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[PMID]:28470848
[Au] Autor:Camprubi E; Jordan SF; Vasiliadou R; Lane N
[Ad] Endereço:Department of Genetics, Evolution and Environment, University College London, London, UK.
[Ti] Título:Iron catalysis at the origin of life.
[So] Source:IUBMB Life;69(6):373-381, 2017 06.
[Is] ISSN:1521-6551
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Iron-sulphur proteins are ancient and drive fundamental processes in cells, notably electron transfer and CO fixation. Iron-sulphur minerals with equivalent structures could have played a key role in the origin of life. However, the 'iron-sulphur world' hypothesis has had a mixed reception, with questions raised especially about the feasibility of a pyrites-pulled reverse Krebs cycle. Phylogenetics suggests that the earliest cells drove carbon and energy metabolism via the acetyl CoA pathway, which is also replete in Fe(Ni)S proteins. Deep differences between bacteria and archaea in this pathway obscure the ancestral state. These differences make sense if early cells depended on natural proton gradients in alkaline hydrothermal vents. If so, the acetyl CoA pathway diverged with the origins of active ion pumping, and ancestral CO fixation might have been equivalent to methanogens, which depend on a membrane-bound NiFe hydrogenase, energy converting hydrogenase. This uses the proton-motive force to reduce ferredoxin, thence CO . The mechanism suggests that pH could modulate reduction potential at the active site of the enzyme, facilitating the difficult reduction of CO by H . This mechanism could be generalised under abiotic conditions so that steep pH differences across semi-conducting Fe(Ni)S barriers drives not just the first steps of CO fixation to C1 and C2 organics such as CO, CH SH and CH COSH, but a series of similar carbonylation and hydrogenation reactions to form longer chain carboxylic acids such as pyruvate, oxaloacetate and α-ketoglutarate, as in the incomplete reverse Krebs cycle found in methanogens. We suggest that the closure of a complete reverse Krebs cycle, by regenerating acetyl CoA directly, displaced the acetyl CoA pathway from many modern groups. A later reliance on acetyl CoA and ATP eliminated the need for the proton-motive force to drive most steps of the reverse Krebs cycle. © 2017 IUBMB Life, 69(6):373-381, 2017.
[Mh] Termos MeSH primário: Acetilcoenzima A/química
Ferredoxinas/química
Proteínas com Ferro-Enxofre/química
Ferro/química
Origem da Vida
[Mh] Termos MeSH secundário: Acetilcoenzima A/metabolismo
Archaea/química
Archaea/metabolismo
Bactérias/química
Bactérias/metabolismo
Ciclo do Carbono
Dióxido de Carbono/química
Dióxido de Carbono/metabolismo
Catálise
Ciclo do Ácido Cítrico
Ferredoxinas/metabolismo
Concentração de Íons de Hidrogênio
Fontes Hidrotermais
Ferro/metabolismo
Proteínas com Ferro-Enxofre/metabolismo
Ácidos Cetoglutáricos/química
Ácidos Cetoglutáricos/metabolismo
Ácido Oxaloacético/química
Ácido Oxaloacético/metabolismo
Prótons
Ácido Pirúvico/química
Ácido Pirúvico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ferredoxins); 0 (Iron-Sulfur Proteins); 0 (Ketoglutaric Acids); 0 (Protons); 142M471B3J (Carbon Dioxide); 2F399MM81J (Oxaloacetic Acid); 72-89-9 (Acetyl Coenzyme A); 8558G7RUTR (Pyruvic Acid); 8ID597Z82X (alpha-ketoglutaric acid); E1UOL152H7 (Iron)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1002/iub.1632


  2 / 2780 MEDLINE  
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[PMID]:29364609
[Ti] Título:[Not Available.]
[So] Source:Mikrobiologiia;85(5):613-616, 2016 Sep.
[Is] ISSN:0026-3656
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Mh] Termos MeSH primário: Actinobacteria/metabolismo
Caprolactama/análogos & derivados
Caprolactama/metabolismo
Polímeros/metabolismo
[Mh] Termos MeSH secundário: Acetilcoenzima A/metabolismo
Actinobacteria/isolamento & purificação
Adipatos/metabolismo
Ácido Aminocaproico/metabolismo
Caproatos/metabolismo
Meios de Cultura/química
Hidrólise
Esgotos/microbiologia
Ácido Succínico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (6-oxohexanoic acid); 0 (Adipates); 0 (Caproates); 0 (Culture Media); 0 (Polymers); 0 (Sewage); 25038-54-4 (nylon 6); 6879X594Z8 (Caprolactam); 72-89-9 (Acetyl Coenzyme A); 76A0JE0FKJ (adipic acid); AB6MNQ6J6L (Succinic Acid); U6F3787206 (Aminocaproic Acid)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180125
[St] Status:MEDLINE


  3 / 2780 MEDLINE  
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[PMID]:29281714
[Au] Autor:Chen R; Xu M; Nagati J; Garcia JA
[Ad] Endereço:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
[Ti] Título:Coordinate regulation of stress signaling and epigenetic events by Acss2 and HIF-2 in cancer cells.
[So] Source:PLoS One;12(12):e0190241, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Survival of cancer cells in the harsh tumor microenvironment, characterized by oxygen and glucose deprivation, requires rapid initiation of cytoprotective measures. Metabolites whose levels change during stress are ideal signaling cues, particularly if used in post-translational modifications of stress-responsive signal transducers. In cancer cells exposed to oxygen or glucose deprivation, there is an increase in cellular levels of acetate, a substrate for acetate-dependent acetyl CoA synthetase 2 (Acss2) that also stimulates translocation of Acss2 from the cytosol to the nucleus. Nuclear, but not cytosolic, Acss2 promotes acetylation of the stress-responsive Hypoxia Inducible Factor 2α (HIF-2α) subunit by the acetyltransferase/coactivator Creb binding protein (Cbp), a process that facilitates stable Cbp/HIF-2α complex formation. In addition to promoting de novo transcription, Cbp and HIF-2α act in concert to regulate local histone 3 epigenetic marks. Exogenous acetate augments Acss2/HIF-2 dependent cancer growth and metastasis in cell culture and mouse models. Thus, an acetate switch in mammals links nutrient intake and stress signaling with tumor growth and metastasis.
[Mh] Termos MeSH primário: Acetato-CoA Ligase/metabolismo
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo
Epigênese Genética
Neoplasias/metabolismo
Estresse Oxidativo
Transdução de Sinais
[Mh] Termos MeSH secundário: Acetilcoenzima A/metabolismo
Animais
Fatores de Transcrição Hélice-Alça-Hélice Básicos/química
Linhagem Celular Tumoral
Células HEK293
Seres Humanos
Lisina/metabolismo
Camundongos
Camundongos Nus
Neoplasias/genética
Neoplasias/patologia
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Basic Helix-Loop-Helix Transcription Factors); 0 (endothelial PAS domain-containing protein 1); 72-89-9 (Acetyl Coenzyme A); EC 6.2.1.1 (ACSS2 protein, human); EC 6.2.1.1 (Acetate-CoA Ligase); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180206
[Lr] Data última revisão:
180206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171228
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190241


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[PMID]:29253849
[Au] Autor:Gallego-Jara J; Écija Conesa A; de Diego Puente T; Lozano Terol G; Cánovas Díaz M
[Ad] Endereço:Department of Biochemistry and Molecular Biology and Immunology (B), Faculty of Chemistry, University of Murcia, Campus of Espinardo, Regional Campus of International Excellence ''Campus Mare Nostrum", Murcia, Spain.
[Ti] Título:Characterization of CobB kinetics and inhibition by nicotinamide.
[So] Source:PLoS One;12(12):e0189689, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lysine acetylation has emerged as a global protein regulation system in all domains of life. Sirtuins, or Sir2-like enzymes, are a family of histone deacetylases characterized by their employing NAD+ as a co-substrate. Sirtuins can deacetylate several acetylated proteins, but a consensus substrate recognition sequence has not yet been established. Product inhibition of many eukaryotic sirtuins by nicotinamide and its analogues has been studied in vitro due to their potential role as anticancer agents. In this work, the kinetics of CobB, the main Escherichia coli deacetylase, have been characterized. To our knowledge, this is the first kinetic characterization of a sirtuin employing a fully acetylated and natively folded protein as a substrate. CobB deacetylated several acetyl-CoA synthetase acetylated lysines with a single kinetic rate. In addition, in vitro nicotinamide inhibition of CobB has been characterized, and the intracellular nicotinamide concentrations have been determined under different growth conditions. The results suggest that nicotinamide can act as a CobB regulator in vivo. A nicotinamidase deletion strain was thus phenotypically characterized, and it behaved similarly to the ΔcobB strain. The results of this work demonstrate the potential regulatory role of the nicotinamide metabolite in vivo.
[Mh] Termos MeSH primário: Proteínas de Escherichia coli/antagonistas & inibidores
Proteínas de Escherichia coli/química
Escherichia coli/enzimologia
Niacinamida/química
Sirtuínas/antagonistas & inibidores
Sirtuínas/química
[Mh] Termos MeSH secundário: Acetatos/química
Acetilcoenzima A/metabolismo
Acetilação
Deleção de Genes
Histonas/metabolismo
Cinética
Lisina/química
NAD/metabolismo
Fenótipo
Plasmídeos/metabolismo
Dobramento de Proteína
Sirtuínas/metabolismo
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetates); 0 (Escherichia coli Proteins); 0 (Histones); 0U46U6E8UK (NAD); 25X51I8RD4 (Niacinamide); 72-89-9 (Acetyl Coenzyme A); EC 3.5.1.- (Sirtuins); EC 3.5.1.- (cobB protein, E Coli); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171219
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189689


  5 / 2780 MEDLINE  
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[PMID]:27771289
[Au] Autor:Dercksen M; Duran M; IJlst L; Kulik W; Ruiter JP; van Cruchten A; Tuchman M; Wanders RJ
[Ad] Endereço:Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Human Metabonomics, North-West University, Potchefstroom Campus, South Africa. Electronic address: marli.dercksen@nwu.ac.za.
[Ti] Título:A novel UPLC-MS/MS based method to determine the activity of N-acetylglutamate synthase in liver tissue.
[So] Source:Mol Genet Metab;119(4):307-310, 2016 12.
[Is] ISSN:1096-7206
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: N-acetylglutamate synthase (NAGS) plays a key role in the removal of ammonia via the urea cycle by catalyzing the synthesis of N-acetylglutamate (NAG), the obligatory cofactor in the carbamyl phosphate synthetase 1 reaction. Enzymatic analysis of NAGS in liver homogenates has remained insensitive and inaccurate, which prompted the development of a novel method. METHODS: UPLC-MS/MS was used in conjunction with stable isotope (N-acetylglutamic-2,3,3,4,4-d acid) dilution for the quantitative detection of NAG produced by the NAGS enzyme. The assay conditions were optimized using purified human NAGS and the optimized enzyme conditions were used to measure the activity in mouse liver homogenates. RESULTS: A low signal-to-noise ratio in liver tissue samples was observed due to non-enzymatic formation of N-acetylglutamate and low specific activity, which interfered with quantitative analysis. Quenching of acetyl-CoA immediately after the incubation circumvented this analytical difficulty and allowed accurate and sensitive determination of mammalian NAGS activity. The specificity of the assay was validated by demonstrating a complete deficiency of NAGS in liver homogenates from Nags -/- mice. CONCLUSION: The novel NAGS enzyme assay reported herein can be used for the diagnosis of inherited NAGS deficiency and may also be of value in the study of secondary hyperammonemia present in various inborn errors of metabolism as well as drug treatment.
[Mh] Termos MeSH primário: Aminoácido N-Acetiltransferase/genética
Carbamoil-Fosfato Sintase (Amônia)/genética
Hiperamonemia/diagnóstico
Distúrbios Congênitos do Ciclo da Ureia/diagnóstico
[Mh] Termos MeSH secundário: Acetilcoenzima A/metabolismo
Aminoácido N-Acetiltransferase/metabolismo
Animais
Carbamoil-Fosfato Sintase (Amônia)/deficiência
Seres Humanos
Hiperamonemia/genética
Hiperamonemia/metabolismo
Hiperamonemia/fisiopatologia
Fígado/enzimologia
Camundongos
Camundongos Knockout
Espectrometria de Massas em Tandem
Distúrbios Congênitos do Ciclo da Ureia/genética
Distúrbios Congênitos do Ciclo da Ureia/metabolismo
Distúrbios Congênitos do Ciclo da Ureia/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
72-89-9 (Acetyl Coenzyme A); EC 2.3.1.1 (Amino-Acid N-Acetyltransferase); EC 2.3.1.1 (NAGS protein, human); EC 6.3.4.16 (Carbamoyl-Phosphate Synthase (Ammonia))
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


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[PMID]:29059435
[Au] Autor:Stacpoole PW
[Ad] Endereço:Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, and Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL.
[Ti] Título:Therapeutic Targeting of the Pyruvate Dehydrogenase Complex/Pyruvate Dehydrogenase Kinase (PDC/PDK) Axis in Cancer.
[So] Source:J Natl Cancer Inst;109(11), 2017 Nov 01.
[Is] ISSN:1460-2105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics. Inhibition of PDC activity by pyruvate dehydrogenase kinase (PDK)-mediated phosphorylation has been associated with the pathobiology of many disorders of metabolic integration, including cancer. Consequently, the PDC/PDK axis has long been a therapeutic target. The most common underlying mechanism accounting for PDC inhibition in these conditions is post-transcriptional upregulation of one or more PDK isoforms, leading to phosphorylation of the E1α subunit of PDC. Such perturbations of the PDC/PDK axis induce a "glycolytic shift," whereby affected cells favor adenosine triphosphate production by glycolysis over mitochondrial oxidative phosphorylation and cellular proliferation over cellular quiescence. Dichloroacetate is the prototypic xenobiotic inhibitor of PDK, thereby maintaining PDC in its unphosphorylated, catalytically active form. However, recent interest in the therapeutic targeting of the PDC/PDK axis for the treatment of cancer has yielded a new generation of small molecule PDK inhibitors. Ongoing investigations of the central role of PDC in cellular energy metabolism and its regulation by pharmacological effectors of PDKs promise to open multiple exciting vistas into the biochemical understanding and treatment of cancer and other diseases.
[Mh] Termos MeSH primário: Neoplasias/tratamento farmacológico
Neoplasias/metabolismo
Complexo Piruvato Desidrogenase/antagonistas & inibidores
[Mh] Termos MeSH secundário: Acetilcoenzima A/metabolismo
Trifosfato de Adenosina/biossíntese
Biomimética
Ciclo do Ácido Cítrico/fisiologia
Ácido Dicloroacético/farmacologia
Metabolismo Energético
Glicólise
Seres Humanos
Isoenzimas/metabolismo
Mitocôndrias/metabolismo
NAD/metabolismo
Fosforilação Oxidativa
Proteínas Serina-Treonina Quinases/metabolismo
Complexo Piruvato Desidrogenase/metabolismo
Ácido Pirúvico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Isoenzymes); 0 (Pyruvate Dehydrogenase Complex); 0U46U6E8UK (NAD); 72-89-9 (Acetyl Coenzyme A); 8558G7RUTR (Pyruvic Acid); 8L70Q75FXE (Adenosine Triphosphate); 9LSH52S3LQ (Dichloroacetic Acid); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.2 (pyruvate dehydrogenase (acetyl-transferring) kinase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171024
[St] Status:MEDLINE
[do] DOI:10.1093/jnci/djx071


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[PMID]:28985053
[Au] Autor:McVey AC; Medarametla P; Chee X; Bartlett S; Poso A; Spring DR; Rahman T; Welch M
[Ad] Endereço:Department of Biochemistry, University of Cambridge , Cambridge CB2 1QW, U.K.
[Ti] Título:Structural and Functional Characterization of Malate Synthase G from Opportunistic Pathogen Pseudomonas aeruginosa.
[So] Source:Biochemistry;56(41):5539-5549, 2017 Oct 17.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pseudomonas aeruginosa is an opportunistic human pathogen recognized as a critical threat by the World Health Organization because of the dwindling number of effective therapies available to treat infections. Over the past decade, it has become apparent that the glyoxylate shunt plays a vital role in sustaining P. aeruginosa during infection scenarios. The glyoxylate shunt comprises two enzymes: isocitrate lyase and malate synthase isoform G. Inactivation of these enzymes has been reported to abolish the ability of P. aeruginosa to establish infection in a mammalian model system, yet we still lack the structural information to support drug design efforts. In this work, we describe the first X-ray crystal structure of P. aeruginosa malate synthase G in the apo form at 1.62 Å resolution. The enzyme is a monomer composed of four domains and is highly conserved with homologues found in other clinically relevant microorganisms. It is also dependent on Mg for catalysis. Metal ion binding led to a change in the intrinsic fluorescence of the protein, allowing us to quantitate its affinity for Mg . We also identified putative drug binding sites in malate synthase G using computational analysis and, because of the high resolution of the experimental data, were further able to characterize its hydration properties. Our data reveal two promising binding pockets in malate synthase G that may be exploited for drug design.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Malato Sintase/metabolismo
Modelos Moleculares
Pseudomonas aeruginosa/enzimologia
[Mh] Termos MeSH secundário: Acetilcoenzima A/química
Acetilcoenzima A/metabolismo
Sequência de Aminoácidos
Apoenzimas/química
Apoenzimas/genética
Apoenzimas/metabolismo
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Sítios de Ligação
Domínio Catalítico
Biologia Computacional
Sequência Conservada
Cristalografia por Raios X
Sistemas Especialistas
Glioxilatos/química
Glioxilatos/metabolismo
Indóis/química
Indóis/metabolismo
Ligantes
Magnésio/química
Magnésio/metabolismo
Malato Sintase/química
Malato Sintase/genética
Simulação de Acoplamento Molecular
Estrutura Molecular
Conformação Proteica
Estrutura Secundária de Proteína
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Alinhamento de Sequência
Homologia Estrutural de Proteína
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apoenzymes); 0 (Bacterial Proteins); 0 (Glyoxylates); 0 (Indoles); 0 (Ligands); 0 (Recombinant Proteins); 59711R38B0 (indole-3-carboxylic acid); 72-89-9 (Acetyl Coenzyme A); EC 2.3.3.9 (Malate Synthase); I38ZP9992A (Magnesium); JQ39C92HH6 (glyoxylic acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171007
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00852


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[PMID]:28954258
[Au] Autor:Li L; Peng M; Ge C; Yu L; Ma H
[Ti] Título:(-)-Hydroxycitric Acid Reduced Lipid Droplets Accumulation Via Decreasing Acetyl-Coa Supply and Accelerating Energy Metabolism in Cultured Primary Chicken Hepatocytes.
[So] Source:Cell Physiol Biochem;43(2):812-831, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: (-)-Hydroxycitric acid (HCA) had been shown to suppress fat accumulation in animals and humans, while the underlying biochemical mechanism is not fully understood, especially little information is available on whether (-)-HCA regulates energy metabolism and consequently affects fat deposition. METHODS: Hepatocytes were cultured for 24 h and then exposed to (-)-HCA (0, 1, 10, 50 µM), enzyme protein content was determined by ELISA; lipid metabolism gene mRNA levels were detected by RT-PCR. RESULTS: (-)-HCA significantly decreased the number and total area of lipid droplets. ATP-citrate lyase, fatty acid synthase and sterol regulatory element binding protein-1c mRNA level were significantly decreased after (-)-HCA treatment, whereas peroxisome proliferator-activated receptor α mRNA level was significantly increased. (-)-HCA significantly decreased ATP-citrate lyase activity and acetyl-CoA content in cytosol, but significantly increased glucose consumption and mitochondrial oxygen consumption rate. (-)-HCA promoted the activity/content of glucokinase, phosphofructokinase-1, pyruvate kinase, pyruvate dehydrogenase, citrate synthase, aconitase, succinate dehydrogenase, malate dehydrogenase, NADH dehydrogenase and ATP synthase remarkably. CONCLUSIONS: (-)-HCA decreased lipid droplets accumulation by reducing acetyl-CoA supply, which mainly achieved via inhibition of ATP-citrate lyase, and accelerating energy metabolism in chicken hepatocytes. These results proposed a biochemical mechanism of fat reduction by (-)-HCA in broiler chickens in term of energy metabolism.
[Mh] Termos MeSH primário: Acetilcoenzima A/metabolismo
Galinhas/metabolismo
Citratos/metabolismo
Metabolismo Energético
Hepatócitos/metabolismo
Gotículas Lipídicas/metabolismo
Metabolismo dos Lipídeos
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Citrates); 72-89-9 (Acetyl Coenzyme A); 8W94T9026R (hydroxycitric acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170928
[St] Status:MEDLINE
[do] DOI:10.1159/000481564


  9 / 2780 MEDLINE  
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[PMID]:28865727
[Au] Autor:Ferreira A; Cunha-Oliveira T; Simões RF; Carvalho FS; Burgeiro A; Nordgren K; Wallace KB; Oliveira PJ
[Ad] Endereço:CNC-Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech Building, Biocant Park, 3060-197 Cantanhede, Portugal.
[Ti] Título:Altered mitochondrial epigenetics associated with subchronic doxorubicin cardiotoxicity.
[So] Source:Toxicology;390:63-73, 2017 Sep 01.
[Is] ISSN:1879-3185
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Doxorubicin (DOX), a potent and broad-spectrum antineoplastic agent, causes an irreversible, cumulative and dose-dependent cardiomyopathy that ultimately leads to congestive heart failure. The mechanisms responsible for DOX cardiotoxicity remain poorly understood, but seem to involve mitochondrial dysfunction on several levels. Epigenetics may explain a portion of this effect. Since mitochondrial dysfunction may affect the epigenetic landscape, we hypothesize that this cardiac toxicity may result from epigenetic changes related to disruption of mitochondrial function. To test this hypothesis, eight-week-old male Wistar rats (n=6/group) were administered 7 weekly injections with DOX (2mgkg ) or saline, and sacrificed two weeks after the last injection. We assessed gene expression patterns by qPCR, global DNA methylation by ELISA, and proteome lysine acetylation status by Western blot in cardiac tissue from saline and DOX-treated rats. We show for the first time that DOX treatment decreases global DNA methylation in heart but not in liver. These differences were accompanied by alterations in mRNA expression of multiple functional gene groups. DOX disrupted cardiac mitochondrial biogenesis, as demonstrated by decreased mtDNA levels and altered transcript levels for multiple mitochondrial genes encoded by both nuclear and mitochondrial genomes. Transcription of genes involved in lipid metabolism and epigenetic modulation were also affected. Western blotting analyses indicated a differential protein acetylation pattern in cardiac mitochondrial fractions of DOX-treated rats compared to controls. Additionally, DOX treatment increased the activity of histone deacetylases. These results suggest an interplay between mitochondrial dysfunction and epigenetic alterations, which may be a primary determinant of DOX-induced cardiotoxicity.
[Mh] Termos MeSH primário: Antibióticos Antineoplásicos
Metilação de DNA
DNA Mitocondrial/genética
Doxorrubicina
Epigênese Genética
Cardiopatias/induzido quimicamente
Mitocôndrias Cardíacas/genética
Proteínas Mitocondriais/genética
[Mh] Termos MeSH secundário: 5-Metilcitosina/metabolismo
Acetilcoenzima A/metabolismo
Acetilação
Animais
Cardiotoxicidade
Modelos Animais de Doenças
Cardiopatias/genética
Cardiopatias/metabolismo
Cardiopatias/patologia
Histona Desacetilases/metabolismo
Lisina
Masculino
Mitocôndrias Cardíacas/metabolismo
Mitocôndrias Cardíacas/patologia
Proteínas Mitocondriais/metabolismo
Biogênese de Organelas
Processamento de Proteína Pós-Traducional
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Ratos Wistar
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibiotics, Antineoplastic); 0 (DNA, Mitochondrial); 0 (Mitochondrial Proteins); 0 (RNA, Messenger); 6R795CQT4H (5-Methylcytosine); 72-89-9 (Acetyl Coenzyme A); 80168379AG (Doxorubicin); EC 3.5.1.98 (Histone Deacetylases); K3Z4F929H6 (Lysine)
[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:170904
[St] Status:MEDLINE


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[PMID]:28863176
[Au] Autor:Arber C; Angelova PR; Wiethoff S; Tsuchiya Y; Mazzacuva F; Preza E; Bhatia KP; Mills K; Gout I; Abramov AY; Hardy J; Duce JA; Houlden H; Wray S
[Ad] Endereço:Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom.
[Ti] Título:iPSC-derived neuronal models of PANK2-associated neurodegeneration reveal mitochondrial dysfunction contributing to early disease.
[So] Source:PLoS One;12(9):e0184104, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mutations in PANK2 lead to neurodegeneration with brain iron accumulation. PANK2 has a role in the biosynthesis of coenzyme A (CoA) from dietary vitamin B5, but the neuropathological mechanism and reasons for iron accumulation remain unknown. In this study, atypical patient-derived fibroblasts were reprogrammed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into cortical neuronal cells for studying disease mechanisms in human neurons. We observed no changes in PANK2 expression between control and patient cells, but a reduction in protein levels was apparent in patient cells. CoA homeostasis and cellular iron handling were normal, mitochondrial function was affected; displaying activated NADH-related and inhibited FADH-related respiration, resulting in increased mitochondrial membrane potential. This led to increased reactive oxygen species generation and lipid peroxidation in patient-derived neurons. These data suggest that mitochondrial deficiency is an early feature of the disease process and can be explained by altered NADH/FADH substrate supply to oxidative phosphorylation. Intriguingly, iron chelation appeared to exacerbate the mitochondrial phenotype in both control and patient neuronal cells. This raises caution for the use iron chelation therapy in general when iron accumulation is absent.
[Mh] Termos MeSH primário: Células-Tronco Pluripotentes Induzidas/citologia
Doenças Mitocondriais/fisiopatologia
Neurodegeneração Associada a Pantotenato-Quinase/fisiopatologia
Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
[Mh] Termos MeSH secundário: Acetilcoenzima A/química
Adolescente
Biópsia
Encéfalo/metabolismo
Diferenciação Celular
Criança
Coenzima A/metabolismo
Feminino
Fibroblastos/metabolismo
Seres Humanos
Células-Tronco Pluripotentes Induzidas/metabolismo
Ferro/química
Cariotipagem
Peroxidação de Lipídeos
Masculino
Potencial da Membrana Mitocondrial
Mitocôndrias/patologia
Mutação
NAD/química
Neurônios/metabolismo
Ácido Pantotênico/química
Fenótipo
Fosfotransferases (Aceptor do Grupo Álcool)/genética
Plasmídeos/metabolismo
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Reactive Oxygen Species); 0U46U6E8UK (NAD); 19F5HK2737 (Pantothenic Acid); 72-89-9 (Acetyl Coenzyme A); E1UOL152H7 (Iron); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC 2.7.1.33 (pantothenate kinase); SAA04E81UX (Coenzyme A)
[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:170902
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184104



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