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PubMed2000

Valine dehydrogenase from Streptomyces albus: gene cloning, heterologous expression and identification of active site by site-directed mutagenesis.

A gene encoding valine dehydrogenase (Vdh) has been cloned from Streptomyces albus, a salinomycin producer, and expressed in Escherichia coli. The S. albus Vdh is composed of 364 amino acids that showed high homology with several other amino acid dehydrogenases as well as Vdhs from Streptomyces spp. and leucine and phenylalanine dehydrogenases (Ldh and Pdh) from Bacillus spp. A protein of 38 kDa, corresponding to the approximate mass of the predicted S. albus Vdh product (38.4 kDa) exhibiting specific Vdh activity, was observed when the S. albus vdh gene was overexpressed in E. coli under the controlled T7 promoter and was subsequently purified to homogeneity. Among branched- and straight-chain amino acids, L-valine and L-alpha-aminobutyrate were the preferred substrates for the enzyme. Lys-79 and Lys-91 of S. albus Vdh were highly conserved in the corresponding region of NAD(P)(+)-dependent amino acid dehydrogenase sequences. To elucidate the functional roles of the lysyl residues, the Lys residues have individually been replaced with Ala by site-directed mutagenesis. Kinetic analyses of the Lys-79 and Lys-91-mutated enzymes revealed that they are involved in the substrate binding site and catalysis, respectively, analogous to the corresponding residues in the homologous Ldh and Pdh.

Amino Acid Oxidoreductases↗
PubMed1964

ISOLEUCINE AND VALINE METABOLISM IN ESCHERICHIA COLI. XII. CHARACTERIZATION OF A FACTOR INVOLVED IN ACETOLACTATE FORMATION.

Leavitt, Richard I. (Long Island Biological Association, Cold Spring Harbor, N.Y.). Isoleucine and valine metabolism in Escherichia coli. XII. Characterization of a factor involved in acetolactate formation. J. Bacteriol. 88:172-178. 1964.-An unknown factor required for the formation of acetolactate, the first five-carbon precursor of valine, is described. The presence of this factor eliminates the dilution effect encountered when studying the effect of increasing enzyme concentration on the formation of acetolactate. It is suggested that this factor functions by increasing the enzyme affinities of both pyruvate and thiamine pyrophosphate.

Acetaldehyde↗
PubMed1964

ENZYMATIC ACTIVITIES OF STREPTOMYCIN-DEPENDENT ESCHERICHIA COLI IN RELATION TO VALINE FORMATION.

Bragg, P. D. (University of British Columbia, Vancouver, B.C., Canada), and W. J. Polglase. Enzymatic activities of streptomycin-dependent Escherichia coli in relation to valine formation. J. Bacteriol. 88:1399-1402. 1964.-The activities of several enzymes were compared in antibiotic-depleted and antibiotic-supplemented streptomycin-dependent Escherichia coli. Depleted cells were somewhat lower than supplemented cells in several oxidase activities. Isocitric dehydrogenase was very much lower in depleted cells than in supplemented cells. The lactic dehydrogenase activity of depleted and supplemented cells was similar. The balance of enzymatic activities in depleted and supplemented cells was thus found to correlate well with the observed extracellular products. Thus, depleted cells excreted lactic acid and were deficient in oxidase activity (although normal in lactic dehydrogenase activity), whereas supplemented cells excreted valine and were rich in the reduced nicotinamide adenine dinucleotide phosphate-producing enzyme, isocitric dehydrogenase. Since antibiotic-depleted cells were not deficient in lactic dehydrogenase, it appeared probable that the failure of depleted cells to metabolize lactate was related to a deficiency in the electron-transport system.

Canada↗
PubMed1965

REGULATORY MECHANISMS IN THE BIOSYNTHESIS OF ISOLEUCINE AND VALINE. 3. MAP ORDER OF THE STRUCTURAL GENES AND OPERATOR GENES.

Ramakrishnan, T. (Yale University, New Haven, Conn.), and Edward A. Adelberg. Regulatory mechanisms in the biosynthesis of isoleucine and valine. III. Map order of the structural genes and operator genes. J. Bacteriol. 89:661-664. 1965.-A new method has been employed to determine the map order of the structural genes and operator genes governing the enzymes of the isoleucine-valine biosynthetic pathway. This method relies on the observation that phage transduction of markers carried on an F-genote leads to the establishment in the recipient of F-genotes of various lengths. Using this method, we have established that the order of loci is the following: F/ilvE ilvD ilvA oprA/ilvC/ilvB oprB. The operator locus, oprA, regulates the activity of structural genes ilvE (transaminase B), ilvD (dehydrase), and ilvA (threonine deaminase). The operator locus, oprB, regulates the activity of ilvB (condensing enzyme). An operator for ilvC (reductoisomerase) can be inferred to exist, but has not yet been detected genetically. The loci ilvB and oprB have been shown to be at the extreme right end of the sequence, but their positions relative to each other remain to be established.

Amino Acids↗
PubMed1965

LINKAGE RELATIONSHIPS OF GENES CONTROLLING ISOLEUCINE, VALINE, AND LEUCINE BIOSYNTHESIS IN BACILLUS SUBTILIS.

Barat, M. (Centre National de la Recherche Scientifique, Gif-sur-Yvette, Seine et Oise, France), C. Anagnostopoulos, and A.-M. Schneider. Linkage relationships of genes controlling isoleucine, valine, and leucine biosynthesis in Bacillus subtilis. J. Bacteriol.90:357-369. 1965.-In Bacillus subtilis, the genetic loci controlling isoleucine and valine biosynthesis are not all clustered. Some of them were located on two distinct transforming deoxyribonucleic acid "molecules." One of these molecules (the "ileilva(2-4)-met segment") carries the threonine deaminase and the dihydroxy acid dehydrase loci linked to methionine markers. The other (the "ilva(1-3)-leu segment") bears the reductoisomerase locus and one or more loci involved in leucine synthesis. A phenylalanine marker was also shown to be weakly linked to this latter group. In transduction mediated by phage PBS-1, these groups are transferred jointly with other gene clusters. The phage appears to convey chromosome fragments considerably longer than the transforming "molecules." The genetic maps of both the above segments were extended by transduction. Some groups previously studied by transformation can be placed in the following linear order: the ile-ilva(2-4)-met segment, the cluster of loci involved in aromatic amino acid synthesis (try segment), and a lysine locus. An arginine locus is cotransduced with the phe-ilva(1-2)-leu segment. Recombination frequencies between linked markers are much lower in transduction by this phage than in transformation.

Amino Acids↗
PubMed1999

Identification and quantitation of N-(carboxymethyl)valine adduct in hemoglobin by gas chromatography/mass spectrometry.

A sensitive, specific and reproducible method was developed for the quantitation of the hemoglobin (Hb) adduct N-(carboxymethyl)valine (CMV). This adduct is one of various products from the Maillard reaction, involving reducing sugars and amino acids, proteins or other molecules with a free amino group. Such adducts, including N epsilon-(carboxymethyl)lysine (CML), are called advanced glycation end products (AGE) and have been correlated with aging and severity of diabetes in human tissues. This method was developed to examine the CMV-Hb adduct as a possible AGE formed by reaction of Hb with glucose or other oxidation products. CMV was cleaved selectively from isolated globin using pentafluorophenyl isothiocyanate (PFPITC) in a modified Edman degradation at pH 9.5. The carboxyl group of the adduct was derivatized to its methyl ester with diazomethane. The resulting derivative, 5-isopropyl-1-(methyl acetate)-3-pentafluorophenyl-2-thiohydantoin, was detected by gas chromatography/mass spectrometry with selected ion monitoring (GC/SIM/MS). Quantitation was based on the response factor of the derivative molecular ion (m/z 396) from synthesized CMV and N-(2-carboxyethyl)valine (molecular ion m/z 410) as internal standard. This method exhibits reproducibility and linearity in the range 0.2-100 ng CMV. The limit of quantitation (0.2 ng CMV) gave a signal-to-noise ratio greater than 5:1 using a 1:30 sample aliquot. The GC/SIM/MS method can detect CMV adduct in 5 mg globin samples with relative standard deviations less than 5%. This approach avoids tedious acid hydrolysis and interference from other amino acids. The molecular ion and other CMV derivative ion assignments from samples were confirmed by accurate mass determinations using GC/high resolution SIM/MS. Measurements from random mouse, rat and human globin samples gave mean CMV levels of about 6, 5 and 14 nmol g-1 Hb in these species, respectively.

Animals↗
PubMed1999

Enantioselectivity of bunitrolol 4-hydroxylation is reversed by the change of an amino acid residue from valine to methionine at position 374 of cytochrome P450-2D6.

The enantioselectivity of 4-hydroxylation of bunitrolol (BTL), a beta-adrenoceptor blocking drug, was studied in microsomes from human liver, human hepatoma (Hep G2) cells expressing CYP2D6, and lymphoblastoid cells expressing CYP2D6. Kinetics in human liver microsomes showed that the Vmax value for (+)-BTL was 2.1-fold that of (-)-BTL, and that the Km value for (+)-BTL was lower than that for the (-)-antipode, resulting in the intrinsic clearance (Vmax/Km) of (+)-BTL being 2.1-fold over its (-)-antipode. CYP2D6 (CYP2D6-met) expressed in Hep G2 cells had a methionine residue at position 373 of the amino acid sequence and a rat-type N-terminal peptide (MELLNGTGLWSM) instead of the human-type (MGLEALVPLAVIV), and showed enantioselectivity of [(+)-BTL < (-)-BTL] for the rate of BTL 4-hydroxylation. In contrast, enantioselectivity [(+)-BTL > (-)-BTL] for Hep G2-CYP2D6 (CYP2D6-val) with a human-type N-terminal peptide that had a valine residue at 374, which corresponds to the methionine of the CYP2D6-met variant, was the same as that for human liver microsomes. We further confirmed that CYP2D6-met and CYP2D6-val expressed in human lymphoblastoid cells, both of which have methionine and valine, respectively, at position 374 and a human-type N-terminal peptide, exhibited the same enantioselectivities as those obtained from CYP2D6-met and CYP2D6-val expressed in the Hep G2 cell system. These results indicate that the amino acid at 374 of CYP2D6 is one of the key factors influencing the enantioselectivity of BTL 4-hydroxylation.

Adrenergic beta-Antagonists↗
PubMed2005

Application of model discriminating experimental design for modeling and development of a fermentative fed-batch L-valine production process.

A model discriminating experimental design approach for fed-batch processes has been developed and applied to the fermentative production of L-valine by a genetically modified Corynebacterium glutamicum strain possessing multiple auxotrophies as an example. Being faced with the typical situation of uncertain model information based on preliminary experiments, model discriminating design was successfully applied to improve discrimination between five competing models. Within the same modeling and experimental design framework, also the planning of an optimized production process with respect to the total volumetric productivity is shown. Simulation results were experimentally affirmed, yielding an increased total volumetric productivity of 6.2 mM L-valine per hour. However, also so far unknown metabolic mechanisms were observed in the optimized process, underlining the importance of process optimization during modeling to avoid problems of extreme extrapolation of model predictions during the final process optimization.

Biotechnology↗
PubMed1996

The valine catabolic pathway in human liver: effect of cirrhosis on enzyme activities.

The activities of key enzymes in the valine catabolic pathway--branched-chain aminotransferase, branched-chain alpha-keto acid dehydrogenase complex, methacrylyl (MC)-coenzyme A (CoA) hydratase (crotonase), and 3-hydroxyisobutyryl-CoA (HIB-CoA) hydrolase--were measured in normal and cirrhotic human livers. Unlike rat liver, which does not contain branched-chain aminotransferase, the aminotransferase activity in the normal liver was measurable and is increased somewhat in cirrhosis of the human liver. The total activity of branched-chain alpha-keto acid dehydrogenase complex in the normal human liver was approximately 1% of that in rat liver, and 20% to 30% of the complex was in the active form in both normal and cirrhotic livers. Only the actual activity of the enzyme was significantly decreased by cirrhosis. These results suggest that human liver is less active than rat liver in the catabolism of branched-chain amino and alpha-keto acids. Activities of MC-CoA hydratase and HIB-CoA hydrolase in human liver were very high compared with that of branched-chain alpha-keto acid dehydrogenase complex, suggesting an important role for these enzymes in catabolism of a potentially toxic compound, MC-CoA, formed as an intermediate in the catabolism of valine and isobutyrate. Cirrhosis resulted in a significant decrease in HIB-CoA hydrolase activity but had no effect on the citrate synthase activity, suggesting that the decrease in HIB-CoA hydrolase activity does not reflect a general decrease in mitochondria but that it may contribute to cellular damage that culminates in liver failure.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1986

A monoclonal antibody reactive with an activated ras protein expressing valine at position 12.

Activated ras transforming genes have been described in a variety of neoplasms and encode 21,000-Dalton (p21) proteins with amino acid substitutions at positions 12, 13, and 61. In this report we describe a monoclonal antibody designated DWP that reacts specifically with synthetic dodecapeptides containing valine at position 12, to a lesser extent with peptides containing cysteine at position 12 and not with peptides containing glycine, arginine, serine, aspartic acid, glutamic acid or alanine at the same position. Western blot and immunoperoxidase studies showed that DWP specifically reacts with activated rasH or rasK proteins in NIH cells transformed by DNA from the human carcinoma cells that encode valine at position 12. DWP did not react with normal p21s encoding glycine at position 12, nor with activated p21s encoding aspartic acid, glutamic acid, arginine, serine, or cysteine at position 12. A survey of human tumor cell lines demonstrated that DWP reacted with the human bladder carcinoma cell line T24 but not with human tumor cell lines previously shown to contain other activating mutations at positions 12 or 61. DWP and perhaps additional antibodies that specifically react with alterations at positions 12 or 61 of the ras protein may be valuable in determining the presence and frequency of activated ras proteins in human malignancy.

Amino Acid Sequence↗
PubMed1982

Effect of l-valine and l-isoleucine on fatty acid composition of Streptomyces hygroscopicus and S. griseus.

The effects of L-valine and L-isoleucine on the composition of mycelial fatty acids were investigated during growth of differentiating parent strains of Streptomyces hygroscopicus and Streptomyces griseus as well as their non-differentiating derivatives (Amy-strains) on a synthetic medium. Both in the Amy+ and Amy- strains, in the presence of L-valine, the portion of the isopalmitic acid (iC16:0) increased, but the addition of L-isoleucine led to an elevated level of the 12-methyltetradecanoic acid (aC15:0). The results suggest that the genetically determined alterations in the ratio of both fatty acids in the non-differentiating derivatives may be due to specific changes in the biosynthetic pathways of both amino acid precursors rather than due to changes of their catabolism.

Fatty Acids↗
PubMed1996

Specific cleavage of recombinant protein tau3 between valine-220 and tyrosine-221 (val-309 and tyr-310 of tau4) by a double-stranded DNA-stimulated protease.

The protein tau was degraded to distinct products by a DNA-stimulated protease isolated from human leukemia HL-60 cell extracts. The enzyme partially purified by sequential chromatography on GTP-agarose, DEAE-cellulose, and TSK 3000 (0.6 X 60 mm) columns eluted as a 300-450 kDa protein which appeared as 60-90 kDa polypeptides on SDS-PAGE. Protease activity was stimulated by synthetic and natural DNAs and was most active at pH 8.5. Human recombinant tau3 was degraded by the DEAE-cellulose-eluted protease to a 26-kDa and several 14- to 16-kDa peptides. Degradation of tau was partially blocked by preincubation with tubulin, suggesting that the DNA-stimulated cleavage of tau occurred at the carboxyl-terminus, at or near the "tubulin-interactive" domains. The 26-kDa fragment was shown by amino acid sequencing to correspond to the N-terminus of tau whereas sequencing of the 16-kDa fragment yielded YKPVDLSKVT. These results show the existence of a DNA-stimulated protease capable of cleaving tau3 between valine-220 and tyrosine-221 (equivalent to valine 309 and tyrosine-310 of tau4).

Amino Acid Sequence↗
PubMed1997

The roles of valine 208 and histidine 211 in ligand binding and receptor function of the ovine Mel1a beta melatonin receptor.

Site-directed mutagenesis was used to study two residues, valine 208 and histidine 211, in transmembrane domain 5 of the ovine Mel1a beta melatonin receptor. A series of 4 mutants were constructed (V208A, V208L, H211F, H211L), and each engineered to contain a FLAG-epitope. Immunocytochemistry demonstrated that all the mutants were expressed in COS-7 cells at levels comparable to the FLAG-epitope tagged wild-type Mel1a beta receptor (approximately 120 fmol/mg protein). Ligand binding revealed however that all mutants had reduced affinities for 2-[125I]-iodomelatonin (Kd wild-type 139 pM, Kd mutants 320 to 989 pM). Competition studies, with a series of melatonin analogues, identified a probable interaction between histidine 211 and the 5-methoxy group of melatonin. The wild-type receptor and both valine 208 mutants displayed a dose-dependent melatonin mediated inhibition of cyclic AMP levels in HEK293 cells, with IC50 values in the same rank-order as their melatonin binding affinities. Both H211F and H211L, however, did not display any melatonin mediated effects and may suggest that histidine 211 is critical for melatonin mediated receptor activation.

Amino Acid Sequence↗
PubMed1999

Formation of N-(2-hydroxyethyl)valine due to exposure to ethylene oxide via tobacco smoke: A risk factor for onset of cancer.

Human exposure to ethylene oxide (EtO) occurs mainly through inhalation of occupational polluted air and tobacco smoke. EtO is able to react with DNA and proteins producing some molecular adducts. One of these, resulting from reaction between EtO and valine in hemoglobin, is N-(2-hydroxyethyl) valine (HOEtVal). This adduct represents a biological effective dose marker, the level of which correlates linearly with the alkylating activity occurring in DNA. The aim of the present study was to measure HOEtVal in 146 urbanized adult and healthy subjects, nonoccupationally exposed to EtO, and to correlate it with smoke habits. HOEtVal showed a direct positive relationship to tobacco smoke exposure quantified by questionnaire, urinary cotinine (r=0.64509), and the number of cigarettes (r=0. 6308) actively or passively smoked. Results relative to HOEtVal and urinary cotinine in adults distinguish well between active and passive smokers but do not allow distinguishment between passive smokers and nonsmokers. Nevertheless, several authors demonstrated a very good capacity of cotinine to discriminate inside groups of adolescents passive smokers. Therefore, the future objective of the present study is a closer inspection of the two biomarkers with respect to passive exposure to tobacco smoke considering a large group of adolescents. Finally, the correlation between urinary cotinine and HOEtVal increases knowledge about early steps of the carcinogenic process due to active exposure to tobacco smoke.

Adolescent↗
PubMed1992

Effects of starvation on valine and alanine transport across the intestinal mucosal border in sea bass, Dicentrarchus labrax.

Kinetics of intestinal transport of L-alanine and L-valine (substrates of the A-system and the L-system, respectively, in mammals) across the brush-border membrane in sea bass, Dicentrarchus labrax, were studied on intact mucosa using a short-term uptake technique. When fish were starved for 4-8 weeks, total influx (mucosa-to-cell) of valine fell owing to disappearance or modification of the diffusion component. The maximum influx rate of saturable component increased but its affinity (reflected by the Michaelis constant) decreased. Alanine transport by Na(+)-dependent and diffusion pathways was unchanged after starvation. Fasting also induced an almost 20% decrease in the length of intestinal microvilli.

Alanine↗
PubMed1976

Expression of a valine-resistant acetolactate synthase activity mediated by the ilv O and ilv G genes of Escherichia coli K-12.

A strain carrying the ilv0603 mutation has been isolated in E. coli K-12 and its characteristics were found to be very similar to those previously reported by Ramakrishnan and Adelberg (1965a) for other ilv0 mutants. The strain carrying the ilv0603 mutation is resistant to valine inhibition (Valr) and we show that this resistance depends on the expression of a newly recognized gene, ilvG, which is located at min 75, between ilvE and ilvD on the E. coli K-12 map. The ilvG gene causes the expression of a Valr acetolactate synthase, which is detectable only when the ilv0603 mutation is also present in cis on the same chromosome. Under these conditions the Valr acetolactate synthase activity is eluted, on a hydroxylapatite column, at an ionic strength slightly lower than that required for elution of the remaining acetolactate synthase activity (sensitive to valine inhibition). The Valr peak is missing in a strain carrying an ilvG (amber) mutation.

Acetolactate Synthase↗
PubMed1977

Alpha-isopropylmalate synthase from Alcaligenes eutrophus H 16. III. Endproduct inhibition and its relief by valine and isoleucine.

The alpha-isopropylmalate synthase (EC 4.1.3.12) from Alcaligenes eutrophus H 16 was inhibited by L-leucine and alpha-ketoisocaproate. The extent of inhibition was influenced by substrate- and inhibitor concentrations as well as by the pH. Intermediary plateaus, which always appeared in the inhibition curves, suggested cooperative effects. The maximal Hill coefficient was found to be two. At low concentrations of leucine the inhibition mechanism was of the competitive type with respect to substrate acetyl coenzyme A and of the noncompetitive type with respect to substrate alpha-ketoisovalerate. The inhibition was specifically relieved by the addition of valine or isoleucine. The anomalous effect of temperature on enzyme activity was diminished by leucine. The Arrhenius energy of the reaction increased from about 11 kcal/mole in the absence of leucine to about 18 kcal/mole in the presence of leucine. The further addition of valine reversed this effect. The physiological relevance of the alpha-ketoisocaproate-mediated inhibition is discussed.

2-Isopropylmalate Synthase↗
PubMed1991

Valine inhibition of beta-isopropylmalate dehydrogenase takes part in the regulation of leucine biosynthesis in Candida maltosa.

The beta-isopropylmalate (IPM) dehydrogenase (EC 1.1.1.85) of Candida maltosa, the third pathway-specific enzyme of leucine biosynthesis, was purified, some properties of the enzyme were studied and a novel regulatory pattern was found. The Km values of the enzyme were estimated to be 0.42 mM for beta-IPM and 0.34 mM for NAD+. It is demonstrated that the enzyme can be regulated by L-valine. The inhibition was competitive with respect to beta-IPM (Ki = 1.84 mM) and non-competitive with respect to NAD+ (Ki = 5.67 mM). Exogenous addition of L-valine to C. maltosa cells increased the intracellular pool of some intermediates of leucine biosynthesis (alpha-ketoisovalerate, alpha-IPM, beta-IPM), but has hardly influence on the leucine pool.

3-Isopropylmalate Dehydrogenase↗