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Requerimentos, metabolismo e antagonismos dos aminoácidos de cadeia ramificada na nutrição de monogástricos; Requirements, metabolism and antagonism of branched-chain amino acids in monogastric nutrition

Cemin, Henrique Scher
Fonte: Universidade Federal do Rio Grande do Sul Publicador: Universidade Federal do Rio Grande do Sul
Tipo: Trabalho de Conclusão de Curso Formato: application/pdf
POR
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Os aminoácidos de cadeia ramificada (AACR) valina, leucina e isoleucina devem ser estudados a parte dos demais aminoácidos por possuírem características únicas em sua estrutura e compartilhar rotas de metabolismo, que se inicia com uma reação de transaminação no músculo esquelético, com formação de α-cetoácidos que podem ser descarboxilados no fígado e gerar derivados de Acil-CoA. Os AACR podem interagir entre si negativamente, de modo que altas concentrações de leucina levam a um estímulo exacerbado do metabolismo dos outros AACR, reduzindo as concentrações de valina e isoleucina. Este fenômeno ocasiona piora no desempenho zootécnico, principalmente no ganho de peso e na conversão alimentar. Além disso, valina e isoleucina são aminoácidos limitantes para monogástricos, o que demonstra a importância do conhecimento das exigências dos AACR e da composição dos ingredientes utilizados na dieta para maximizar o desempenho zootécnico e evitar os possíveis antagonismos.; Branched-chain amino acids valine, leucine and isoleucine must be studied apart from other amino acids because they have unique structural characteristics and share metabolism routes, which begin with a transamination reaction in the skeletal muscle...

Role of BkdR, a Transcriptional Activator of the SigL-Dependent Isoleucine and Valine Degradation Pathway in Bacillus subtilis

Debarbouille, Michel; Gardan, Rozenn; Arnaud, Maryvonne; Rapoport, George
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /04/1999 EN
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A new gene, bkdR (formerly called yqiR), encoding a regulator with a central (catalytic) domain was found in Bacillus subtilis. This gene controls the utilization of isoleucine and valine as sole nitrogen sources. Seven genes, previously called yqiS, yqiT, yqiU, yqiV, bfmBAA, bfmBAB, and bfmBB and now referred to as ptb, bcd, buk, lpd, bkdA1, bkdA2, and bkdB, are located downstream from the bkdR gene in B. subtilis. The products of these genes are similar to phosphate butyryl coenzyme A transferase, leucine dehydrogenase, butyrate kinase, and four components of the branched-chain keto acid dehydrogenase complex: E3 (dihydrolipoamide dehydrogenase), E1α (dehydrogenase), E1β (decarboxylase), and E2 (dihydrolipoamide acyltransferase). Isoleucine and valine utilization was abolished in bcd and bkdR null mutants of B. subtilis. The seven genes appear to be organized as an operon, bkd, transcribed from a −12, −24 promoter. The expression of the bkd operon was induced by the presence of isoleucine or valine in the growth medium and depended upon the presence of the sigma factor SigL, a member of the sigma 54 family. Transcription of this operon was abolished in strains containing a null mutation in the regulatory gene bkdR. Deletion analysis showed that upstream activating sequences are involved in the expression of the bkd operon and are probably the target of bkdR. Transcription of the bkd operon is also negatively controlled by CodY...

Interference by methionine on valine uptake in Acremonium chrysogenum.

Alonso, M J; Luengo, J M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/1987 EN
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The incorporation of L-[U-14C]valine into delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine (ACV), a direct biosynthetic precursor of penicillins and cephalosporins, was studied. When DL-methionine was added to Acremonium chrysogenum culture broths, no labeled ACV was found, while a large amount of radioactive ACV was detected when methionine was not present. DL-Norleucine, a nonsulfur analog of methionine, also inhibited the synthesis of radioactive ACV to some degree. This effect was due to the inhibition of valine transport by methionine and norleucine.

Isolation and characterization of valine dehydrogenase from Streptomyces aureofaciens.

Vancurová, I; Vancura, A; Volc, J; Neuzil, J; Flieger, M; Basarová, G; Bĕhal, V
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/1988 EN
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Valine dehydrogenase was purified to homogeneity from the crude extracts of Streptomyces aureofaciens. The molecular weight of the native enzyme was 116,000 by equilibrium ultracentrifugation and 118,000 by size exclusion high-performance liquid chromatography. The enzyme was composed of four subunits with molecular weights of 29,000. The isoelectric point was 5.1. The enzyme required NAD+ as a cofactor, which could not be replaced by NADP+. Sulfhydryl reagents inhibited the enzyme activity. The pH optimum was 10.7 for oxidative deamination of L-valine and 9.0 for reductive amination of alpha-ketoisovalerate. The Michaelis constants were 2.5 mM for L-valine and 0.10 mM for NAD+. For reductive amination the Km values were 1.25 mM for alpha-ketoisovalerate, 0.023 mM for NADH, and 18.2 mM for NH4Cl.

Role of alanine-valine transaminase in Salmonella typhimurium and analysis of an avtA::Tn5 mutant.

Berg, C M; Whalen, W A; Archambault, L B
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1983 EN
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In Salmonella typhimurium, as in Escherichia coli, mutations in avtA, the gene encoding the alanine-valine transaminase (transaminase C), are silent unless they are combined with mutations involved in isoleucine-valine biosynthesis. avtA is repressed by leucine or alanine but not by valine. Transaminase C is found at reduced levels upon starvation for any one of several amino acids. We hypothesize that this is due to repression of avtA by the elevated alanine and leucine pools found in amino acid-starved cells.

Altered regulation of isoleucine-valine biosynthesis in a hisW mutant of Salmonella typhimurium.

Davis, L; Williams, L S
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1982 EN
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Control of isoleucine-valine biosynthesis was examined in the cold-sensitive hisW3333 mutant strain of Salmonella typhimurium. During growth at the permissive temperature (37 degrees C), the isoleucine-valine (ilv) biosynthetic enzyme levels of the hisW mutant were two- to fourfold below these levels in an isogenic hisW+ strain. Upon a reduction in growth temperature to partially permissive (30 degrees C), the synthesis of these enzymes in the hisW mutant was further reduced. However, synthesis of the ilv enzymes was responsive to the repression signal(s) caused by the addition of excess amounts of isoleucine, valine, and leucine to the hisW mutants. Such a "super-repressed" phenotype as that observed in this hisW mutant is similar to that previously shown for the hisU1820 mutant, but was different from the regulatory response of the hisT1504 mutant strain. Moreover, by the use of growth-rate-limiting amounts of the branched-chain amino acids, it was shown that this hisW mutant generally did not increase the synthesis of the ilv enzymes as did the hisW+ strain. Overall, these results are in agreement with the hypothesis that the hisW mutant is less responsive to ilv specific attenuation control than is the hisW+ strain and suggest that this limited regulatory response is due to an alteration in the amount or structure of an element essential to attenuation control of the ilv operons.

Exogenous Valine Reduces Conversion of Leucine to 3-Methyl-1-Butanol in Saccharomyces cerevisiae

Bigelis, Ramunas; Weir, Paul D.; Jones, Richard R. M.; Umbarger, H. E.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/1983 EN
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Mutant strains of the yeast Saccharomyces cerevisiae that require branched-chain amino acids must be supplemented with large concentrations (up to 10 mM) of these amino acids to satisfy their nutritional requirement. The utilization of one branched-chain amino acid, leucine, was examined in several leul strains of yeast grown aerobically in a glucose-ammonium salts minimal medium containing a limiting concentration (0.2 mM) of leucine. In this medium, the leucine requirement of the auxotrophic strains could be reduced by valine, another branched-chain amino acid. Increasing the valine concentration increased the cell yields of cultures and also reduced the levels of 3-methyl-1-butanol detected in the medium by gas chromatography. The concentration of 3-methyl-1-butanol was reduced from 122.0 to 48.9 μM when 5.0 mM valine was supplemented to limiting-leucine cultures. The amino acids isoleucine, threonine, norleucine, norvaline, α-amino-butyrate, alanine, and glycine also spared the leucine requirement of leucine auxotrophs, most likely because they resembled leucine and competed for its uptake. We propose that leucine analogs restrict the entry and degradation of leucine and thus reduce its conversion to 3-methyl-1-butanol, a major component of fusel oil.

Isoleucine and Valine Metabolism in Escherichia coli K-12: Detection and Measurement of ilv-Specific Messenger Ribonucleic Acid

Haar, R. A. Vonder; Umbarger, H. E.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/1974 EN
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Ribonucleic acid-deoxyribonucleic acid (RNA-DNA) hybridization was employed for the determination of messenger RNA transcribed from the ilv gene cluster of Escherichia coli K-12. Strains with derepressed levels of the isoleucine and valine biosynthetic enzymes owing to linked or unlinked genetic lesions were found to exhibit ilv messenger RNA levels from 1.5- to 4-fold higher than did their isogenic parents. When grown under conditions that specifically repressed the synthesis of isoleucine- and valine-forming enzymes, most strains exhibited drastically reduced ilv messenger RNA levels. Hybridization performed with the separated strands of ilv DNA showed that all the ilv genes are transcribed from the same strand, the “l strand” of λφ80CI857St68dilv DNA. Sucrose gradient analyses of RNA extracted from cells starved for isoleucine, valine, or leucine resulted in the detection of at least two distinct types of ilv messenger RNA.

Separate regulation of transport and biosynthesis of leucine, isoleucine, and valine in bacteria.

Quay, S C; Oxender, D L; Tsuyumu, S; Umbarger, H E
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1975 EN
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Since both transport activity and the leucine biosynthetic enzymes are repressed by growth on leucine, the regulation of leucine, isoleucine, and valine biosynthetic enzymes was examined in Escherichia coli K-12 strain EO312, a constitutively derepressed branched-chain amino acid transport mutant, to determine if the transport derepression affected the biosynthetic enzymes. Neither the iluB gene product, acetohydroxy acid synthetase (acetolactate synthetase, EC 4.1.3.18), NOR THE LEUB gene product, 3-isopropylmalate dehydrogenase (2-hydroxy-4-methyl-3-carboxyvalerate-nicotinamide adenine dinucleotide oxido-reductase, EC 1.1.1.85), were significantly affected in their level of derepression or repression compared to the parental strain. A number of strains with alterations in the regulation of the branched-chain amino acid biosynthetic enzymes were examined for the regulation of the shock-sensitive transport system for these amino acids (LIV-I). When transport activity was examined in strains with mutations leading to derepression of the iluB, iluADE, and leuABCD gene clusters, the regulation of the LIV-I transport system was found to be normal. The regulation of transport in an E. coli strain B/r with a deletion of the entire leucine biosynthetic operon was normal...

Enzymes of the Isoleucine-Valine Pathway in Acinetobacter

Twarog, Robert
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1972 EN
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Regulation of four of the enzymes required for isoleucine and valine biosynthesis in Acinetobacter was studied. A three- to fourfold derepression of acetohydroxyacid synthetase was routinely observed in two different wild-type strains when grown in minimal medium relative to cells grown in minimal medium supplemented with leucine, valine, and isoleucine. A similar degree of synthetase derepression was observed in appropriately grown isoleucine or leucine auxotrophs. No significant derepression of threonine deaminase or transaminase B occurred in either wild-type or mutant cells grown under a variety of conditions. Three amino acid analogues were tested with wild-type cells; except for a two- to threefold derepression of dihydroxyacid dehydrase when high concentrations of aminobutyric acid were added to the medium, essentially the same results were obtained. Experiments showed that threonine deaminase is subject to feedback inhibition by isoleucine and that valine reverses this inhibition. Cooperative effects in threonine deaminase were demonstrated with crude extracts. The data indicate that the synthesis of isoleucine and valine in Acinetobacter is regulated by repression control of acetohydroxyacid synthetase and feedback inhibition of threonine deaminase and acetohydroxyacid synthetase.

Biochemical and Genetic Analysis of Isoleucine and Valine, Biosynthesis in Staphylococcus aureus

Smith, C. D.; Pattee, P. A.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1967 EN
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After a prototrophic strain of Staphylococcus aureus had been exposed to diethyl sulfate, 28 isoleucine- and isoleucine-valine-dependent mutants (ilv mutants) were isolated. On the basis of auxanography, their ability to accumulate intermediates of isoleucine and valine biosynthesis, and intergeneric syntrophism with ilv mutants of Salmonella typhimurium, all mutants were placed into four groups, each of which corresponded to a presumed enzymatic deficiency, as follows: group A, deficient in l-threonine deaminase; group B, deficient in the condensing enzyme; group C, deficient in reductoisomerase; group D, deficient in α-β-dihydroxy acid dehydrase. No mutants blocked in the terminal (transaminase) reactions were isolated. Transduction analyses (best-fit, ratio, and complementation tests) with the use of phage 83 established that the linear arrangement of the structural genes is identical with the order of participation of their enzymes in isoleucine and valine biosynthesis, and that these genes comprise a single linkage group which can exist on a single donor fragment during transduction.

ROLE OF VALINE AND ISOLEUCINE AS REGULATORS OF ACTINOMYCIN PEPTIDE FORMATION BY STREPTOMYCES CHRYSOMALLUS

Katz, Edward; Waldron, Clarence R.; Meloni, Mary Lou
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1961 EN
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Katz, Edward (Rutgers, The State University, New Brunswick, N. J.), Clarence R. Waldron, and Mary Lou Meloni. Role of valine and isoleucine as regulators of actinomycin peptide formation by Streptomyces chrysomallus. J. Bacteriol. 82:600–608. 1961—d-Valine is an effective inhibitor of actinomycin synthesis by Streptomyces chrysomallus; l-valine stimulates actinomycin production and reverses the inhibition due to the d-enantiomorph. The incorporation of l-valine into the medium results, particularly, in a marked increase in actinomycin IV formation. In studies with various isoleucine isomers it was shown that l-isoleucine enhances actinomycin VII production; the principal effect of d-alloisoleucine and, especially, d-isoleucine, is to bring about synthesis of two new actinomycins which contain N-methylisoleucine. Both l- and d-threonine were observed to have an effect similar to that obtained with l-isoleucine. An interpretation of these findings has been discussed.

Utilization of α-Keto and α-Hydroxy Analogues of Valine by the Growing Rat

Chawla, Rajender K.; Rudman, Daniel
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1974 EN
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When 70-80-g male albino rats eat a diet furnishing daily requirement of valine for optimal growth (70 μmol/g) and all other nutrients (“complete diet”), they gain weight at an average rate of 3.0 g/100 g body wt/day. When valine is removed, they lose weight at an average 2.1 g/100 g body wt/day. The growth retardation is improved or corrected by adding valine to the diet, daily weight gain being proportional to dietary valine content over a range of 0-70 μmol/g.

Effect of peptide histidine valine on cardiovascular and respiratory function in normal subjects.

Chilvers, E R; Dixon, C M; Yiangou, Y; Bloom, S R; Ind, P W
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1988 EN
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Non-adrenergic inhibitory nerves may have an important role in regulating airway calibre. A recently discovered peptide, peptide histidine valine, is a potent relaxer of airway smooth muscle in vitro and has been proposed as a possible neurotransmitter in this tissue. The cardiovascular and respiratory effects of graded infusions of this peptide (2.5-10 pmol kg-1 min-1) have been examined in six normal subjects in a placebo controlled, randomised double blind study. The mean (SEM) peak plasma concentration of peptide histidine valine during the highest infusion rate was 2392 (170) pmol/l, representing a 29 fold increase above the basal concentration. This was accompanied by flushing, a significant increase in heart rate of 28 (3.7) beats/min and skin temperature of 1.8 degrees (0.16 degrees) C, but no effect on systolic or diastolic blood pressure. Despite these high plasma concentrations of the peptide and the substantial tachycardia and increase in skin blood flow, there was no change in partial expiratory flow at 40% of vital capacity (Vp40) or in the airway response to inhaled histamine (geometric PD40 9.37 and 9.73 mumol during saline and peptide histidine valine infusion respectively). Although these findings provide no support for a physiological role of peptide histidine valine in controlling airway function in healthy subjects...

The effect of electrical stimulation and ouabain on the uptake and efflux of l-[U-14C]valine in chopped tissue from guinea-pig cerebral cortex

Jones, C. T.; Banks, P.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1970 EN
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1. Chopped tissue from guinea-pig cerebral cortex carried out an energy-dependent accumulation of l-[14C]valine. 2. The uptake was dependent on the extracellular concentration of Na+ and was markedly inhibited by ouabain (20μm). The extent of the inhibition of uptake by ouabain was also Na+-dependent. 3. The accumulation of labelled valine was not directly dependent on the ATP and creatine phosphate contents of the slices. 4. Electrical stimulation increased the rate of [14C]valine uptake at first but ultimately led to a net loss of the label so that the amount of label present in the tissue was lower than in the controls. 5. The rate of loss of label during prolonged stimulation was dependent on the extracellular concentration of Na+. 6. The efflux of labelled valine from slices preloaded at 164mm-Na+ was studied at 164, 80 and 40mm-Na+ with and without electrical stimulation or ouabain. 7. Lowering the Na+ concentration or adding ouabain increased the rate of efflux. 8. Electrical stimulation had little effect on the rate of efflux at first but ultimately led to a more complete loss of label from the tissue than occurred in the control. A kinetic analysis of the efflux curves was attempted.

2-Amino-3-(Oxirane-2,3-Dicarboxamido)-Propanoyl-Valine, an Effective Peptide Antibiotic from the Epiphyte Pantoea agglomerans 48b/90 ▿

Sammer, Ulrike F.; Völksch, Beate; Möllmann, Ute; Schmidtke, Michaela; Spiteller, Peter; Spiteller, Michael; Spiteller, Dieter
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
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The epiphyte Pantoea agglomerans 48b/90, which has been isolated from soybean leaves, belongs to the Enterobacteriaceae, as does the plant pathogen Erwinia amylovora, which causes fire blight on rosaceous plants such as apples and leads to severe economic losses. Since P. agglomerans efficiently antagonizes phytopathogenic bacteria, the P. agglomerans strain C9-1 is used as a biocontrol agent (BlightBan C9-1). Here we describe the bioassay-guided isolation of a peptide antibiotic that is highly active against the plant pathogen E. amylovora and pathovars of Pseudomonas syringae, and we elucidate its structure. Bioassay-guided fractionation using anion-exchange chromatography followed by hydrophobic interaction liquid chromatography yielded the bioactive, highly polar antibiotic. The compound was identified as 2-amino-3-(oxirane-2,3-dicarboxamido)-propanoyl-valine by using high-resolution electrospray ionization mass spectrometry and nuclear magnetic resonance techniques. This peptide was found to be produced by three of the nine P. agglomerans strains analyzed. Notably, the biocontrol strain P. agglomerans C9-1 also produces 2-amino-3-(oxirane-2,3-dicarboxamido)-propanoyl-valine. Previously, 2-amino-3-(oxirane-2,3-dicarboxamido)-propanoyl-valine has been characterized only from Serratia plymuthica. 2-Amino-3-(oxirane-2...

Comparative 13C Metabolic Flux Analysis of Pyruvate Dehydrogenase Complex-Deficient, l-Valine-Producing Corynebacterium glutamicum▿†

Bartek, Tobias; Blombach, Bastian; Lang, Siegmund; Eikmanns, Bernhard J.; Wiechert, Wolfgang; Oldiges, Marco; Nöh, Katharina; Noack, Stephan
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /09/2011 EN
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l-Valine can be formed successfully using C. glutamicum strains missing an active pyruvate dehydrogenase enzyme complex (PDHC). Wild-type C. glutamicum and four PDHC-deficient strains were compared by 13C metabolic flux analysis, especially focusing on the split ratio between glycolysis and the pentose phosphate pathway (PPP). Compared to the wild type, showing a carbon flux of 69% ± 14% through the PPP, a strong increase in the PPP flux was observed in PDHC-deficient strains with a maximum of 113% ± 22%. The shift in the split ratio can be explained by an increased demand of NADPH for l-valine formation. In accordance, the introduction of the Escherichia coli transhydrogenase PntAB, catalyzing the reversible conversion of NADH to NADPH, into an l-valine-producing C. glutamicum strain caused the PPP flux to decrease to 57% ± 6%, which is below the wild-type split ratio. Hence, transhydrogenase activity offers an alternative perspective for sufficient NADPH supply, which is relevant for most amino acid production systems. Moreover, as demonstrated for l-valine, this bypass leads to a significant increase of product yield due to a concurrent reduction in carbon dioxide formation via the PPP.

Platform Engineering of Corynebacterium glutamicum with Reduced Pyruvate Dehydrogenase Complex Activity for Improved Production of l-Lysine, l-Valine, and 2-Ketoisovalerate

Buchholz, Jens; Schwentner, Andreas; Brunnenkan, Britta; Gabris, Christina; Grimm, Simon; Gerstmeir, Robert; Takors, Ralf; Eikmanns, Bernhard J.; Blombach, Bastian
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /09/2013 EN
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Exchange of the native Corynebacterium glutamicum promoter of the aceE gene, encoding the E1p subunit of the pyruvate dehydrogenase complex (PDHC), with mutated dapA promoter variants led to a series of C. glutamicum strains with gradually reduced growth rates and PDHC activities. Upon overexpression of the l-valine biosynthetic genes ilvBNCE, all strains produced l-valine. Among these strains, C. glutamicum aceE A16 (pJC4 ilvBNCE) showed the highest biomass and product yields, and thus it was further improved by additional deletion of the pqo and ppc genes, encoding pyruvate:quinone oxidoreductase and phosphoenolpyruvate carboxylase, respectively. In fed-batch fermentations at high cell densities, C. glutamicum aceE A16 Δpqo Δppc (pJC4 ilvBNCE) produced up to 738 mM (i.e., 86.5 g/liter) l-valine with an overall yield (YP/S) of 0.36 mol per mol of glucose and a volumetric productivity (QP) of 13.6 mM per h [1.6 g/(liter × h)]. Additional inactivation of the transaminase B gene (ilvE) and overexpression of ilvBNCD instead of ilvBNCE transformed the l-valine-producing strain into a 2-ketoisovalerate producer, excreting up to 303 mM (35 g/liter) 2-ketoisovalerate with a YP/S of 0.24 mol per mol of glucose and a QP of 6.9 mM per h [0.8 g/(liter × h)]. The replacement of the aceE promoter by the dapA-A16 promoter in the two C. glutamicum l-lysine producers DM1800 and DM1933 improved the production by 100% and 44%...

Design, synthesis and biological evaluation of (S)-valine thiazole-derived cyclic and non-cyclic peptidomimetic oligomers as modulators of human P-glycoprotein (ABCB1)

Singh, Satyakam; Prasad, Nagarajan Rajendra; Kapoor, Khyati; Chufan, Eduardo E.; Patel, Bhargav A.; Ambudkar, Suresh V.; Talele, Tanaji T.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
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Multidrug resistance (MDR) caused by ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) through extrusion of anticancer drugs from the cells is a major cause of failure to cancer chemotherapy. Previously, selenazole containing cyclic peptides were reported as P-gp inhibitors and these were also used for co-crystallization with mouse P-gp, which has 87% homology to human P-gp. It has been reported that human P-gp, can simultaneously accommodate 2-3 moderate size molecules at the drug binding pocket. Our in-silico analysis based on the homology model of human P-gp spurred our efforts to investigate the optimal size of (S)-valine-derived thiazole units that can be accommodated at drug-binding pocket. Towards this goal, we synthesized varying lengths of linear and cyclic derivatives of (S)-valine-derived thiazole units to investigate the optimal size, lipophilicity and the structural form (linear and cyclic) of valine-derived thiazole peptides that can accommodate well in the P-gp binding pocket and affects its activity, previously an unexplored concept. Among these oligomers, lipophilic linear- (13) and cyclic-trimer (17) derivatives of QZ59S-SSS were found to be the most and equally potent inhibitors of human P-gp (IC50 = 1.5 μM). Cyclic trimer and linear trimer being equipotent...

Regulation of yeast acetohydroxyacid synthase by valine and ATP.

Pang, S S; Duggleby, R G
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/08/2001 EN
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The first step in the common pathway for the biosynthesis of branched-chain amino acids is catalysed by acetohydroxyacid synthase (AHAS; EC 4.1.3.18). The enzyme is found in plants, fungi and bacteria, and is regulated by controls on transcription and translation, and by allosteric modulation of catalytic activity. It has long been known that the bacterial enzyme is composed of two types of subunit, and a similar arrangement has been found recently for the yeast and plant enzymes. One type of subunit contains the catalytic machinery, whereas the other has a regulatory function. Previously, we have shown [Pang and Duggleby (1999) Biochemistry 38, 5222--5231] that yeast AHAS can be reconstituted from its separately purified subunits. The reconstituted enzyme is inhibited by valine, and ATP reverses this inhibition. In the present work, we further characterize the structure and the regulatory properties of reconstituted yeast AHAS. High phosphate concentrations are required for reconstitution and it is shown that these conditions are necessary for physical association between the catalytic and regulatory subunits. It is demonstrated by CD spectral changes that ATP binds to the regulatory subunit alone, most probably as MgATP. Neither valine nor MgATP causes dissociation of the regulatory subunit from the catalytic subunit. The specificity of valine inhibition and MgATP activation are examined and it is found that the only effective analogue of either regulator of those tested is the non-hydrolysable ATP mimic...