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[PMID]:29235326
[Au] Autor:Minchenko OH; Riabovol OO; Tsymbal DO; Minchenko DO; Ratushna OO
[Ti] Título:Effect of hypoxia on the expression of nuclear genes encoding mitochondrial proteins in U87 glioma cells.
[So] Source:Ukr Biochem J;88(3):54-65, 2016 May-Jun.
[Is] ISSN:2409-4943
[Cp] País de publicação:Ukraine
[La] Idioma:eng
[Ab] Resumo:We have studied the effect of hypoxia on the expression of nuclear genes encoding mitochondrial proteins in U87 glioma cells under the inhibition of IRE1 (inositol requiring enzyme-1), which controls cell proliferation and tumor growth as a central mediator of endoplasmic reticulum stress. It was shown that hypoxia down-regulated gene expression of malate dehydrogenase 2 (MDH2), malic enzyme 2 (ME2), mitochondrial aspartate aminotransferase (GOT2), and subunit B of succinate dehydrogenase (SDHB) in control (transfected by empty vector) glioma cells in a gene specific manner. At the same time, the expression level of mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) and subunit D of succinate dehydrogenase (SDHD) genes in these cells does not significantly change in hypoxic conditions. It was also shown that the inhibition of ІRE1 signaling enzyme function in U87 glioma cells decreases the effect of hypoxia on the expression of ME2, GOT2, and SDHB genes and introduces the sensitivity of IDH2 gene to hypoxia. Furthermore, the expression of all studied genes depends on IRE1-mediated endoplasmic reticulum stress signaling in gene specific manner, because ІRE1 knockdown significantly decreases their expression in normoxic conditions, except for IDH2 gene, which expression level is strongly up-regulated. Therefore, changes in the expression level of nuclear genes encoding ME2, MDH2, IDH2, SDHB, SDHD, and GOT2 proteins possibly reflect metabolic reprogramming of mitochondria by hypoxia and IRE1-mediated endoplasmic reticulum stress signaling and correlate with suppression of glioma cell proliferation under inhibition of the IRE1 enzyme function.
[Mh] Termos MeSH primário: Núcleo Celular/genética
Estresse do Retículo Endoplasmático/genética
Endorribonucleases/genética
Regulação Neoplásica da Expressão Gênica
Mitocôndrias/genética
Neuroglia/enzimologia
Proteínas Serina-Treonina Quinases/genética
[Mh] Termos MeSH secundário: Aspartato Aminotransferases/genética
Aspartato Aminotransferases/metabolismo
Hipóxia Celular
Linhagem Celular Tumoral
Núcleo Celular/enzimologia
Proliferação Celular
Endorribonucleases/deficiência
Seres Humanos
Isocitrato Desidrogenase/genética
Isocitrato Desidrogenase/metabolismo
Malato Desidrogenase/genética
Malato Desidrogenase/metabolismo
Mitocôndrias/enzimologia
Proteínas Mitocondriais/genética
Proteínas Mitocondriais/metabolismo
Neuroglia/patologia
Proteínas Nucleares/genética
Proteínas Nucleares/metabolismo
Transporte Proteico
Proteínas Serina-Treonina Quinases/deficiência
Transdução de Sinais
Succinato Desidrogenase/genética
Succinato Desidrogenase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Mitochondrial Proteins); 0 (Nuclear Proteins); 0 (SDHD protein, human); EC 1.1.1.37 (MDH2 protein, human); EC 1.1.1.37 (Malate Dehydrogenase); EC 1.1.1.37 (malic enzyme 2; human); EC 1.1.1.41 (Isocitrate Dehydrogenase); EC 1.1.1.41 (isocitrate dehydrogenase 2, human); EC 1.3.5.1 (SDHB protein, human); EC 1.3.99.1 (Succinate Dehydrogenase); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.7.11.1 (ERN1 protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 3.1.- (Endoribonucleases)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE
[do] DOI:10.15407/ubj88.03.054


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[PMID]:28450391
[Au] Autor:Korge P; Calmettes G; John SA; Weiss JN
[Ad] Endereço:From the UCLA Cardiovascular Research Laboratory and the Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095.
[Ti] Título:Reactive oxygen species production induced by pore opening in cardiac mitochondria: The role of complex III.
[So] Source:J Biol Chem;292(24):9882-9895, 2017 06 16.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent evidence has implicated succinate-driven reverse electron transport (RET) through complex I as a major source of damaging reactive oxygen species (ROS) underlying reperfusion injury after prolonged cardiac ischemia. However, this explanation may be incomplete, because RET on reperfusion is self-limiting and therefore transient. RET can only generate ROS when mitochondria are well polarized, and it ceases when permeability transition pores (PTP) open during reperfusion. Because prolonged ischemia/reperfusion also damages electron transport complexes, we investigated whether such damage could lead to ROS production after PTP opening has occurred. Using isolated cardiac mitochondria, we demonstrate a novel mechanism by which antimycin-inhibited complex III generates significant amounts of ROS in the presence of Mg and NAD and the absence of exogenous substrates upon inner membrane pore formation by alamethicin or Ca -induced PTP opening. We show that H O production under these conditions is related to Mg -dependent NADH generation by malic enzyme. H O production is blocked by stigmatellin, indicating its origin from complex III, and by piericidin, demonstrating the importance of NADH-related ubiquinone reduction for ROS production under these conditions. For maximal ROS production, the rate of NADH generation has to be equal or below that of NADH oxidation, as further increases in [NADH] elevate ubiquinol-related complex III reduction beyond the optimal range for ROS generation. These results suggest that if complex III is damaged during ischemia, PTP opening may result in succinate/malate-fueled ROS production from complex III due to activation of malic enzyme by increases in matrix [Mg ], [NAD ], and [ADP].
[Mh] Termos MeSH primário: Complexo III da Cadeia de Transporte de Elétrons/metabolismo
Malato Desidrogenase/metabolismo
Mitocôndrias Cardíacas/metabolismo
Espécies Reativas de Oxigênio/agonistas
[Mh] Termos MeSH secundário: Difosfato de Adenosina/metabolismo
Alameticina/farmacologia
Animais
Antimicina A/análogos & derivados
Antimicina A/farmacologia
Biocatálise/efeitos dos fármacos
Sinalização do Cálcio/efeitos dos fármacos
Complexo III da Cadeia de Transporte de Elétrons/antagonistas & inibidores
Ativação Enzimática/efeitos dos fármacos
Inibidores Enzimáticos/farmacologia
Peróxido de Hidrogênio/metabolismo
Ionóforos/farmacologia
Magnésio/metabolismo
Malato Desidrogenase/química
Mitocôndrias Cardíacas/química
Mitocôndrias Cardíacas/efeitos dos fármacos
NAD/metabolismo
Oxirredução
Polienos/farmacologia
Porosidade/efeitos dos fármacos
Piridinas/farmacologia
Coelhos
Espécies Reativas de Oxigênio/metabolismo
Ubiquinona/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Ionophores); 0 (Polyenes); 0 (Pyridines); 0 (Reactive Oxygen Species); 0U46U6E8UK (NAD); 11118-72-2 (antimycin); 1339-63-5 (Ubiquinone); 27061-78-5 (Alamethicin); 61D2G4IYVH (Adenosine Diphosphate); 642-15-9 (Antimycin A); 8VT513UJ9R (piericidin A); 91682-96-1 (stigmatellin); BBX060AN9V (Hydrogen Peroxide); EC 1.1.1.37 (Malate Dehydrogenase); EC 1.10.2.2 (Electron Transport Complex III); I38ZP9992A (Magnesium)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171228
[Lr] Data última revisão:
171228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.768317


  3 / 7782 MEDLINE  
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[PMID]:29173220
[Au] Autor:Lu L; Wang M; Liao X; Zhang L; Luo X
[Ad] Endereço:Mineral Nutrition Research Division,Institute of Animal Science,Chinese Academy of Agricultural Sciences (CAAS),Beijing 100193,People's Republic of China.
[Ti] Título:Manganese influences the expression of fatty acid synthase and malic enzyme in cultured primary chicken hepatocytes.
[So] Source:Br J Nutr;118(11):881-888, 2017 Dec.
[Is] ISSN:1475-2662
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Two experiments were designed to investigate the effects of Mn source and concentration on the mRNA expression and enzymatic activities of fatty acid synthase (FAS) and malic enzyme (ME) in cultured primary broiler hepatocytes. In Expt 1, primary broiler hepatocytes were treated with 0 (control), 0·25, 0·50 or 0·75 mmol/l of Mn as inorganic manganese chloride (MnCl2.4H2O) for 24 and 48 h. In Expt 2, primary broiler hepatocytes were incubated with 0 (control), 0·25 or 0·50 mmol/l of Mn as either manganese chloride or Mn-amino acid chelate for 48 h. The mRNA levels and activities of FAS and ME in the hepatocytes were measured in Expts 1 and 2. The results in Expt 1 showed that only at 48 h mRNA expression levels of FAS and ME in the hepatocytes decreased linearly (P0·33) on any of the measured cellular parameters. The results suggested that Mn might reduce cell damage and regulate FAS and ME expression at a transcriptional level in primary cultured broiler hepatocytes.
[Mh] Termos MeSH primário: Ácido Graxo Sintases/metabolismo
Hepatócitos/enzimologia
Malato Desidrogenase/metabolismo
Manganês/farmacologia
[Mh] Termos MeSH secundário: Animais
Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
Galinhas
Ácido Graxo Sintases/genética
Regulação da Expressão Gênica
Fígado/citologia
Fígado/efeitos dos fármacos
Fígado/metabolismo
Malato Desidrogenase/genética
Masculino
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Messenger); 42Z2K6ZL8P (Manganese); EC 1.1.1.37 (Malate Dehydrogenase); EC 2.3.1.85 (Fatty Acid Synthases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171218
[Lr] Data última revisão:
171218
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1017/S0007114517002987


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[PMID]:28946929
[Au] Autor:Chen GH; Hogstrand C; Luo Z; Zhang DG; Ling SC; Wu K
[Ad] Endereço:1Key Laboratory of Freshwater Animal Breeding,Ministry of Agriculture of P.R.C.,Fishery College,Huazhong Agricultural University,Wuhan 430070,People's Republic of China.
[Ti] Título:Dietary zinc addition influenced zinc and lipid deposition in the fore- and mid-intestine of juvenile yellow catfish Pelteobagrus fulvidraco.
[So] Source:Br J Nutr;118(8):570-579, 2017 Oct.
[Is] ISSN:1475-2662
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The present study explored the mechanisms of dietary Zn influencing Zn and lipid deposition in the fore- and mid- intestine in yellow catfish Pelteobagrus fulvidraco, and investigated whether the mechanism was intestinal-region dependent. For this purpose, yellow catfish were fed three diets containing Zn levels of 8·83, 19·20 and 146·65 mg Zn/kg, respectively. Growth performance, intestinal TAG and Zn contents as well as activities and mRNA expression of enzymes and genes involved in Zn transport and lipid metabolism in the fore- and mid-intestine were analysed. Dietary Zn increased Zn accumulation as well as activities of Cu-, Zn-superoxide dismutase and ATPase in the fore- and mid-intestine. In the fore-intestine, dietary Zn up-regulated mRNA levels of ZnT1, ZnT5, ZnT7, metallothionein (MT) and metal response element-binding transcription factor-1 (MTF-1), but down-regulated mRNA levels of ZIP4 and ZIP5. In the mid-intestine, dietary Zn up-regulated mRNA levels of ZnT1, ZnT5, ZnT7, MT and MTF-1, but down-regulated mRNA levels of ZIP4 and ZIP5. Dietary Zn reduced TAG content, down-regulated activities of 6-phosphogluconate dehydrogenase (6PGD), glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME) and fatty acid synthase (FAS) activities, and reduced mRNA levels of 6PGD, G6PD, FAS, PPARγ and sterol-regulator element-binding protein (SREBP-1), but up-regulated mRNA levels of carnitine palmitoyltransferase IA, hormone-sensitive lipase (HSLa), adipose TAG lipase (ATGL) and PPARα in the fore-intestine. In the mid-intestine, dietary Zn reduced TAG content, activities of G6PD, ME, isocitrate dehydrogenase and FAS, down-regulated mRNA levels of 6PGD, G6PD, FAS, acetyl-CoA carboxylase a, PPARγ and SREBP-1, but up-regulated mRNA expression of HSLa, ATGL and PPARγ. The reduction in TAG content following Zn addition was attributable to reduced lipogenesis and increased lipolysis, and similar regulatory mechanisms were observed between the fore- and mid-intestine.
[Mh] Termos MeSH primário: Peixes-Gato/metabolismo
Intestinos/efeitos dos fármacos
Metabolismo dos Lipídeos/efeitos dos fármacos
Zinco/administração & dosagem
[Mh] Termos MeSH secundário: Acetil-CoA Carboxilase/genética
Acetil-CoA Carboxilase/metabolismo
Ração Animal/análise
Animais
Carnitina O-Palmitoiltransferase/genética
Carnitina O-Palmitoiltransferase/metabolismo
Dieta/veterinária
Regulação para Baixo
Regulação da Expressão Gênica
Glucosefosfato Desidrogenase/genética
Glucosefosfato Desidrogenase/metabolismo
Intestinos/metabolismo
Malato Desidrogenase/genética
Malato Desidrogenase/metabolismo
PPAR alfa/genética
PPAR alfa/metabolismo
PPAR gama/genética
PPAR gama/metabolismo
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Esterol Esterase/genética
Esterol Esterase/metabolismo
Proteína de Ligação a Elemento Regulador de Esterol 1/genética
Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
Superóxido Dismutase/genética
Superóxido Dismutase/metabolismo
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (PPAR alpha); 0 (PPAR gamma); 0 (RNA, Messenger); 0 (Sterol Regulatory Element Binding Protein 1); EC 1.1.1.37 (Malate Dehydrogenase); EC 1.1.1.39 (malate dehydrogenase (decarboxylating)); EC 1.1.1.49 (Glucosephosphate Dehydrogenase); EC 1.15.1.1 (Superoxide Dismutase); EC 2.3.1.21 (Carnitine O-Palmitoyltransferase); EC 3.1.1.13 (Sterol Esterase); EC 6.4.1.2 (Acetyl-CoA Carboxylase); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170927
[St] Status:MEDLINE
[do] DOI:10.1017/S0007114517002446


  5 / 7782 MEDLINE  
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[PMID]:28848047
[Au] Autor:Yao P; Sun H; Xu C; Chen T; Zou B; Jiang P; Du W
[Ad] Endereço:From the School of Life Sciences, Tsinghua University, Beijing 100084, China and.
[Ti] Título:Evidence for a direct cross-talk between malic enzyme and the pentose phosphate pathway via structural interactions.
[So] Source:J Biol Chem;292(41):17113-17120, 2017 Oct 13.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent studies have revealed that the oxidative entose hosphate athway (PPP), malic enzyme (ME), and folate metabolism are the three major routes for generating cellular NADPH, a key cofactor involved in redox control and reductive biosynthesis. Many tumor cells exhibit altered NADPH metabolism to fuel their rapid proliferation. However, little is known about how NADPH metabolism is coordinated in tumor cells. Here we report that ME1 increases the PPP flux by forming physiological complexes with 6-phosphogluconate dehydrogenase (6PGD). We found that ME1 and 6PGD form a hetero-oligomer that increases the capability of 6PGD to bind its substrate 6-phosphogluconate. Through activating 6PGD, ME1 enhances NADPH generation, PPP flux, and tumor cell growth. Interestingly, although ME1 could bind either the dimer-defect mutant 6PGD (K294R) or the NADP -binding defect 6PGD mutants, only 6PGD (K294R) activity was induced by ME1. Thus, ME1/6PGD hetero-complexes may mimic the active oligomer form of 6PGD. Together, these findings uncover a direct cross-talk mechanism between ME1 and PPP, may reveal an alternative model for signaling transduction via protein conformational simulation, and pave the way for better understanding how metabolic pathways are coordinated in cancer.
[Mh] Termos MeSH primário: Malato Desidrogenase/metabolismo
Proteínas de Neoplasias/metabolismo
Neoplasias/enzimologia
Via de Pentose Fosfato
Multimerização Proteica
Transdução de Sinais
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Gluconatos/química
Gluconatos/metabolismo
Seres Humanos
Hidroliases/química
Hidroliases/genética
Hidroliases/metabolismo
Malato Desidrogenase/química
Malato Desidrogenase/genética
Mutação de Sentido Incorreto
NADP/química
NADP/genética
NADP/metabolismo
Proteínas de Neoplasias/química
Proteínas de Neoplasias/genética
Neoplasias/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gluconates); 0 (Neoplasm Proteins); 53-59-8 (NADP); EC 1.1.1.37 (Malate Dehydrogenase); EC 1.1.1.39 (malate dehydrogenase (decarboxylating)); EC 4.2.1.- (Hydro-Lyases); EC 4.2.1.12 (phosphogluconate dehydratase); W31WK7B8U0 (6-phosphogluconic acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170830
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.810309


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[PMID]:28720843
[Au] Autor:Barrett MT; Deiotte R; Lenkiewicz E; Malasi S; Holley T; Evers L; Posner RG; Jones T; Han H; Sausen M; Velculescu VE; Drebin J; O'Dwyer P; Jameson G; Ramanathan RK; Von Hoff DD
[Ad] Endereço:Mayo Clinic in Arizona, Scottsdale, AZ 85259, USA.
[Ti] Título:Clinical study of genomic drivers in pancreatic ductal adenocarcinoma.
[So] Source:Br J Cancer;117(4):572-582, 2017 Aug 08.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two clinical trials. METHODS: Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples. We profiled biopsies from 68 patients enrolled in two Stand Up to Cancer (SU2C)-sponsored clinical trials. These included 38 resected chemoradiation naïve tumours (SU2C 20206-003) and metastases from 30 patients who progressed on prior therapies (SU2C 20206-001). Patient outcomes including progression-free survival (PFS) and overall survival (OS) were observed. RESULTS: We defined: (a) CDKN2A homozygous deletions that included the adjacent MTAP gene, only its' 3' region, or excluded MTAP; (b) SMAD4 homozygous deletions that included ME2; (c) a pancreas-specific MYC super-enhancer region; (d) DNA repair-deficient genomes; and (e) copy number aberrations present in PDA patients with long-term (⩾ 40 months) and short-term (⩽ 12 months) survival after surgical resection. CONCLUSIONS: We provide a clinically relevant framework for genomic drivers of PDA and for advancing novel treatments.
[Mh] Termos MeSH primário: Sequência de Bases
Carcinoma Ductal Pancreático/genética
Neoplasias Pancreáticas/genética
Deleção de Sequência
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Biópsia
Carcinoma Ductal Pancreático/tratamento farmacológico
Carcinoma Ductal Pancreático/secundário
Inibidor de Quinase Dependente de Ciclina p18/genética
Variações do Número de Cópias de DNA
Análise Mutacional de DNA
Reparo do DNA/genética
Intervalo Livre de Doença
Elementos Facilitadores Genéticos
Exoma
Feminino
Genes myc
Homozigoto
Seres Humanos
Malato Desidrogenase/genética
Masculino
Proteínas Associadas aos Microtúbulos/genética
Meia-Idade
Pâncreas/patologia
Neoplasias Pancreáticas/tratamento farmacológico
Neoplasias Pancreáticas/patologia
Proteínas Proto-Oncogênicas p21(ras)/genética
Purina-Núcleosídeo Fosforilase/genética
Proteína Smad4/genética
Taxa de Sobrevida
Proteína Supressora de Tumor p53/genética
[Pt] Tipo de publicação:CLINICAL STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CDKN2A protein, human); 0 (Cyclin-Dependent Kinase Inhibitor p18); 0 (KRAS protein, human); 0 (Microtubule-Associated Proteins); 0 (SMAD4 protein, human); 0 (Smad4 Protein); 0 (Tumor Suppressor Protein p53); EC 1.1.1.37 (Malate Dehydrogenase); EC 1.1.1.37 (malic enzyme 2; human); EC 2.4.2.1 (Purine-Nucleoside Phosphorylase); EC 2.4.2.28 (5'-methylthioadenosine phosphorylase); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170720
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.209


  7 / 7782 MEDLINE  
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[PMID]:28700220
[Au] Autor:Chow C; Hegde S; Blanchard JS
[Ad] Endereço:Department of Biochemistry, Albert Einstein College of Medicine , 1300 Morris Park Avenue, Bronx, New York 10461, United States.
[Ti] Título:Mechanistic Characterization of Escherichia coli l-Aspartate Oxidase from Kinetic Isotope Effects.
[So] Source:Biochemistry;56(31):4044-4052, 2017 Aug 08.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:l-Aspartate oxidase, encoded by the nadB gene, is the first enzyme in the de novo synthesis of NAD in bacteria. This FAD-dependent enzyme catalyzes the oxidation of l-aspartate to generate iminoaspartate and reduced flavin. Distinct from most amino acid oxidases, it can use either molecular oxygen or fumarate to reoxidize the reduced enzyme. Sequence alignments and the three-dimensional crystal structure have revealed that the overall fold and catalytic residues of NadB closely resemble those of the succinate dehydrogenase/fumarate reductase family rather than those of the prototypical d-amino acid oxidases. This suggests that the enzyme can catalyze amino acid oxidation via typical amino acid oxidase chemistry, involving the removal of protons from the α-amino group and the transfer of the hydride from C2, or potentially deprotonation at C3 followed by transfer of the hydride from C2, similar to chemistry occurring during succinate oxidation. We have investigated this potential mechanistic ambiguity using a combination of primary, solvent, and multiple deuterium kinetic isotope effects in steady state experiments. Our results indicate that the chemistry is similar to that of typical amino acid oxidases in which the transfer of the hydride from C2 of l-aspartate to FAD is rate-limiting and occurs in a concerted manner with respect to deprotonation of the α-amine. Together with previous kinetic and structural data, we propose that NadB has structurally evolved from succinate dehydrogenase/fumarate reductase-type enzymes to gain the new functionality of oxidizing amino acids while retaining the ability to reduce fumarate.
[Mh] Termos MeSH primário: Aminoácido Oxirredutases/metabolismo
Ácido Aspártico/metabolismo
Coenzimas/metabolismo
Escherichia coli K12/enzimologia
Proteínas de Escherichia coli/metabolismo
Flavina-Adenina Dinucleotídeo/metabolismo
Modelos Moleculares
[Mh] Termos MeSH secundário: Algoritmos
Aminoácido Oxirredutases/química
Aminoácido Oxirredutases/genética
Animais
Ácido Aspártico/química
Sítios de Ligação
Biocatálise
Domínio Catalítico
Coenzimas/química
Medição da Troca de Deutério
Proteínas de Escherichia coli/química
Proteínas de Escherichia coli/genética
Flavina-Adenina Dinucleotídeo/química
Concentração de Íons de Hidrogênio
Cinética
Malato Desidrogenase/metabolismo
Oxirredução
Conformação Proteica
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Sus scrofa
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Coenzymes); 0 (Escherichia coli Proteins); 0 (Recombinant Proteins); 146-14-5 (Flavin-Adenine Dinucleotide); 30KYC7MIAI (Aspartic Acid); EC 1.1.1.37 (Malate Dehydrogenase); EC 1.4.- (Amino Acid Oxidoreductases); EC 1.4.3.16 (L-aspartate oxidase, E coli)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00307


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[PMID]:28673962
[Au] Autor:Nadtochiy SM; Wang YT; Zhang J; Nehrke K; Schafer X; Welle K; Ghaemmaghami S; Munger J; Brookes PS
[Ad] Endereço:Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY 14642, U.S.A.
[Ti] Título:Potential mechanisms linking SIRT activity and hypoxic 2-hydroxyglutarate generation: no role for direct enzyme (de)acetylation.
[So] Source:Biochem J;474(16):2829-2839, 2017 Aug 10.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:2-Hydroxyglutarate (2-HG) is a hypoxic metabolite with potentially important epigenetic signaling roles. The mechanisms underlying 2-HG generation are poorly understood, but evidence suggests a potential regulatory role for the sirtuin family of lysine deacetylases. Thus, we hypothesized that the acetylation status of the major 2-HG-generating enzymes [lactate dehydrogenase (LDH), isocitrate dehydrogenase (IDH) and malate dehydrogenase (MDH)] may govern their 2-HG-generating activity. acetylation of these enzymes, with confirmation by western blotting, mass spectrometry, reversibility by recombinant sirtuins and an assay for global lysine occupancy, yielded no effect on 2-HG-generating activity. In addition, while elevated 2-HG in hypoxia is associated with the activation of lysine deacetylases, we found that mice lacking mitochondrial SIRT3 exhibited hyperacetylation and elevated 2-HG. These data suggest that there is no direct link between enzyme acetylation and 2-HG production. Furthermore, our observed effects of acetylation on the canonical activities of IDH, MDH and LDH appeared to contrast with previous findings wherein acetyl-mimetic lysine mutations resulted in the inhibition of these enzymes. Overall, these data suggest that a causal relationship should not be assumed between acetylation of metabolic enzymes and their activities, canonical or otherwise.
[Mh] Termos MeSH primário: Glutaratos/metabolismo
Lisina/metabolismo
Mitocôndrias Cardíacas/enzimologia
Proteínas Mitocondriais/genética
Processamento de Proteína Pós-Traducional
Sirtuína 3/genética
[Mh] Termos MeSH secundário: Acetilação
Animais
Hipóxia Celular
Ensaios Enzimáticos
Células HEK293
Seres Humanos
Isocitrato Desidrogenase/genética
Isocitrato Desidrogenase/metabolismo
Cinética
L-Lactato Desidrogenase/genética
L-Lactato Desidrogenase/metabolismo
Malato Desidrogenase/genética
Malato Desidrogenase/metabolismo
Masculino
Camundongos
Camundongos Knockout
Proteínas Mitocondriais/metabolismo
Transdução de Sinais
Sirtuína 3/deficiência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glutarates); 0 (Mitochondrial Proteins); 0 (Sirt3 protein, mouse); 2889-31-8 (alpha-hydroxyglutarate); EC 1.1.1.27 (L-Lactate Dehydrogenase); EC 1.1.1.37 (Malate Dehydrogenase); EC 1.1.1.41 (Isocitrate Dehydrogenase); EC 3.5.1.- (Sirtuin 3); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170705
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170389


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[PMID]:28576465
[Au] Autor:Tyszka-Czochara M; Bukowska-Strakova K; Majka M
[Ad] Endereço:Department of Radioligands, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland. Electronic address: mtyszka@poczta.fm.
[Ti] Título:Metformin and caffeic acid regulate metabolic reprogramming in human cervical carcinoma SiHa/HTB-35 cells and augment anticancer activity of Cisplatin via cell cycle regulation.
[So] Source:Food Chem Toxicol;106(Pt A):260-272, 2017 Aug.
[Is] ISSN:1873-6351
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Metformin shows benefits in anticancer prevention in humans. In this study, normal human fibroblasts (FB) and metastatic cervical cancer cells (SiHa) were exposed to 10 mM Metformin (Met), 100 µM Caffeic Acid (trans-3,4-dihydroxycinnamic acid, CA) or combination of the compounds. Both drugs were selectively toxic towards cancer cells, but neither Met nor CA treatment suppressed growth of normal cells. Met and CA regulated metabolic reprogramming in SiHa tumor cells through different mechanisms: Met suppressed regulatory enzymes Glurtaminase (GLS) and Malic Enzyme 1 (ME1) and enhanced pyruvate oxidation via tricarboxylic acids (TCA) cycle, while CA acted as glycolytic inhibitor. Met/CA treatment impaired expression of Sterol Regulatory Element-Binding Protein 1 (SREBP1c) which resulted in alleviation of de novo synthesis of unsaturated fatty acid. The toxic action of CisPt was supported by Met and CA not only in tumor cells, but also during co-culture of SiHa GFP+ cells with fibroblasts. Furthermore, Met and CA augmented Cisplatin (CisPt) action against quiescent tumor cells involving reprogramming of cell cycle. Our findings provide new insights into specific targeting of mitochondrial metabolism in neoplastic cells and into designing new cisplatin-based selective strategies for treating cervical cancer in humans with regard to the role of tumor microenvironment.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Ácidos Cafeicos/farmacologia
Ciclo Celular/efeitos dos fármacos
Cisplatino/farmacologia
Metformina/farmacologia
Neoplasias do Colo do Útero/fisiopatologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Sinergismo Farmacológico
Quimioterapia Combinada
Feminino
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Malato Desidrogenase/genética
Malato Desidrogenase/metabolismo
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Proteína de Ligação a Elemento Regulador de Esterol 1/genética
Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
Neoplasias do Colo do Útero/tratamento farmacológico
Neoplasias do Colo do Útero/genética
Neoplasias do Colo do Útero/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Caffeic Acids); 0 (Sterol Regulatory Element Binding Protein 1); 9100L32L2N (Metformin); EC 1.1.1.37 (Malate Dehydrogenase); EC 1.1.1.39 (malate dehydrogenase (decarboxylating)); Q20Q21Q62J (Cisplatin); U2S3A33KVM (caffeic acid)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170927
[Lr] Data última revisão:
170927
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170604
[St] Status:MEDLINE


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[PMID]:28506033
[Au] Autor:He D; Pengtao G; Ju Y; Jianhua L; He L; Guocai Z; Xichen Z
[Ad] Endereço:College of Veterinary Medicine, Jilin University, Changchun 130062, P. R. China.
[Ti] Título:Differential Protein Expressions in Virus-Infected and Uninfected .
[So] Source:Korean J Parasitol;55(2):121-128, 2017 Apr.
[Is] ISSN:1738-0006
[Cp] País de publicação:Korea (South)
[La] Idioma:eng
[Ab] Resumo:Protozoan viruses may influence the function and pathogenicity of the protozoa. is a parasitic protozoan that could contain a double stranded RNA (dsRNA) virus, virus (TVV). However, there are few reports on the properties of the virus. To further determine variations in protein expression of , we detected 2 strains of ; the virus-infected (V ) and uninfected (V ) isolates to examine differentially expressed proteins upon TVV infection. Using a stable isotope N-terminal labeling strategy (iTRAQ) on soluble fractions to analyze proteomes, we identified 293 proteins, of which 50 were altered in V compared with V isolates. The results showed that the expression of 29 proteins was increased, and 21 proteins decreased in V isolates. These differentially expressed proteins can be classified into 4 categories: ribosomal proteins, metabolic enzymes, heat shock proteins, and putative uncharacterized proteins. Quantitative PCR was used to detect 4 metabolic processes proteins: glycogen phosphorylase, malate dehydrogenase, triosephosphate isomerase, and glucose-6-phosphate isomerase, which were differentially expressed in V and V isolates. Our findings suggest that mRNA levels of these genes were consistent with protein expression levels. This study was the first which analyzed protein expression variations upon TVV infection. These observations will provide a basis for future studies concerning the possible roles of these proteins in host-parasite interactions.
[Mh] Termos MeSH primário: Expressão Gênica
Proteínas de Protozoários/genética
Vírus de RNA
Trichomonas vaginalis/genética
Trichomonas vaginalis/virologia
[Mh] Termos MeSH secundário: Feminino
Glucose-6-Fosfato Isomerase/análise
Glucose-6-Fosfato Isomerase/isolamento & purificação
Glicogênio Fosforilase/análise
Glicogênio Fosforilase/isolamento & purificação
Glicólise/genética
Seres Humanos
Malato Desidrogenase/análise
Malato Desidrogenase/isolamento & purificação
Masculino
Reação em Cadeia da Polimerase
Proteínas de Protozoários/análise
Proteínas de Protozoários/classificação
Proteínas de Protozoários/isolamento & purificação
RNA de Cadeia Dupla
RNA Mensageiro/análise
Tricomoníase/parasitologia
Trichomonas vaginalis/crescimento & desenvolvimento
Trichomonas vaginalis/metabolismo
Triose-Fosfato Isomerase/análise
Triose-Fosfato Isomerase/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protozoan Proteins); 0 (RNA, Double-Stranded); 0 (RNA, Messenger); EC 1.1.1.37 (Malate Dehydrogenase); EC 2.4.1.- (Glycogen Phosphorylase); EC 5.3.1.1 (Triose-Phosphate Isomerase); EC 5.3.1.9 (Glucose-6-Phosphate Isomerase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170517
[St] Status:MEDLINE
[do] DOI:10.3347/kjp.2017.55.2.121



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