gene (ILV1) of Saccharomyces cerevisiae has been designated "multifunctional" since Bollon (1974) indicated its involvement both in the catalysis of the first step in isoleucine biosynthesis and in the regulation of the isoleucine-valine pathway. Its role in regulation is characterized by a decrease in the activity of the five isoleucine-valine enzymes when cells are grown in the presence of the three branched-chain amino acids, isoleucine, valine and leucine (multivalent repression). We have demonstrated that the regulation of AHA reductoisomerase (encoded by ILV5) and branched-chain amino acid transaminase is unaffected by the deletion of ILV1, subsequently revealing that the two enzymes can be regulated in the absence of threonine deaminase. Both threonine deaminase activity and ILV1 mRNA levels increase in mutants (gcd2 and gcd3) having constitutively depressed levels of enzymes under the general control of amino acid biosynthesis, as well as in response to starvation for tryptophan and branched-chain amino acid imbalance. Thus, the ILV1 gene is under general amino acid control, as is the case for both the ILV5 and the transaminase gene. Multivalent repression of reductoisomerase and transaminase can be observed in mutants defective in general control (gcn and gcd), whereas this is not the case for threonine deaminase. Our analysis suggests that repression effected by general control is not complete in minimal medium. Amino acid dependent regulation of threonine deaminase is only through general control, while the branched-chain amino acid repression of AHA reducto isomerase and the transaminase is caused both by general control and an amino acid-specific regulation.

Enzyme Repression↗
PubMed1993

Deleting valine-125 and cysteine-126 in glycoprotein gI of pseudorabies virus strain NIA-3 decreases plaque size and reduces virulence in mice.

We investigated the function of antigenic domains on gI in virulence and immunogenicity. Three PRV gI mutants were constructed by deleting nucleotides coding for the following amino acids: valine-125 and cysteine-126, located in a discontinuous antigenic domain (M 303); glycine-59 and aspartic acid-60 located in a continuous antigenic domain (M304); and arginine-67 and alanine-68, located in a discontinuous antigenic domain (M305). Mismatch primers in the polymerase chain reaction were used to introduce the deletions. Anti-gI monoclonal antibodies were used in an immunoperoxidase monolayer assay to distinguish PRV gI mutants from wild-type PRV. The gI mutant viruses were tested for their growth in vitro and for their virulence in mice. The growth properties of PRV gI mutant virus M303 were comparable to the growth properties of a PRV gI-negative mutant (M301): both mutants produced small plaques in various cells, and when grown on swine kidney cells and chicken embryo fibroblasts, their growth was disadvantaged compared to wild-type PRV. However, in embryonal Balb/c mouse cells expressing gI, gI mutant viruses and wild-type PRV produced plaques of the same size, confirming that the mutations in gI are responsible for the small plaque phenotype. The growth properties of PRV gI mutant viruses M 304 and M 305 were comparable to the growth properties of wild-type PRV. When the mean time to death was used as the criterion, the gI mutant viruses M 301 and M 303 were significantly less virulent in mice than wild-type PRV. Four other, independently obtained, PRV mutants all carrying the valine-125 and cysteine-126 deletion (M 308, M 309, M 310 and M 311 respectively) exhibit the same phenotype. Our results show that deleting valine-125 and cysteine-126 in gI decreases plaque size and reduces virulence in mice to the same degree as deleting the gI protein.

Amino Acid Sequence↗
PubMed1975

A comparison of the rate equations, kinetic parameters, and activation energies for the initial uptake of L-lysine, L-valine, gamma-aminobutyric acid, and alpha-aminoisobutyric acid by mouse brain slices.

At substrate concentrations, in medium, of 0.2 to 20 mM and at temperatures of 25 and 37 degrees C, the initial concentrative influx of the amino acids L-lysine (30 and 37 degrees C), L-valine, and gamma-aminobutyric acid into incubated mouse-cerebrum slices follows the rate equation for the initial influx of alpha-aminoisobutyric acid (Cohen, J. Physiol. 228:105, 1973), v equals Vmax/(1+Kt/S)+kuS. Kinetic constants at 37 degrees C are: Vmax equals 0.089 mumoles/g final wet wt of slices, min, Kt equals 0.69 mM, ku equals 0.037 mumoles/g final wet wt, mM-substrate, min for L-lysine; Vmax equals 0.60, Kt equals 1.30, ku equals 0.067 for L-valine; and Vmax equals 1.71, Kt equals 1.58, ku equals 0.094 for gamma-aminobutyric acid. The linear term, kuS, is due to an unsaturable process of concentrative uptake, not diffusion. Comparison of temperature coefficients reveals a "reference" pattern for typical low affinity transport of amino acids into brain slices. Its characteristics are: Activation energies associated with Vmax and ku are in range 14 to 20 kcal/mole; K, varies only slightly with temperature, L-Lysine and alpha-aminoisobutyric acid fit this pattern; L-valine and gamma-aminobutyric acid deviate in part. The Akedo-Christensen plot (J. Biol. Chem. 237:118, 1962) does not distinguish between the rateequation v equals Vmax/(1+Kt/S)+kuS for saturable uptake plus first-order unsaturable concentrative uptake, and the rate equation v equals Vmax/(1 + Kt/S)+kd(S minus Si) for saturable uptake plus first-order nonconcentrative "passive diffusion".

Amino Acids↗
PubMed1995

Regulation of L-valine absorption by opioids interacting with mu-receptors in rabbit ileum.

In intact tissue, [D-Ala2,MePhe4,Gly-ol5]enkephalin (10(-5) M; mu-ligand), diminished short-circuit current (Isc) and increased water, Na+ and Cl- net fluxes in vitro under open circuit conditions; it also inhibited L-valine absorption and L-valine-dependent variations of short-circuit current (delta Isc,val). Naloxone (10(-6) M) antagonized these effects. In the absence of the muscularis and myenteric plexus this enkephalin or morphine (mu-ligand) reduced Isc and delta Isc,val. These enkephalin effects occurred at different times. Different concentrations of enkephalin were tested for their effects on delta Isc,val. [D-Ala2,D-Leu5]enkephalin (mainly a delta-ligand) significantly decreased Isc but not delta Isc,val. The reduction of L-valine absorption does not depend on the effects on basal ion transport. Interaction of opioids with mu-receptors located in the submucosal plexus and/or in the epithelial cell accounts for this reduction. This enkephalin effect seems to be at least partially under the control of the myenteric plexus.

Analgesics↗
PubMed1985

Properties of a microsomal enzyme system from Linum usitatissimum (linen flax) which oxidizes valine to acetone cyanohydrin and isoleucine to 2-methylbutanone cyanohydrin.

Microsomal preparations from flax seedlings have recently been shown to convert L-valine to acetone cyanohydrin, the precursor of the cyanogenic glucoside linamarin [A. J. Cutler and E. E. Conn (1981) Arch. Biochem. Biophys. 212, 468-474]. Further details of this four-step biosynthetic sequence and also details of the analogous reactions in lotaustralin biosynthesis have been obtained. The lotaustralin precursor, 2-methylbutyraldoxime, is the best substrate for cyanide production (Vmax = 413 nmol h-1 g fresh wt-1) and inhibits the conversion of valine and isoleucine into products. Similarly, the linamarin precursor isobutyraldoxime is an excellent substrate (Vmax = 400 nmol h-1 g fresh wt-1) and also inhibits oxidation of the amino acids. The substrate specificity of the oxime-metabolizing step is low and a variety of aliphatic oximes are converted to cyanide. On the other hand, the activity of the microsomal extract is highly selective with regard to the amino acid substrate since, of the aliphatic amino acids tested, only valine and isoleucine are metabolized. We were unable to demonstrate product formation from isobutyronitrile (a linamarin precursor) but did observe detectable cyanide formation from 2-methylcyanobutane, the corresponding precursor of lotaustralin. Competition experiments showed that the biosynthesis of linamarin and lotaustralin is not likely to be catalyzed by separate enzyme systems.

Chromatography, Gas↗
PubMed1976

Influence of valine deprivation and its reversal on fatty acid metabolism in HeLa cells.

The effects that amino acid starvation and re-supplementation have on fatty acid metabolism in HeLa cells have been studied using radio gas chromatographic techniques. Deprivation of valine for 13.5 h caused fatty acid de novo biosynthesis, elongation and desaturation to cease. This effect was reversed within 5 h by adding valine back to the culture. During deprivation accumulation of triacylglycerol occurred. The return of valine to the culture caused compositional changes in the triacylglycerols and phosphatidylcholines.

Chromatography, Gas↗
PubMed1984

A basal unit of valine-sensitive acetolactate synthase of Neurospora crassa.

Valine-sensitivity as well as activity of acetolactate synthase of Neurospora crassa was stabilized with 1.2 M potassium phosphate buffer during extraction from mitochondria and early stages of purification, and with 20% glycerol plus 5 mM sodium pyruvate during Sephadex G200 gel chromatography. The enzyme was expressed as four molecular species having the molecular weights of about 500,000, 140,000, 68,000 and 51,000, respectively. The first and the third species showed valine-sensitivity, but the second and the fourth did not. The third molecular species with a molecular weight of 68,000 may be the basal unit of valine-sensitive acetolactate synthase of Neurospora crassa.

Acetolactate Synthase↗
PubMed1996

Arginine vasopressin reduces the blood-brain transfer of L-tyrosine and L-valine: further evidence of the effect of the peptide on the L-system transporter at the blood-brain barrier.

Arginine vasopressin (AVP) coinjected into the carotid artery in physiological concentrations (0.1 nmol/l), with either L-[3H]tyrosine or L-[3H]valine, induced changes in the kinetic parameters of the blood-to-brain transfer of both large neutral amino acids (LNAA) without alterations in brain haemodynamics. The half-saturation constant (Km), the maximum velocity of transport (V(max)) and Kd, the nonsaturable transport constant, were estimated in 9 brain regions of male Wistar rats anaesthetized with ether. Apart from Kd, significant changes in Km and V(max) were observed in all brain regions investigated. On average Km decreased from 0.17 to 0.048 mmol/l for tyrosine, and from 0.61 to 0.059 mmol/l for valine, whereas V(max) declined from 22 to 9.9 nmol/min/g for tyrosine, and from 29 to 3.2 nmol/min/g for valine, respectively. The results provide further evidence that vasopressin-receptor interactions at the blood-brain barrier (BBB) induce changes in the properties of the common transporter, the L-system, which eventually result in a suppression of the blood-to-brain transfer of LNAA. Data analysis of the 5 LNAA tested so far reveals a significant negative correlation (R = 0.98, P < 0.05) between the respective substrate affinity for the transporter and the corresponding magnitude of transport reduction induced by circulating AVP. Calculations of the unidirectional influx (J) of the LNAA indicate that AVP (1) reduces J by approximately one-third for every LNAA, but (2) does not change the relative contribution for each single LNAA to the total influx across the BBB.

Animals↗
PubMed1996

Protein synthesis measurement in cancer patients with 13C valine.

The flooding dose technique is a method that uses tracer amino acids to measure the rate of protein synthesis in tissues in vivo. This technique involves the injection of a large amount of unlabelled amino acid together with the tracer to minimize difference in isotopic enrichment of the free amino acid in plasma and tissue compartments which represent the precursor pool of protein synthesis. Seven patients with localized colorectal carcinoma received a total parenteral nutrition before surgery and protein synthesis was measured in tumour and colon after administration of a large dose of valine (20% atom percent excess). The enrichment of free valine in plasma and tissues was measured by GCMS and the enrichment of protein-bound valine into tumour and colon by IRMS. The fractional synthesis rate in tumours was 13.44 +/- 6.9%/day compared to a value of 10.9 +/- 8.1%/day in healthy colon. The lack of significant difference probably relates to the low number of patients and the variability of protein synthesis rate in tumours.

Aged↗
PubMed1986

Identification of the 1H resonances of valine and leucine residues in dihydrofolate reductase by using a combination of selective deuteration and two-dimensional correlation spectroscopy.

Lactobacillus casei dihydrofolate reductase (Mr 18 500) contains 16 valine and 14 leucine residues. By comparing the 2D COSY NMR spectra of normal and [gamma-2H6]valine enzyme we have been able to identify all 60 methyl resonances from these residues, and to connect the pairs arising from the same residue. This pairing of the methyl resonances was aided by the examination of the 2D RELAY spectrum which also allowed the C alpha H resonances (and hence the complete spin systems) of 14 of the valine residues to be identified. The combination of selective deuteration with 2D NMR techniques is shown to be a powerful general method for resolving 1H resonances in the complex spectra of proteins and for assigning them to amino-acid type.

Deuterium↗
PubMed1991

Functional role of the distal valine (E11) residue of alpha subunits in human haemoglobin.

We have expressed human alpha-globin to a high level in Escherichia coli as a fusion protein, purified it and removed the N-terminal leader sequence by site-specific proteolysis with blood coagulation factor Xa. The apo globin has been refolded and reconstituted with haem and native beta-globin to form fully functional haemoglobin (Hb) with properties identical to those of native human Hb. By site-directed mutagenesis we have altered the distal residues of the alpha subunits and compared the functional properties of these mutant proteins. The rates of various ligands binding to these proteins in the R-state have been reported by Mathews et al. Here, we present the oxygen equilibrium curves of three E11 alpha mutants and the crystal structures of two of these mutants in the deoxy form. Replacing the distal valine residue of alpha-globin with alanine, leucine or isoleucine has no effect on the oxygen affinity of the protein in either quaternary state, in contrast to the equivalent mutations of beta subunits. The crystal structure of the valine E11 alpha----isoleucine mutant shows that the larger E11 residue excludes water from the haem pocket, but causes no significant movement of other amino acid residues. We conclude that the distal valine residue of alpha-globin does not control the oxygen affinity of the protein by sterically hindering ligand binding.

Escherichia coli↗
PubMed1977

The exclusion of L-isoleucine or of L-leucine from the brain of the rat, caused by raised levels of L-valine in the circulation, and the manner in which this exclusion can be partially overcome.

The amino acids L-isoleucine, L-leucine and L-valine appear to compete for a shared transport carrier for entry into the brain of the living rat, since high concentrations of L-valine in the plasma reduced the influx both of L-isoleucine and of L-leucine into the brain to 10-15% of the normal. The exclusion of L-isoleucine or of L-leucine from the brain by a raised level of L-valine in the circulation can be partially overcome by simultaneously raising the concentration of L-isoleucine or of L-leucine in the circulation. These results indicate the important role played by a saturable shared carrier-mediated transport system in ensuring that an adequate supply of these amino acids reaches the brain from the circulation during life. The bearing of our findings on two inborn errors of amino acid metabolism, maple-syrup-urine disease and hypervalinaemia, is discussed.

Animals↗
PubMed1980

Rhythmic variations of valine and leucine decarboxylation in rat diaphragm.

Daily rhythmic variations of valine and leucine decarboxylation in the rat diaphragm were measured. Both valine and leucine decarboxylation increased during the hours of darkness and decreased during hours of light. Hypophysectomy eliminated the daily variation of decarboxylation. When food is available ad lib. to normal rats, the time of most active feeding coincides with the hours of darkness. Therefore, the period of darkness and maximum feeding coincides with the maximum oxidation of these two essential amino acids, valine and leucine, by diaphragm, and an active pituitary appears to be necessary to maintain this relationship. This model can be used to study interrelationships to behavioral, neurohumoral, and metabolic rhythms.

Animals↗
PubMed1994

Insulin production following intravenous glucose, arginine, and valine: different pattern in patients with impaired glucose tolerance and non-insulin-dependent diabetes mellitus.

To better understand abnormal insulin production (IP) in states of carbohydrate intolerance, insulin release was quantified following equimolar (2.4 mmol/kg) infusions of glucose, arginine, and valine in healthy subjects ([HS] age, 45 +/- 3 years; body mass index [BMI, kg/m2], 26.3 +/- 2.4; means +/- SEM), obese subjects with impaired glucose tolerance ([IGT] age, 43 +/- 5 years; BMI, 35.4 +/- 2.4), and non-obese patients with chronic non-insulin-dependent diabetes mellitus ([NIDDM] age, 55 +/- 3 years; BMI, 26.4 +/- 1.4; duration of disease, 13 +/- 3 years). There were eight subjects per group. Incremental IP (metabolic clearance rate of C-peptide [MCRCP] x total incremental area under the curve of plasma C-peptide [AUCCP], pmol/kg) following substrate infusion was as follows: glucose: HS, 227 +/- 14; IGT, 1,050 +/- 184 (P < .001 v HS); NIDDM, 114 +/- 27 (P < .001 v HS); arginine: HS, 139 +/- 23; IGT, 488 +/- 106 (P < .01 v HS); NIDDM, 206 +/- 47; and valine: HS, 21 +/- 7; IGT, 32 +/- 10; NIDDM, 54 +/- 12 (P < .01 v HS). The fractional clearance rate ([FCR] k, %/min) was impaired in IGT and NIDDM for glucose (HS, 3.9 +/- 0.4; IGT, 2.3 +/- 0.3 [P < .01 v HS]; NIDDM, 1.4 +/- 0.1 [P < .001 v HS]), arginine (2.4 +/- 0.1; 1.9 +/- 0.2 [P < .01 v HS]; 1.9 +/- 0.2 [P < .01 v HS]), and valine (0.95 +/- 0.06; 0.65 +/- 0.09 [P < .05 v HS]; 0.74 +/- 0.1 [P < .05 v HS]).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

An Arabidopsis mutant disrupted in valine catabolism is also compromised in peroxisomal fatty acid beta-oxidation.

Characterisation of the Arabidopsis dbr5 mutant, which was isolated on the basis of 2,4-dichlorophenoxybutyric acid (2,4-DB) resistance, revealed that it is disrupted in the CHY1 gene. CHY1 encodes a peroxisomal protein that is 43% identical to the mammalian beta-hydroxyisobutryl-CoA hydrolase of valine catabolism. We show that 2,4-DB resistance and the associated sucrose dependent seedling growth are due to a large activity decrease of 3-ketoacyl-CoA thiolase, which is involved in peroxisomal fatty acid beta-oxidation. (14)C-feeding studies demonstrate that dbr5 and chy1 seedlings are reduced in valine catabolism. These data support the hypothesis that CHY1 plays a key role in peroxisomal valine catabolism and that disruption of this enzyme results in accumulation of a toxic intermediate, methacrylyl-CoA, that inhibits 3-ketoacyl-CoA thiolase activity and thus blocks peroxisomal beta-oxidation. We also show that CHY1 is repressed in seedlings grown on sugars, which suggests that branched chain amino acid catabolism is transcriptionally regulated by nutritional status.

2,4-Dichlorophenoxyacetic Acid↗
PubMed2005

The presence of valine at residue 129 in human prion protein accelerates amyloid formation.

The polymorphism at residue 129 of the human PRNP gene modulates disease susceptibility and the clinico-pathological phenotypes in human transmissible spongiform encephalopathies. The molecular mechanisms by which the effect of this polymorphism are mediated remain unclear. It has been shown that the folding, dynamics and stability of the physiological, alpha-helix-rich form of recombinant PrP are not affected by codon 129 polymorphism. Consistent with this, we have recently shown that the kinetics of amyloid formation do not differ between protein containing methionine at codon 129 and valine at codon 129 when the reaction is initiated from the alpha-monomeric PrP(C)-like state. In contrast, we have shown that the misfolding pathway leading to the formation of beta-sheet-rich, soluble oligomer was favoured by the presence of methionine, compared with valine, at position 129. In the present work, we examine the effect of this polymorphism on the kinetics of an alternative misfolding pathway, that of amyloid formation using partially folded PrP allelomorphs. We show that the valine 129 allelomorph forms amyloids with a considerably shorter lag phase than the methionine 129 allelomorph both under spontaneous conditions and when seeded with pre-formed amyloid fibres. Taken together, our studies demonstrate that the effect of the codon 129 polymorphism depends on the specific misfolding pathway and on the initial conformation of the protein. The inverse propensities of the two allelomorphs to misfold in vitro through the alternative oligomeric and amyloidogenic pathways could explain some aspects of prion diseases linked to this polymorphism such as age at onset and disease incubation time.

Alleles↗
PubMed2006

Both experimental and theoretical investigations of solid-state 17O NMR for L-valine and L-isoleucine.

We have presented an experimental investigation of the carboxyl oxygen NMR parameters for four distinct sites in l-valine and l-isoleucine. The carboxyl (17)O quadrupolar coupling constant, C(Q), and isotropic chemical shift, delta(iso), for these compounds are obtained by analyzing two-dimensional (17)O multiple-quantum magic-angle spinning (MQMAS) and/or 1D MAS spectra. The values of C(Q) and delta(iso) found to be in the range of 7.00-7.85 MHz, and 264-314 ppm, respectively. Extensive quantum chemical calculations at the density functional levels have been performed for a full cluster of l-valine molecules and a few theoretical models. The calculated results indicated that there was a correlation between the (17)O NMR parameters and C-O bond lengths, which was helpful for the spectral assignment. They also demonstrated that the torsion angle of l-valine plays an important role in determining the magnitudes of (17)O NMR parameters.

Isoleucine↗