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[PMID]:29199988
[Au] Autor:Mydy LS; Mashhadi Z; Knight TW; Fenske T; Hagemann T; Hoppe RW; Han L; Miller TR; Schwabacher AW; Silvaggi NR
[Ad] Endereço:Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA.
[Ti] Título:Swit_4259, an acetoacetate decarboxylase-like enzyme from Sphingomonas wittichii RW1.
[So] Source:Acta Crystallogr F Struct Biol Commun;73(Pt 12):672-681, 2017 Dec 01.
[Is] ISSN:2053-230X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Gram-negative bacterium Sphingomonas wittichii RW1 is notable for its ability to metabolize a variety of aromatic hydrocarbons. Not surprisingly, the S. wittichii genome contains a number of putative aromatic hydrocarbon-degrading gene clusters. One of these includes an enzyme of unknown function, Swit_4259, which belongs to the acetoacetate decarboxylase-like superfamily (ADCSF). Here, it is reported that Swit_4259 is a small (28.8 kDa) tetrameric ADCSF enzyme that, unlike the prototypical members of the superfamily, does not have acetoacetate decarboxylase activity. Structural characterization shows that the tertiary structure of Swit_4259 is nearly identical to that of the true decarboxylases, but there are important differences in the fine structure of the Swit_4259 active site that lead to a divergence in function. In addition, it is shown that while it is a poor substrate, Swit_4259 can catalyze the hydration of 2-oxo-hex-3-enedioate to yield 2-oxo-4-hydroxyhexanedioate. It is also demonstrated that Swit_4259 has pyruvate aldolase-dehydratase activity, a feature that is common to all of the family V ADCSF enzymes studied to date. The enzymatic activity, together with the genomic context, suggests that Swit_4259 may be a hydratase with a role in the metabolism of an as-yet-unknown hydrocarbon. These data have implications for engineering bioremediation pathways to degrade specific pollutants, as well as structure-function relationships within the ADCSF in general.
[Mh] Termos MeSH primário: Proteínas de Bactérias/química
Proteínas de Bactérias/metabolismo
Carboxiliases/química
Sphingomonas/enzimologia
[Mh] Termos MeSH secundário: Acetoacetatos/química
Acetoacetatos/metabolismo
Proteínas de Bactérias/genética
Carboxiliases/genética
Carboxiliases/metabolismo
Domínio Catalítico
Cristalografia por Raios X
Ácidos Cetoglutáricos/metabolismo
Espectroscopia de Ressonância Magnética
Modelos Moleculares
Conformação Proteica
Ácido Pirúvico/química
Ácido Pirúvico/metabolismo
Espectrometria de Massas por Ionização por Electrospray
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetoacetates); 0 (Bacterial Proteins); 0 (Ketoglutaric Acids); 4ZI204Y1MC (acetoacetic acid); 8558G7RUTR (Pyruvic Acid); 8ID597Z82X (alpha-ketoglutaric acid); EC 4.1.1.- (Carboxy-Lyases); EC 4.1.1.4 (acetoacetate decarboxylase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE
[do] DOI:10.1107/S2053230X17015862


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[PMID]:28467058
[Au] Autor:Bouzon M; Perret A; Loreau O; Delmas V; Perchat N; Weissenbach J; Taran F; Marlière P
[Ad] Endereço:CEA, Genoscope , 2 rue Gaston Crémieux, 91000 Evry, France.
[Ti] Título:A Synthetic Alternative to Canonical One-Carbon Metabolism.
[So] Source:ACS Synth Biol;6(8):1520-1533, 2017 Aug 18.
[Is] ISSN:2161-5063
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:One-carbon metabolism is an ubiquitous metabolic pathway that encompasses the reactions transferring formyl-, hydroxymethyl- and methyl-groups bound to tetrahydrofolate for the synthesis of purine nucleotides, thymidylate, methionine and dehydropantoate, the precursor of coenzyme A. An alternative cyclic pathway was designed that substitutes 4-hydroxy-2-oxobutanoic acid (HOB), a compound absent from known metabolism, for the amino acids serine and glycine as one-carbon donors. It involves two novel reactions, the transamination of l-homoserine and the transfer of a one-carbon unit from HOB to tetrahydrofolate releasing pyruvate as coproduct. Since canonical reactions regenerate l-homoserine from pyruvate by carboxylation and subsequent reduction, every one-carbon moiety made available for anabolic reactions originates from CO . The HOB-dependent pathway was established in an Escherichia coli auxotroph selected for prototrophy using long-term cultivation protocols. Genetic, metabolic and biochemical evidence support the emergence of a functional HOB-dependent one-carbon pathway achieved with the recruitment of the two enzymes l-homoserine transaminase and HOB-hydroxymethyltransferase and of HOB as an essential metabolic intermediate. Escherichia coli biochemical reprogramming was achieved by minimally altering canonical metabolism and leveraging on natural selection mechanisms, thereby launching the resulting strain on an evolutionary trajectory diverging from all known extant species.
[Mh] Termos MeSH primário: Acetoacetatos/metabolismo
Carbono/metabolismo
Proteínas de Escherichia coli/metabolismo
Escherichia coli/metabolismo
Melhoramento Genético/métodos
Engenharia Metabólica/métodos
Redes e Vias Metabólicas/genética
[Mh] Termos MeSH secundário: Escherichia coli/genética
Proteínas de Escherichia coli/genética
Glicina/genética
Glicina/metabolismo
Ácido Pirúvico/metabolismo
Serina/genética
Serina/metabolismo
Biologia Sintética/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetoacetates); 0 (Escherichia coli Proteins); 452VLY9402 (Serine); 4ZI204Y1MC (acetoacetic acid); 7440-44-0 (Carbon); 8558G7RUTR (Pyruvic Acid); TE7660XO1C (Glycine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180201
[Lr] Data última revisão:
180201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1021/acssynbio.7b00029


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[PMID]:28468827
[Au] Autor:Zhao L; Fan J; Xia S; Pan Y; Liu S; Qian G; Qian Z; Kang HB; Arbiser JL; Pollack BP; Kudchadkar RR; Lawson DH; Rossi M; Abdel-Wahab O; Merghoub T; Khoury HJ; Khuri FR; Boise LH; Lonial S; Chen F; Chen J; Lin R
[Ad] Endereço:From the Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322.
[Ti] Título:HMG-CoA synthase 1 is a synthetic lethal partner of BRAF in human cancers.
[So] Source:J Biol Chem;292(24):10142-10152, 2017 06 16.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Contributions of metabolic changes to cancer development and maintenance have received increasing attention in recent years. Although many human cancers share similar metabolic alterations, it remains unclear whether oncogene-specific metabolic alterations are required for tumor development. Using an RNAi-based screen targeting the majority of the known metabolic proteins, we recently found that oncogenic BRAF up-regulates HMG-CoA lyase (HMGCL), which converts HMG-CoA to acetyl-CoA and a ketone body, acetoacetate, that selectively enhances BRAF -dependent MEK1 activation in human cancer. Here, we identified HMG-CoA synthase 1 (HMGCS1), the upstream ketogenic enzyme of HMGCL, as an additional "synthetic lethal" partner of BRAF Although HMGCS1 expression did not correlate with BRAF mutation in human melanoma cells, HMGCS1 was selectively important for proliferation of BRAF -positive melanoma and colon cancer cells but not control cells harboring active N/KRAS mutants, and stable knockdown of HMGCS1 only attenuated colony formation and tumor growth potential of BRAF melanoma cells. Moreover, cytosolic HMGCS1 that co-localized with HMGCL and BRAF was more important than the mitochondrial HMGCS2 isoform in BRAF -expressing cancer cells in terms of acetoacetate production. Interestingly, HMGCL knockdown did not affect HMGCS1 expression levels, whereas HMGCS1 knockdown caused a compensating increase in HMGCL protein level because of attenuated protein degradation. However, this increase did not reverse the reduced ketogenesis in HMGCS1 knockdown cells. Mechanistically, HMGCS1 inhibition decreased intracellular acetoacetate levels, leading to reduced BRAF -MEK1 binding and consequent MEK1 activation. We conclude that the ketogenic HMGCS1-HMGCL-acetoacetate axis may represent a promising therapeutic target for managing BRAF -positive human cancers.
[Mh] Termos MeSH primário: Neoplasias do Colo/enzimologia
Hidroximetilglutaril-CoA Sintase/metabolismo
MAP Quinase Quinase 1/metabolismo
Melanoma/enzimologia
Proteínas de Neoplasias/metabolismo
Oxo-Ácido-Liases/metabolismo
Proteínas Proto-Oncogênicas B-raf/metabolismo
[Mh] Termos MeSH secundário: Acetoacetatos/metabolismo
Substituição de Aminoácidos
Animais
Linhagem Celular Tumoral
Proliferação Celular
Neoplasias do Colo/metabolismo
Neoplasias do Colo/patologia
Citosol/enzimologia
Citosol/metabolismo
Ativação Enzimática
Estabilidade Enzimática
Feminino
Seres Humanos
Hidroximetilglutaril-CoA Sintase/antagonistas & inibidores
Hidroximetilglutaril-CoA Sintase/genética
Isoenzimas/antagonistas & inibidores
Isoenzimas/genética
Isoenzimas/metabolismo
MAP Quinase Quinase 1/química
Melanoma/metabolismo
Melanoma/patologia
Camundongos Nus
Mutação
Proteínas de Neoplasias/antagonistas & inibidores
Proteínas de Neoplasias/química
Proteínas de Neoplasias/genética
Transplante de Neoplasias
Oxo-Ácido-Liases/antagonistas & inibidores
Oxo-Ácido-Liases/química
Oxo-Ácido-Liases/genética
Proteólise
Proteínas Proto-Oncogênicas B-raf/genética
Interferência de RNA
Carga Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Acetoacetates); 0 (Isoenzymes); 0 (Neoplasm Proteins); 4ZI204Y1MC (acetoacetic acid); EC 2.3.3.10 (HMGCS1 protein, human); EC 2.3.3.10 (Hydroxymethylglutaryl-CoA Synthase); EC 2.7.11.1 (BRAF protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); EC 2.7.12.2 (MAP Kinase Kinase 1); EC 2.7.12.2 (MAP2K1 protein, human); EC 4.1.3.- (Oxo-Acid-Lyases); EC 4.1.3.4 (3-hydroxy-3-methylglutaryl-coenzyme A lyase)
[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:170505
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.788778


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[PMID]:28820963
[Au] Autor:Salomón T; Sibbersen C; Hansen J; Britz D; Svart MV; Voss TS; Møller N; Gregersen N; Jørgensen KA; Palmfeldt J; Poulsen TB; Johannsen M
[Ad] Endereço:Department of Forensic Medicine, Aarhus University, Aarhus 8200, Denmark.
[Ti] Título:Ketone Body Acetoacetate Buffers Methylglyoxal via a Non-enzymatic Conversion during Diabetic and Dietary Ketosis.
[So] Source:Cell Chem Biol;24(8):935-943.e7, 2017 Aug 17.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The α-oxoaldehyde methylglyoxal is a ubiquitous and highly reactive metabolite known to be involved in aging- and diabetes-related diseases. If not detoxified by the endogenous glyoxalase system, it exerts its detrimental effects primarily by reacting with biopolymers such as DNA and proteins. We now demonstrate that during ketosis, another metabolic route is operative via direct non-enzymatic aldol reaction between methylglyoxal and the ketone body acetoacetate, leading to 3-hydroxyhexane-2,5-dione. This novel metabolite is present at a concentration of 10%-20% of the methylglyoxal level in the blood of insulin-starved patients. By employing a metabolite-alkyne-tagging strategy it is clarified that 3-hydroxyhexane-2,5-dione is further metabolized to non-glycating species in human blood. The discovery represents a new direction within non-enzymatic metabolism and within the use of alkyne-tagging for metabolism studies and it revitalizes acetoacetate as a competent endogenous carbon nucleophile.
[Mh] Termos MeSH primário: Acetoacetatos/química
Corpos Cetônicos/química
Aldeído Pirúvico/sangue
[Mh] Termos MeSH secundário: Acetoacetatos/metabolismo
Alquinos/química
Sequência de Aminoácidos
Cromatografia Líquida de Alta Pressão
Diabetes Mellitus/metabolismo
Diabetes Mellitus/patologia
Hexanonas/análise
Hexanonas/sangue
Hexanonas/metabolismo
Seres Humanos
Corpos Cetônicos/metabolismo
Espectrometria de Massas
Aldeído Pirúvico/análise
Aldeído Pirúvico/metabolismo
Albumina Sérica/química
Albumina Sérica/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetoacetates); 0 (Alkynes); 0 (Hexanones); 0 (Ketone Bodies); 0 (Serum Albumin); 4ZI204Y1MC (acetoacetic acid); 722KLD7415 (Pyruvaldehyde)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170819
[St] Status:MEDLINE


  5 / 2234 MEDLINE  
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[PMID]:28320515
[Au] Autor:Hu LT; Zhu BL; Lai YJ; Long Y; Zha JS; Hu XT; Zhang JH; Chen GJ
[Ad] Endereço:Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China; Department of Neurology, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong 637000, Sic
[Ti] Título:HMGCS2 promotes autophagic degradation of the amyloid-ß precursor protein through ketone body-mediated mechanisms.
[So] Source:Biochem Biophys Res Commun;486(2):492-498, 2017 Apr 29.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HMGCS2 (mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2) is a control enzyme in ketogenesis. The mitochondrial localization and interaction with APP (ß-amyloid precursor protein) suggest that HMGCS2 may play a role in the pathophysiology of AD (Alzheimer's disease). Here we report that overexpression of HMGCS2 decreased levels of APP and related CTFs (carboxy-terminal fragments), which was largely prevented by an autophagic inhibitor chloroquine. In addition, HMGCS2 enhancement of autophagic marker LC3II was diminished by rapamycin, an inhibitor of mechanistic target of rapamycin. Moreover, deprivation of EBSS (Earle's Balanced Salt Solution) significantly augmented the effect of HMGCS2 on LC3II, while acetoacetate reversed the reduction of LC3II, APP and CTFs which was induced by HMGCS2 knockdown. In the presence of acetoacetate, rapamycin failed to induce further increase of LC3II, which mimicked the effect of HMGCS2 overexpression. Finally, HMGCS2 enhanced the antioxidant response. Collectively, HMGCS2 shares with ketone bodies common features in autophagic clearance of APP and CTFs, suggesting that ketone bodies play an important role in HMGCS2 regulation of the autophagy.
[Mh] Termos MeSH primário: Precursor de Proteína beta-Amiloide/metabolismo
Autofagia/genética
Hidroximetilglutaril-CoA Sintase/genética
Corpos Cetônicos/metabolismo
Proteínas Associadas aos Microtúbulos/genética
Serina-Treonina Quinases TOR/genética
[Mh] Termos MeSH secundário: Acetoacetatos/farmacologia
Animais
Linhagem Celular
Cloroquina/farmacologia
Regulação da Expressão Gênica
Células HEK293
Hipocampo/citologia
Hipocampo/efeitos dos fármacos
Hipocampo/metabolismo
Seres Humanos
Hidroximetilglutaril-CoA Sintase/antagonistas & inibidores
Hidroximetilglutaril-CoA Sintase/metabolismo
Camundongos
Proteínas Associadas aos Microtúbulos/metabolismo
Neurônios/citologia
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
Proteólise/efeitos dos fármacos
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Transdução de Sinais
Sirolimo/farmacologia
Serina-Treonina Quinases TOR/antagonistas & inibidores
Serina-Treonina Quinases TOR/metabolismo
Transgenes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetoacetates); 0 (Amyloid beta-Protein Precursor); 0 (HMGCS2 protein, human); 0 (Ketone Bodies); 0 (MAP1LC3A protein, human); 0 (Microtubule-Associated Proteins); 0 (RNA, Small Interfering); 0 (Recombinant Proteins); 4ZI204Y1MC (acetoacetic acid); 886U3H6UFF (Chloroquine); EC 2.3.3.10 (Hydroxymethylglutaryl-CoA Synthase); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); W36ZG6FT64 (Sirolimus)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170605
[Lr] Data última revisão:
170605
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170322
[St] Status:MEDLINE


  6 / 2234 MEDLINE  
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[PMID]:28294308
[Au] Autor:Kadowaki A; Sada N; Juge N; Wakasa A; Moriyama Y; Inoue T
[Ad] Endereço:Department of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
[Ti] Título:Neuronal inhibition and seizure suppression by acetoacetate and its analog, 2-phenylbutyrate.
[So] Source:Epilepsia;58(5):845-857, 2017 May.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: The ketogenic diet is clinically used to treat drug-resistant epilepsy. The diet treatment markedly increases ketone bodies (acetoacetate and ß-hydroxybutyrate), which work as energy metabolites in the brain. Here, we investigated effects of acetoacetate on voltage-dependent Ca channels (VDCCs) in pyramidal cells of the hippocampus. We further explored an acetoacetate analog that inhibited VDCCs in pyramidal cells, reduced excitatory postsynaptic currents (EPSCs), and suppressed seizures in vivo. METHODS: The effects of acetoacetate and its analogs on VDCCs and EPSCs were evaluated using patch-clamp recordings from CA1 pyramidal cells of mouse hippocampal slices. The in vivo effects of these reagents were also evaluated using a chronic seizure model induced by intrahippocampal injection of kainate. RESULTS: Acetoacetate inhibited VDCCs in pyramidal cells of hippocampal slices, and reduced EPSCs in slices exhibiting epileptiform activity. More potent EPSC inhibitors were then explored by modifying the chemical structure of acetoacetate, and 2-phenylbutyrate was identified as an acetoacetate analog that inhibited VDCCs and EPSCs more potently. Although acetoacetate is known to inhibit vesicular glutamate transporters (VGLUTs), 2-phenylbutyrate did not inhibit VGLUTs, showing that 2-phenylbutyrate is an acetoacetate analog that preferably inhibits VDCCs. In addition, 2-phenylbutyrate markedly reduced EPSCs in slices exhibiting epileptiform activity, and suppressed hippocampal seizures in vivo in a mouse model of epilepsy. The in vivo antiseizure effects of 2-phenylbutyrate were more potent than those of acetoacetate. Finally, intraperitoneal 2-phenylbutyrate was delivered to the brain, and its brain concentration reached the level enough to reduce EPSCs. SIGNIFICANCE: These results demonstrate that 2-phenylbutyrate is an acetoacetate analog that inhibits VDCCs and EPSCs in pyramidal cells, suppresses hippocampal seizures in vivo, and has brain penetration ability. Thus 2-phenylbutyrate provides a useful chemical structure as a lead compound to develop new antiseizure drugs originating from ketone bodies.
[Mh] Termos MeSH primário: Acetoacetatos/farmacologia
Dieta Cetogênica
Hipocampo/efeitos dos fármacos
Inibição Neural/efeitos dos fármacos
Fenilbutiratos/farmacologia
Células Piramidais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Canais de Cálcio/efeitos dos fármacos
Modelos Animais de Doenças
Eletroencefalografia/efeitos dos fármacos
Feminino
Técnicas In Vitro
Injeções
Ácido Caínico
Masculino
Camundongos
Camundongos Endogâmicos ICR
Técnicas de Cultura de Órgãos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetoacetates); 0 (Calcium Channels); 0 (Phenylbutyrates); 4ZI204Y1MC (acetoacetic acid); S7S079H2C2 (2-phenylbutyric acid); SIV03811UC (Kainic Acid)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170316
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13718


  7 / 2234 MEDLINE  
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[PMID]:28089569
[Au] Autor:Xia S; Lin R; Jin L; Zhao L; Kang HB; Pan Y; Liu S; Qian G; Qian Z; Konstantakou E; Zhang B; Dong JT; Chung YR; Abdel-Wahab O; Merghoub T; Zhou L; Kudchadkar RR; Lawson DH; Khoury HJ; Khuri FR; Boise LH; Lonial S; Lee BH; Pollack BP; Arbiser JL; Fan J; Lei QY; Chen J
[Ad] Endereço:Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA.
[Ti] Título:Prevention of Dietary-Fat-Fueled Ketogenesis Attenuates BRAF V600E Tumor Growth.
[So] Source:Cell Metab;25(2):358-373, 2017 Feb 07.
[Is] ISSN:1932-7420
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lifestyle factors, including diet, play an important role in the survival of cancer patients. However, the molecular mechanisms underlying pathogenic links between diet and particular oncogenic mutations in human cancers remain unclear. We recently reported that the ketone body acetoacetate selectively enhances BRAF V600E mutant-dependent MEK1 activation in human cancers. Here we show that a high-fat ketogenic diet increased serum levels of acetoacetate, leading to enhanced tumor growth potential of BRAF V600E-expressing human melanoma cells in xenograft mice. Treatment with hypolipidemic agents to lower circulating acetoacetate levels or an inhibitory homolog of acetoacetate, dehydroacetic acid, to antagonize acetoacetate-BRAF V600E binding attenuated BRAF V600E tumor growth. These findings reveal a signaling basis underlying a pathogenic role of dietary fat in BRAF V600E-expressing melanoma, providing insights into the design of conceptualized "precision diets" that may prevent or delay tumor progression based on an individual's specific oncogenic mutation profile.
[Mh] Termos MeSH primário: Gorduras na Dieta/efeitos adversos
Corpos Cetônicos/metabolismo
Melanoma/patologia
Mutação/genética
Proteínas Proto-Oncogênicas B-raf/genética
[Mh] Termos MeSH secundário: Ácido 3-Hidroxibutírico/farmacologia
Acetoacetatos/administração & dosagem
Acetoacetatos/sangue
Acetoacetatos/farmacologia
Animais
Proliferação Celular/efeitos dos fármacos
Feminino
Seres Humanos
Hipolipemiantes/farmacologia
Injeções Intraperitoneais
Melanoma/sangue
Camundongos
Camundongos Nus
Pironas/química
Pironas/farmacologia
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetoacetates); 0 (Dietary Fats); 0 (Hypolipidemic Agents); 0 (Ketone Bodies); 0 (Pyrones); 2KAG279R6R (dehydroacetic acid); 4ZI204Y1MC (acetoacetic acid); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); TZP1275679 (3-Hydroxybutyric Acid)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171121
[Lr] Data última revisão:
171121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170117
[St] Status:MEDLINE


  8 / 2234 MEDLINE  
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[PMID]:27923567
[Au] Autor:Basak S; Ghosh SK; Punetha VD; Aphale AN; Patra PK; Sahoo NG
[Ad] Endereço:Dr. B.C. Roy College of Pharmacy & Allied Health Sciences, Durgapur, WB, India. Electronic address: souvik_basak1@yahoo.com.
[Ti] Título:An experimental modeling of trinomial bioengineering- crp, rDNA, and transporter engineering within single cell factory for maximizing two-phase bioreduction.
[So] Source:Int J Biol Macromol;95:818-825, 2017 Feb.
[Is] ISSN:1879-0003
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:A carbonyl reductase (cr) gene from Candida glabrata CBS138 has been heterologously expressed in cofactor regenerating E. coli host to convert Ethyl-4-chloro-3-oxobutanoate (COBE) into Ethyl-4-chloro-3-hydroxybutanoate (CHBE). The CR enzyme exhibited marked velocity at substrate concentration as high as 363mM with highest turnover number (112.77±3.95s ). Solitary recombineering of such catalytic cell reproduced CHBE 161.04g/L per g of dry cell weight (DCW). Introduction of combinatorially engineered crp (crp*, F136I) into this heterologous E. coli host yielded CHBE 477.54g/L/gDCW. Furthermore, using nerolidol as exogenous cell transporter, the CHBE productivity has been towered to 710.88g/L/gDCW. The CHBE production has thus been upscaled to 8-12 times than those reported so far. qRT-PCR studies revealed that both membrane efflux channels such as acrAB as well as ROS scavenger genes such as ahpCF have been activated by engineering crp. Moreover, membrane protecting genes such as manXYZ together with solvent extrusion associated genes such as glpC have been upregulated inside mutant host. Although numerous proteins have been investigated to convert COBE to CHBE; this is the first approach to use engineering triad involving crp engineering, recombinant DNA engineering and transporter engineering together for improving cell performance during two-phase biocatalysis.
[Mh] Termos MeSH primário: Oxirredutases do Álcool/genética
DNA Ribossômico/genética
Escherichia coli/citologia
Escherichia coli/genética
Engenharia de Proteínas
[Mh] Termos MeSH secundário: Acetatos/farmacologia
Acetoacetatos/metabolismo
Biotransformação/efeitos dos fármacos
Butiratos/metabolismo
Candida glabrata/enzimologia
Candida glabrata/genética
Relação Dose-Resposta a Droga
Escherichia coli/metabolismo
Sesquiterpenos/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetates); 0 (Acetoacetates); 0 (Butyrates); 0 (DNA, Ribosomal); 0 (Sesquiterpenes); 0 (ethyl 4-chloro-3-hydroxybutanoate); 464P5N1905 (butyl acetate); 5AE82250CM (ethyl 4-chloro-3-oxobutanoate); EC 1.1.- (Alcohol Oxidoreductases); QR6IP857S6 (nerolidol)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161208
[St] Status:MEDLINE


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[PMID]:27812898
[Au] Autor:Dai Y; Huan B; Zhang HS; He YC
[Ad] Endereço:School of Chemical and Chemistry Engineering, Yancheng Institute of Technology, Yancheng, China. daiyong_yc@163.com.
[Ti] Título:Effective Biotransformation of Ethyl 4-Chloro-3-Oxobutanoate into Ethyl (S)-4-Chloro-3-Hydroxybutanoate by Recombinant E. coli CCZU-T15 Whole Cells in [ChCl][Gly]-Water Media.
[So] Source:Appl Biochem Biotechnol;181(4):1347-1359, 2017 Apr.
[Is] ISSN:1559-0291
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:To increase the biocatalytic activity of Escherichia coli CCZU-T15 whole cells, choline chloride/glycerol ([ChCl][Gly]) was firstly used as biocompatible solvent for the effective biotransformation of ethyl 4-chloro-3-oxobutanoate (COBE) into ethyl (S)-4-chloro-3-hydroxybutanoate [(S)-CHBE]. Furthermore, L-glutamine (150 mM) was added into [ChCl][Gly]-water ([ChCl][Gly] 12.5 vol%, pH 6.5) media instead of NAD for increasing the biocatalytic efficiency. To further improve the biosynthesis of (S)-CHBE (>99 % e.e.) by E. coli CCZU-T15 whole cells, Tween-80 (7.5 mM) was also added into this reaction media, and (S)-CHBE (>9 % e.e.) could be effectively synthesized from 2000 and 3000 mM COBE in the yields of 100 and 93.0 % by whole cells of recombinant E. coli CCZU-T15, respectively. TEM image indicated that the cell membrane was permeabilized and lost its integrity and when the cell was exposed to [ChCl][Gly]-water media with Tween-80. Clearly, this bioprocess has high potential for the effective biosynthesis of (S)-CHBE (>99 % e.e.).
[Mh] Termos MeSH primário: Acetoacetatos/metabolismo
Butiratos/metabolismo
Meios de Cultura/química
Meios de Cultura/farmacologia
DNA Recombinante/genética
Escherichia coli/citologia
Escherichia coli/metabolismo
[Mh] Termos MeSH secundário: Biotransformação/efeitos dos fármacos
Colina/química
Relação Dose-Resposta a Droga
Escherichia coli/efeitos dos fármacos
Escherichia coli/genética
Etilenoglicol/química
Glutamina/química
Polissorbatos/química
Água/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetoacetates); 0 (Butyrates); 0 (Culture Media); 0 (DNA, Recombinant); 0 (Polysorbates); 0 (ethyl 4-chloro-3-hydroxybutanoate); 059QF0KO0R (Water); 0RH81L854J (Glutamine); 5AE82250CM (ethyl 4-chloro-3-oxobutanoate); FC72KVT52F (Ethylene Glycol); N91BDP6H0X (Choline)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE
[do] DOI:10.1007/s12010-016-2288-0


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[PMID]:27788628
[Au] Autor:White H; Venkatesh B; Jones M; Fuentes H
[Ad] Endereço:a Department of Intensive Care, Logan Hospital , Griffiths University , Brisbane , Australia.
[Ti] Título:Serial changes in plasma ketone concentrations in patients with acute brain injury.
[So] Source:Neurol Res;39(1):1-6, 2017 Jan.
[Is] ISSN:1743-1328
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Objective Acute brain injury (ABI) is a catastrophic event, leading to disruption of the normal cerebral metabolic pathways and a subsequent cerebral energy deficit. Ketones (beta-hydroxybutyrate (BHB) and acetoacetate) may represent an alternative metabolic substrate with the potential to improve cerebral energy supply and decrease injury. The purpose of this study was to evaluate baseline ketone concentrations in the ABI population. Methods Thirty-eight patients with ABI were enrolled into the study and followed for up to 7 days. We collected arterial blood samples immediately after admission and daily to measure the levels of BHB and acetoacetate. Where possible, matching cerebrospinal fluid (CSF) specimens were also collected. Results During the study period, plasma BHB levels were increased initially but normalized by day 3 while acetoacetate levels remained within the normal range. The change in BHB was significant. There were 30 observations in 10 patients where BHB could be measured in both blood and CSF. When the data were averaged over patients there was a weak correlation between blood and CSF BHB (Spearman's ρ = 0.62, p = 0.054). Conclusion Blood ketone concentrations remain low within the ABI population. An external source of ketones will be required to increase blood concentrations to clinically relevant levels.
[Mh] Termos MeSH primário: Ácido 3-Hidroxibutírico/sangue
Acetoacetatos/sangue
Lesões Encefálicas/sangue
[Mh] Termos MeSH secundário: Ácido 3-Hidroxibutírico/líquido cefalorraquidiano
Acetoacetatos/líquido cefalorraquidiano
Adulto
Idoso
Lesões Encefálicas/líquido cefalorraquidiano
Feminino
Escala de Coma de Glasgow
Seres Humanos
Unidades de Terapia Intensiva
Masculino
Meia-Idade
Estudos Prospectivos
Estatística como Assunto
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Acetoacetates); 4ZI204Y1MC (acetoacetic acid); TZP1275679 (3-Hydroxybutyric Acid)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170117
[Lr] Data última revisão:
170117
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161030
[St] Status:MEDLINE



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