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[PMID]:29227681
[Au] Autor:Duan Y; Li F; Guo Q; Wang W; Zhang L; Wen C; Chen X; Yin Y
[Ad] Endereço:Laboratory of Animal Nutritional Physiology and Metabolic Process, Institute of Subtropical Agriculture Chinese Academy of Sciences; Key Laboratory of Agro-ecological Processes in Subtropical Region; Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production; Scientifi
[Ti] Título:ß-Hydroxy-ß-methyl Butyrate Is More Potent Than Leucine in Inhibiting Starvation-Induced Protein Degradation in C2C12 Myotubes.
[So] Source:J Agric Food Chem;66(1):170-176, 2018 Jan 10.
[Is] ISSN:1520-5118
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Leucine (Leu) and its metabolites α-ketoisocaproate (KIC) and ß-hydroxy-ß-methyl butyrate (HMB) are potent regulators of protein turnover. The aim of this study was to compare the inhibitory effects of Leu, KIC, and HMB on protein degradation and to investigate the mechanisms involved. The results showed that the inhibitory effect of HMB (0.38 ± 0.04) was more potent than that of Leu (0.76 ± 0.04) and KIC (0.56 ± 0.04, P < 0.01), and was significantly abolished in the presence of LY294002 (1.48 ± 0.02) and rapamycin (1.96 ± 0.02, P < 0.01). In the presence of insulin, the inhibitory effect of HMB (0.34 ± 0.03) was still more effective than that of Leu (0.60 ± 0.04) and KIC (0.57 ± 0.08, P < 0.05). Interestingly, LY294002 treatment markedly attenuated the effect of HMB, while rapamycin treatment failed to exert the same effect. Thus, HMB appears to be more potent than Leu and KIC in inhibiting protein degradation in the absence or presence of insulin, and this inhibitory effect may be dependent on PI3K/Akt signaling pathway regardless of insulin, and mTOR signaling was only involved in this effect of HMB in the absence of insulin.
[Mh] Termos MeSH primário: Leucina/farmacologia
Fibras Musculares Esqueléticas/efeitos dos fármacos
Proteólise/efeitos dos fármacos
Valeratos/farmacologia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Insulina/farmacologia
Cetoácidos/farmacologia
Camundongos
Fibras Musculares Esqueléticas/metabolismo
Proteínas Musculares/genética
Proteínas Musculares/metabolismo
Fosfatidilinositol 3-Quinases/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteínas Ligases SKP Culina F-Box/genética
Proteínas Ligases SKP Culina F-Box/metabolismo
Serina-Treonina Quinases TOR/metabolismo
Proteínas com Motivo Tripartido/metabolismo
Ubiquitina-Proteína Ligases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insulin); 0 (Keto Acids); 0 (Muscle Proteins); 0 (Tripartite Motif Proteins); 0 (Valerates); 3F752311CD (beta-hydroxyisovaleric acid); 816-66-0 (alpha-ketoisocaproic acid); EC 2.3.2.27 (Fbxo32 protein, mouse); EC 2.3.2.27 (SKP Cullin F-Box Protein Ligases); EC 2.3.2.27 (Trim63 protein, mouse); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.1 (mTOR protein, mouse); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); GMW67QNF9C (Leucine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jafc.7b04841


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[PMID]:28464284
[Au] Autor:Su H; Lin J; Wang Y; Chen Q; Wang G; Tan F
[Ad] Endereço:Chongqing Institute of Green and Interligent Technology, Chinese Academy of Science, 266, Fangzheng Avenue, Shuitu High-Tech Park, Beibei, Chongqing 400714, P. R. China.
[Ti] Título:Engineering Brevibacterium flavum for the production of renewable bioenergy: C4-C5 advanced alcohols.
[So] Source:Biotechnol Bioeng;114(9):1946-1958, 2017 09.
[Is] ISSN:1097-0290
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Biosynthesis of advanced biofuels by engineered non-natural microorganisms has been proposed to be the most promising approach for the replacement of dwindling fossil fuel resources. Brevibacterium flavum (Bf) is a model brevibacterium aerobe which lacks basic and applied research that could enable this species to produce biofuels. There are no reports regarding engineering this microorganism to produce advanced alcohols before. Here, for the first time, we developed the bacterium as a novel biosynthetic platform for advanced alcohols production via the mutagenesis and engineering to produce 2-ketoacids derived alcohols. In order to enhance the strain's capability of producing advanced alcohols, we preferentially improved intrinsic metabolism ability of the strain to obtain improved expression host (IEH) via generating mutagenesis libraries by whole cell mutagenesis (WCM). The IEH was determined via screening out the mutant strain with the highest production of branched-chain organic acids (BCOA) using high throughput screening method.. Subsequently, a novel vector system for Bf was established, and the corresponding biosynthetic pathway of directing carbon flux into the target advanced alcohols was recruited to make the bacterium possess the capability of producing advanced alcohols and further enhance the production using the IEH. Specifically, we generated bioengineered strains that were able to synthesize up to the highest 5362 and 4976 mg/L isobutanol, 1945 and 1747 mg/L 2-methyl-1-butanol (2 MB), and 785.34 and 781 mg/L 3-methyl-1-butanol (3 MB) from pure glucose and duckweed substrates, respectively. Our findings confirmed the feasibility and potential of using Bf as a novel biosynthetic platform to generate advanced biofuels with glucose and inexpensive renewable feedstock-duckweed as a fermentation substrate. Biotechnol. Bioeng. 2017;114: 1946-1958. © 2017 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Álcoois/metabolismo
Biocombustíveis/microbiologia
Vias Biossintéticas/fisiologia
Brevibacterium flavum/fisiologia
Cetoácidos/metabolismo
Engenharia Metabólica/métodos
Energia Renovável
[Mh] Termos MeSH secundário: Álcoois/isolamento & purificação
Melhoramento Genético/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Alcohols); 0 (Biofuels); 0 (Keto Acids)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171226
[Lr] Data última revisão:
171226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1002/bit.26324


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[PMID]:28745686
[Au] Autor:Milovanova SY; Milovanov YS; Taranova MV; Dobrosmyslov IA
[Ad] Endereço:I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia.
[Ti] Título:[Effects of keto/amino acids and a low-protein diet on the nutritional status of patients with Stages 3B-4 chronic kidney disease].
[Ti] Título:Vliianie keto/aminokislot i ogranicheniia belka na status pitaniia bol'nykh khronicheskoi bolezn'iu pochek IIIB-IV stadii..
[So] Source:Ter Arkh;89(6):30-33, 2017.
[Is] ISSN:0040-3660
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:AIM: To evaluate the efficacy of keto/amino acids in maintaining protein balance and preventing mineral metabolic disturbances and the development of uremic hyperparathyroidism in the long-term use of a low-protein diet (LPD) in patients with Stages 3B-4 chronic kidney disease (CKD). SUBJECTS AND METHODS: Ninety patients with CKD caused by chronic latent glomerulonephritis in 65 patients and chronic tubulointerstitial nephritis of various etiologies (gout, drug-induced, and infection) in 25 were examined. The investigators conducted clinical, laboratory, and instrumental examinations, including bioelectrical impedance analysis (body mass index (BMI), the percentages of lean and fat mass), echocardiography and radiography of the abdominal aorta in the lateral projection (the presence of cardiac valvular and aortic calcification), and pulse wave velocity measurements using a Sphygmocor apparatus (vessel stiffness estimation). The stages of CKD were defined according to the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) criteria; glomerular filtration rate was calculated using the CKD EPI equation. According to the diet used, all the patients were divided into 3 groups: 1) 30 patients who took LPD (0.6 g of protein per kg of body weight/day) in combination with the keto/amino acid ketosteril (1 tablet per 5 kg of body weight/day; Diet One); 2) 30 patients who used LPD in combination with the other keto/amino acid ketoaminol at the same dose (Diet Two); 3) 30 patients had LPD without using the keto/amino acids (Diet Three) (a control group). RESULTS: During a follow-up, there were no signs of malnutrition in Groups 1 and 2 patients receiving LPD (0.6 g protein per kg/day) in combination with the keto/amino acids ketosteril and ketaminol, respectively. At the same time, 11 (36.6%) patients in Group 3 (a control group) who did not take the keto/amino acids showed a BMI decrease from 24 (23; 26) kg/m2 to 18.5 (17; 19.2) kg/m2 (p < 0.05), including that of lean body mass from 37.4 (36; 38.8) to 30 (29.1; 34.7)% in the men (p<0.05) and from 29.8 (26.8; 31) to 23.9 (22; 25.7)% in the women (p<0.01). In addition, at the end of the study, there were elevated serum phosphorus levels (p<0.05) and mainly higher parathyroid hormone concentrations in Group 3 patients who received LPD without using the amino/keto acids than in Groups 1 and 2. As compared to Group 3, Groups 1 and 2 displayed no differences in the quantity of cardiac and aortic calcification and in the augmentation index (arterial stiffness). The ketosteril and ketaminol groups versus the control group had also higher s-Klotho levels (p<0.01) that were inversely correlated with glomerular filtration rate (r =-0.467; p<0.01). CONCLUSION: The keto/amino acids ketosteril or ketoaminol are an important component of LPD, which prevents malnutrition and an additional source of calcium that inhibits hyperphosphatemia and slows the development of uremic hyperparathyroidism. Incorporation of keto/amino acids into LPD leads to a less pronounced reduction in s-Klotho protein in relation to the degree of renal failure than does LPD without keto/amino acids.
[Mh] Termos MeSH primário: Aminoácidos Essenciais/farmacologia
Aminoácidos/farmacologia
Dieta com Restrição de Proteínas/métodos
Glucuronidase/sangue
Cetoácidos/farmacologia
Avaliação de Resultados (Cuidados de Saúde)
Insuficiência Renal Crônica
[Mh] Termos MeSH secundário: Adulto
Idoso
Aminoácidos/administração & dosagem
Aminoácidos Essenciais/administração & dosagem
Terapia Combinada
Dieta com Restrição de Proteínas/efeitos adversos
Feminino
Seguimentos
Seres Humanos
Cetoácidos/administração & dosagem
Masculino
Meia-Idade
Insuficiência Renal Crônica/sangue
Insuficiência Renal Crônica/diagnóstico
Insuficiência Renal Crônica/dietoterapia
[Pt] Tipo de publicação:CONTROLLED CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids); 0 (Amino Acids, Essential); 0 (Keto Acids); 68934-50-9 (ketosteril); EC 3.2.1.31 (Glucuronidase); EC 3.2.1.31 (klotho protein)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171129
[Lr] Data última revisão:
171129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.17116/terarkh201789630-33


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[PMID]:28764105
[Au] Autor:Zeng W; Zhang H; Xu S; Fang F; Zhou J
[Ad] Endereço:Key Laboratory of Industrial Biotechnology of Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, Jiangsu, China; National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, Jiangsu, China.
[Ti] Título:Biosynthesis of keto acids by fed-batch culture of Yarrowia lipolytica WSH-Z06.
[So] Source:Bioresour Technol;243:1037-1043, 2017 Nov.
[Is] ISSN:1873-2976
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Both α-ketoglutarate (α-KG) and pyruvate (PYR) are important organic acids with promising applications in the food, pharmaceutical and chemical industries. During the production of α-KG by different microorganisms, PYR is always present as a by-product. Strategies have been applied to eliminate PYR accumulation since it can bring difficulties to the downstream separation process. However, modern separation technologies have already conquered this problem. Therefore, this study was aimed at simultaneously enhancing α-KG and PYR production by Yarrowia lipolytica WSH-Z06. Using a fed-batch strategy, in which the initial glycerol concentration was 50g·L , the residual glycerol concentration was maintained 20-30g·L by constant feeding at a rate of 1.25g·L ·h . The titers of α-KG and PYR were increased by 9.6% and 176.8%, and reached 67.4g·L and 39.1g·L , respectively. The final yield of keto acids was 0.71g·g glycerol, which is 42.0% higher than that of the optimal batch fermentation.
[Mh] Termos MeSH primário: Ácidos Cetoglutáricos
Yarrowia
[Mh] Termos MeSH secundário: Técnicas de Cultura Celular por Lotes
Glicerol
Cetoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Keto Acids); 0 (Ketoglutaric Acids); 8ID597Z82X (alpha-ketoglutaric acid); PDC6A3C0OX (Glycerol)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170803
[St] Status:MEDLINE


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[PMID]:28731268
[Au] Autor:Zhang M; Yu XW; Xu Y; Jouhten P; Swapna GVT; Glaser RW; Hunt JF; Montelione GT; Maaheimo H; Szyperski T
[Ad] Endereço:School of Biotechnology, Key Laboratory of Industrial Biotechnology, State Key Laboratory of Food Science and Technology, Ministry of Education, Jiangnan University, Wuxi, China.
[Ti] Título: C metabolic flux profiling of Pichia pastoris grown in aerobic batch cultures on glucose revealed high relative anabolic use of TCA cycle and limited incorporation of provided precursors of branched-chain amino acids.
[So] Source:FEBS J;284(18):3100-3113, 2017 Sep.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Carbon metabolism of Crabtree-negative yeast Pichia pastoris was profiled using C nuclear magnetic resonance (NMR) to delineate regulation during exponential growth and to study the import of two precursors for branched-chain amino acid biosynthesis, α-ketoisovalerate and α-ketobutyrate. Cells were grown in aerobic batch cultures containing (a) only glucose, (b) glucose along with the precursors, or (c) glucose and Val. The study provided the following new insights. First, C flux ratio analyses of central metabolism reveal an unexpectedly high anaplerotic supply of the tricarboxylic acid cycle for a Crabtree-negative yeast, and show that a substantial fraction of glucose catabolism proceeds through the pentose phosphate pathway. A comparison with previous flux ratio analyses for batch cultures of Crabtree-negative Pichia stipitis and Crabtree-positive Saccharomyces cerevisiae indicate that the overall regulation of central carbon metabolism in P. pastoris is intermediate in between P. stipitis and S. cerevisiae. Second, excess α-ketoisovalerate in the medium is not transported into the cytoplasm indicating that P. pastoris lacks a suitable transporter. In contrast, excess Val is efficiently taken up and largely fulfills demands for both Val and Leu for protein synthesis. Third, excess α-ketobutyrate is transported into the mitochondria for Ile biosynthesis. However, the import does not efficiently inhibit the synthesis of α-ketobutyrate from pyruvate indicating that P. pastoris has not been optimized evolutionarily to take full advantage of this carbon source. These findings have direct implications for preparing uniformly H, C, N-labeled proteins containing protonated Ile, Val, and Leu methyl groups in P. pastoris for NMR-based structural biology. ENZYMES: Acetohydroxy acid isomeroreductase (EC 1.1.1.86), branched-chain amino acid aminotransferase (BCAT, EC 2.6.1.42), fumarase (EC 4.2.1.2), malic enzyme (EC 1.1.1.39/1.1.1.40), phosphoenolpyruvate carboxykinase (EC 4.1.1.49), pyruvate carboxylase (EC 6.4.1.1), pyruvate kinase (EC 2.7.1.40), l-serine hydroxymethyltransferase (EC 2.1.2.1), threonine aldolase (EC 4.1.2.5), threonine dehydratase (EC 4.3.1.19); transketolase (EC 2.2.1.1), transaldolase (EC 2.2.1.2).
[Mh] Termos MeSH primário: Glucose/metabolismo
Isoleucina/metabolismo
Leucina/metabolismo
Metaboloma/fisiologia
Pichia/metabolismo
Valina/metabolismo
[Mh] Termos MeSH secundário: Aerobiose/fisiologia
Técnicas de Cultura Celular por Lotes
Butiratos/metabolismo
Isótopos de Carbono
Ciclo do Ácido Cítrico/fisiologia
Cetoácidos/metabolismo
Espectroscopia de Ressonância Magnética
Mitocôndrias/metabolismo
Via de Pentose Fosfato/fisiologia
Ácido Pirúvico/metabolismo
Saccharomyces cerevisiae/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Butyrates); 0 (Carbon Isotopes); 0 (Keto Acids); 04Y7590D77 (Isoleucine); 600-18-0 (alpha-ketobutyric acid); 759-05-7 (alpha-ketoisovalerate); 8558G7RUTR (Pyruvic Acid); GMW67QNF9C (Leucine); HG18B9YRS7 (Valine); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE
[do] DOI:10.1111/febs.14180


  6 / 3101 MEDLINE  
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[PMID]:28646031
[Au] Autor:Renguet E; Ginion A; Gélinas R; Bultot L; Auquier J; Robillard Frayne I; Daneault C; Vanoverschelde JL; Des Rosiers C; Hue L; Horman S; Beauloye C; Bertrand L
[Ad] Endereço:Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pole of Cardiovascular Research, Brussels, Belgium.
[Ti] Título:Metabolism and acetylation contribute to leucine-mediated inhibition of cardiac glucose uptake.
[So] Source:Am J Physiol Heart Circ Physiol;313(2):H432-H445, 2017 Aug 01.
[Is] ISSN:1522-1539
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:High plasma leucine levels strongly correlate with type 2 diabetes. Studies of muscle cells have suggested that leucine alters the insulin response for glucose transport by activating an insulin-negative feedback loop driven by the mammalian target of rapamycin/p70 ribosomal S6 kinase (mTOR/p70S6K) pathway. Here, we examined the molecular mechanism involved in leucine's action on cardiac glucose uptake. Leucine was indeed able to curb glucose uptake after insulin stimulation in both cultured cardiomyocytes and perfused hearts. Although leucine activated mTOR/p70S6K, the mTOR inhibitor rapamycin did not prevent leucine's inhibitory action on glucose uptake, ruling out the contribution of the insulin-negative feedback loop. α-Ketoisocaproate, the first metabolite of leucine catabolism, mimicked leucine's effect on glucose uptake. Incubation of cardiomyocytes with [ C]leucine ascertained its metabolism to ketone bodies (KBs), which had a similar negative impact on insulin-stimulated glucose transport. Both leucine and KBs reduced glucose uptake by affecting translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Finally, we found that leucine elevated the global protein acetylation level. Pharmacological inhibition of lysine acetyltransferases counteracted this increase in protein acetylation and prevented leucine's inhibitory action on both glucose uptake and GLUT4 translocation. Taken together, these results indicate that leucine metabolism into KBs contributes to inhibition of cardiac glucose uptake by hampering the translocation of GLUT4-containing vesicles via acetylation. They offer new insights into the establishment of insulin resistance in the heart. Catabolism of the branched-chain amino acid leucine into ketone bodies efficiently inhibits cardiac glucose uptake through decreased translocation of glucose transporter 4 to the plasma membrane. Leucine increases protein acetylation. Pharmacological inhibition of acetylation reverses leucine's action, suggesting acetylation involvement in this phenomenon.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/leucine-metabolism-inhibits-cardiac-glucose-uptake/.
[Mh] Termos MeSH primário: Metabolismo Energético/efeitos dos fármacos
Glucose/metabolismo
Cetoácidos/farmacologia
Corpos Cetônicos/farmacologia
Leucina/farmacologia
Miócitos Cardíacos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Acetilação
Animais
Transporte Biológico
Células Cultivadas
Relação Dose-Resposta a Droga
Transportador de Glucose Tipo 4/metabolismo
Resistência à Insulina
Preparação de Coração Isolado
Cetoácidos/metabolismo
Corpos Cetônicos/metabolismo
Leucina/metabolismo
Masculino
Miócitos Cardíacos/metabolismo
Transporte Proteico
Ratos Wistar
Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
Serina-Treonina Quinases TOR/antagonistas & inibidores
Serina-Treonina Quinases TOR/metabolismo
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; WEBCASTS
[Nm] Nome de substância:
0 (Glucose Transporter Type 4); 0 (Keto Acids); 0 (Ketone Bodies); 0 (Slc2a4 protein, rat); 816-66-0 (alpha-ketoisocaproic acid); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.1 (mTOR protein, rat); EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa); GMW67QNF9C (Leucine); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170625
[St] Status:MEDLINE
[do] DOI:10.1152/ajpheart.00738.2016


  7 / 3101 MEDLINE  
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[PMID]:28498544
[Au] Autor:Hou Y; Hossain GS; Li J; Shin HD; Du G; Chen J; Liu L
[Ad] Endereço:Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, Jiangnan University, Wuxi, China, 214122.
[Ti] Título:Metabolic engineering of cofactor flavin adenine dinucleotide (FAD) synthesis and regeneration in Escherichia coli for production of α-keto acids.
[So] Source:Biotechnol Bioeng;114(9):1928-1936, 2017 Sep.
[Is] ISSN:1097-0290
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cofactor flavin adenine dinucleotide (FAD) plays a vital role in many FAD-dependent enzymatic reactions; therefore, how to efficiently accelerate FAD synthesis and regeneration is an important topic in biocatalysis and metabolic engineering. In this study, a system involving the synthesis pathway and regeneration of FAD was engineered in Escherichia coli to improve α-keto acid production-from the corresponding l-amino acids-catalyzed by FAD-dependent l-amino acid deaminase (l-AAD). First, key genes, ribH, ribC, and ribF, were overexpressed and fine-tuned for FAD synthesis. In the resulting E. coli strain PHCF7, strong overexpression of pma, ribC, and ribF and moderate overexpression of ribH yielded a 90% increase in phenylpyruvic acid (PPA) titer: 19.4 ± 1.1 g · L . Next, formate dehydrogenase (FDH) and NADH oxidase (NOX) were overexpressed to strengthen the regeneration rate of cofactors FADH /FAD using FDH for FADH /FAD regeneration and NOX for NAD /NADH regeneration. The resulting E. coli strain PHCF7-FDH-NOX yielded the highest PPA production: 31.4 ± 1.1 g · L . Finally, this whole-cell system was adapted to production of other α-keto acids including α-ketoglutaric acid, α-ketoisocaproate, and keto-γ-methylthiobutyric acid to demonstrate the broad utility of strengthening of FAD synthesis and FADH /FAD regeneration for production of α-keto acids. Notably, the strategy reported herein may be generally applicable to other flavin-dependent biocatalysis reactions and metabolic pathway optimizations. Biotechnol. Bioeng. 2017;114: 1928-1936. © 2017 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Vias Biossintéticas/fisiologia
Escherichia coli/fisiologia
Flavina-Adenina Dinucleotídeo/biossíntese
Melhoramento Genético/métodos
Cetoácidos/metabolismo
Engenharia Metabólica/métodos
[Mh] Termos MeSH secundário: Proteínas de Escherichia coli/genética
Proteínas de Escherichia coli/metabolismo
Flavina-Adenina Dinucleotídeo/genética
Regulação Bacteriana da Expressão Gênica/fisiologia
Regulação Enzimológica da Expressão Gênica/fisiologia
Cetoácidos/isolamento & purificação
Complexos Multienzimáticos/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Escherichia coli Proteins); 0 (Keto Acids); 0 (Multienzyme Complexes); 146-14-5 (Flavin-Adenine Dinucleotide)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170513
[St] Status:MEDLINE
[do] DOI:10.1002/bit.26336


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[PMID]:28478035
[Au] Autor:El Khoury L; Piquemal JP; Fermandjian S; Maroun RG; Gresh N; Hobaika Z
[Ad] Endereço:UR EGP, Centre d'Analyses et de Recherche, Faculté des Sciences, Université Saint-Joseph de Beyrouth, B.P. 11-514 Riad El Solh, Beirut 1107 2050, Lebanon; Laboratoire de Chimie Théorique, UMR7616 CNRS, UPMC, Sorbonne Universités, Paris 75005, France. Electronic address: lea.khoury4@net.usj.edu.lb.
[Ti] Título:The inhibition process of HIV-1 integrase by diketoacids molecules: Understanding the factors governing the better efficiency of dolutegravir.
[So] Source:Biochem Biophys Res Commun;488(3):433-438, 2017 Jul 01.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Human Immunodeficiency Virus-1 integrase is responsible for the covalent insertion of a newly synthesized double-stranded viral DNA into the host cells, and is an emerging target for antivirus drug design. Raltegravir (RAL) and elvitegravir (EVG) are the first two integrase strand transfer inhibitors used in therapy. However, treated patients eventually develop detrimental resistance mutations. By contrast, a recently approved drug, dolutegravir (DTG), presents a high barrier to resistance. This study aims to understand the increased efficiency of DTG upon focusing on its interaction properties with viral DNA. The results showed DTG to be involved in more extended interactions with viral DNA than EVG. Such interactions involve the halobenzene and scaffold of DTG and EVG and bases 5'G 3', 3'A 5'and 3'C 5'.
[Mh] Termos MeSH primário: Inibidores de Integrase de HIV/farmacologia
Integrase de HIV/metabolismo
Compostos Heterocíclicos com 3 Anéis/farmacologia
Cetoácidos/farmacologia
[Mh] Termos MeSH secundário: DNA Viral/efeitos dos fármacos
Relação Dose-Resposta a Droga
Polarização de Fluorescência
Inibidores de Integrase de HIV/química
Compostos Heterocíclicos com 3 Anéis/química
Cetoácidos/química
Modelos Moleculares
Conformação Molecular
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Viral); 0 (HIV Integrase Inhibitors); 0 (Heterocyclic Compounds, 3-Ring); 0 (Keto Acids); 0 (p31 integrase protein, Human immunodeficiency virus 1); DKO1W9H7M1 (dolutegravir); EC 2.7.7.- (HIV Integrase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170508
[St] Status:MEDLINE


  9 / 3101 MEDLINE  
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[PMID]:28476332
[Au] Autor:Chourey S; Ye Q; Reddy CN; Cossette C; Gravel S; Zeller M; Slobodchikova I; Vuckovic D; Rokach J; Powell WS
[Ad] Endereço:Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, 150 West University Boulevard, Melbourne, FL 32901-6982, USA.
[Ti] Título:In vivo α-hydroxylation of a 2-alkylindole antagonist of the OXE receptor for the eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid in monkeys.
[So] Source:Biochem Pharmacol;138:107-118, 2017 Aug 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We have developed a selective indole antagonist (230) targeting the OXE receptor for the potent eosinophil chemoattractant 5-oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid), that may be useful for the treatment of eosinophilic diseases such as asthma. In previous studies we identified ω2-oxidation of the hexyl side chain of racemic 230 as a major metabolic route in monkeys, but also obtained evidence for another pathway that appeared to involve hydroxylation of the hexyl side chain close to the indole. The present study was designed to investigate the metabolism of the active S-enantiomer of 230 (S230) and to identify the novel hydroxy metabolite and its chirality. Following oral administration, S230 rapidly appeared in the blood along with metabolites formed by a novel and highly stereospecific α-hydroxylation pathway, resulting in the formation of αS-hydroxy-S230. The chirality of α-hydroxy-S230 was determined by the total synthesis of the relevant diastereomers. Of the four possible diastereomers of α-hydroxy-230 only αS-hydroxy-S230 has significant OXE receptor antagonist activity and only this diastereomer was found in significant amounts in blood following oral administration of S230. Other novel metabolites of S230 identified in plasma by LC-MS/MS were αS,ω2-dihydroxy-S230 and glucuronides of S230 and ω2-hydroxy-S230. Thus the alkyl side chain of S230, which is essential for its antagonist activity, is also the major target of the metabolic enzymes that terminate its antagonist activity. Modification of this side chain might result in the development of related antagonists with improved metabolic stability and efficacy.
[Mh] Termos MeSH primário: Antiasmáticos/farmacocinética
Anti-Inflamatórios não Esteroides/farmacocinética
Ácidos Araquidônicos/antagonistas & inibidores
Fatores Quimiotáticos/antagonistas & inibidores
Indóis/farmacocinética
Cetoácidos/farmacocinética
Receptores Eicosanoides/antagonistas & inibidores
[Mh] Termos MeSH secundário: Administração Oral
Alquilação
Animais
Antiasmáticos/administração & dosagem
Antiasmáticos/sangue
Antiasmáticos/farmacologia
Anti-Inflamatórios não Esteroides/administração & dosagem
Anti-Inflamatórios não Esteroides/sangue
Anti-Inflamatórios não Esteroides/farmacologia
Ácidos Araquidônicos/metabolismo
Fatores Quimiotáticos/metabolismo
Eosinófilos/efeitos dos fármacos
Eosinófilos/imunologia
Eosinófilos/metabolismo
Feminino
Glucuronídeos/sangue
Glucuronídeos/química
Glucuronídeos/farmacologia
Seres Humanos
Hidroxilação
Inativação Metabólica
Indóis/administração & dosagem
Indóis/sangue
Indóis/química
Indóis/farmacologia
Cetoácidos/administração & dosagem
Cetoácidos/sangue
Cetoácidos/química
Cetoácidos/farmacologia
Macaca fascicularis
Estrutura Molecular
Neutrófilos/efeitos dos fármacos
Neutrófilos/imunologia
Neutrófilos/metabolismo
Receptores Eicosanoides/agonistas
Receptores Eicosanoides/metabolismo
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5-(5-chloro-2-(1-hydroxyhexyl)-1-methyl-1H-indol-3-yl)-3-methyl-5-oxopentanoate); 0 (5-(5-chloro-2-hexyl-1-methyl-1H-indol-3-yl)-3-methyl-5-oxopentanoate); 0 (Anti-Asthmatic Agents); 0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Arachidonic Acids); 0 (Chemotactic Factors); 0 (Glucuronides); 0 (Indoles); 0 (Keto Acids); 0 (Receptors, Eicosanoid); 126432-17-5 (5-oxo-6,8,11,14-eicosatetraenoic acid)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170507
[St] Status:MEDLINE


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[PMID]:28446262
[Au] Autor:Zheng L; Zuo F; Zhao S; He P; Wei H; Xiang Q; Pang J; Peng J
[Ad] Endereço:1Department of Animal Nutrition and Feed Science,College of Animal Science and Technology,Huazhong Agricultural University,Wuhan 430070,People's Republic of China.
[Ti] Título:Dietary supplementation of branched-chain amino acids increases muscle net amino acid fluxes through elevating their substrate availability and intramuscular catabolism in young pigs.
[So] Source:Br J Nutr;117(7):911-922, 2017 Apr.
[Is] ISSN:1475-2662
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Branched-chain amino acids (BCAA) have been clearly demonstrated to have anabolic effects on muscle protein synthesis. However, little is known about their roles in the regulation of net AA fluxes across skeletal muscle in vivo. This study was aimed to investigate the effect and related mechanisms of dietary supplementation of BCAA on muscle net amino acid (AA) fluxes using the hindlimb flux model. In all fourteen 4-week-old barrows were fed reduced-protein diets with or without supplemental BCAA for 28 d. Pigs were implanted with carotid arterial, femoral arterial and venous catheters, and fed once hourly with intraarterial infusion of p-amino hippurate. Arterial and venous plasma and muscle samples were obtained for the measurement of AA, branched-chain α-keto acids (BCKA) and 3-methylhistidine (3-MH). Metabolomes of venous plasma were determined by HPLC-quadrupole time-of-flight-MS. BCAA-supplemented group showed elevated muscle net fluxes of total essential AA, non-essential AA and AA. As for individual AA, muscle net fluxes of each BCAA and their metabolites (alanine, glutamate and glutamine), along with those of histidine, methionine and several functional non-essential AA (glycine, proline and serine), were increased by BCAA supplementation. The elevated muscle net AA fluxes were associated with the increase in arterial and intramuscular concentrations of BCAA and venous metabolites including BCKA and free fatty acids, and were also related to the decrease in the intramuscular concentration of 3-MH. Correlation analysis indicated that muscle net AA fluxes are highly and positively correlated with arterial BCAA concentrations and muscle net BCKA production. In conclusion, supplementing BCAA to reduced-protein diet increases the arterial concentrations and intramuscular catabolism of BCAA, both of which would contribute to an increase of muscle net AA fluxes in young pigs.
[Mh] Termos MeSH primário: Aminoácidos de Cadeia Ramificada/administração & dosagem
Anabolizantes/administração & dosagem
Dieta com Restrição de Proteínas/veterinária
Desenvolvimento Muscular
Proteínas Musculares/biossíntese
Músculo Esquelético/metabolismo
Regulação para Cima
[Mh] Termos MeSH secundário: Aminoácidos/sangue
Aminoácidos/metabolismo
Aminoácidos de Cadeia Ramificada/sangue
Aminoácidos de Cadeia Ramificada/metabolismo
Anabolizantes/sangue
Anabolizantes/metabolismo
Animais
China
Cruzamentos Genéticos
Dieta com Restrição de Proteínas/efeitos adversos
Ácidos Graxos não Esterificados/sangue
Ácidos Graxos não Esterificados/metabolismo
Membro Posterior
Técnicas de Diluição do Indicador
Cetoácidos/sangue
Cetoácidos/metabolismo
Masculino
Metabolômica/métodos
Metilistidinas/sangue
Metilistidinas/metabolismo
Músculo Esquelético/irrigação sanguínea
Músculo Esquelético/crescimento & desenvolvimento
Orquiectomia/veterinária
Fluxo Sanguíneo Regional
Sus scrofa
Ganho de Peso
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Amino Acids); 0 (Amino Acids, Branched-Chain); 0 (Anabolic Agents); 0 (Fatty Acids, Nonesterified); 0 (Keto Acids); 0 (Methylhistidines); 0 (Muscle Proteins); 368-16-1 (3-methylhistidine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170428
[St] Status:MEDLINE
[do] DOI:10.1017/S0007114517000757



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