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Pesquisa : D08.811.277.087.520.200.650 [Categoria DeCS]
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  1 / 2383 MEDLINE  
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[PMID]:29416026
[Au] Autor:Wang YQ; Wang HL; Xu J; Tan J; Fu LN; Wang JL; Zou TH; Sun DF; Gao QY; Chen YX; Fang JY
[Ad] Endereço:Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.
[Ti] Título:Sirtuin5 contributes to colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation-dependent manner.
[So] Source:Nat Commun;9(1):545, 2018 02 07.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Reversible post-translational modifications represent a mechanism to control tumor metabolism. Here we show that mitochondrial Sirtuin5 (SIRT5), which mediates lysine desuccinylation, deglutarylation, and demalonylation, plays a role in colorectal cancer (CRC) glutamine metabolic rewiring. Metabolic profiling identifies that deletion of SIRT5 causes a marked decrease in C-glutamine incorporation into tricarboxylic-acid (TCA) cycle intermediates and glutamine-derived non-essential amino acids. This reduces the building blocks required for rapid growth. Mechanistically, the direct interaction between SIRT5 and glutamate dehydrogenase 1 (GLUD1) causes deglutarylation and functional activation of GLUD1, a critical regulator of cellular glutaminolysis. Consistently, GLUD1 knockdown diminishes SIRT5-induced proliferation, both in vivo and in vitro. Clinically, overexpression of SIRT5 is significantly correlated with poor prognosis in CRC. Thus, SIRT5 supports the anaplerotic entry of glutamine into the TCA cycle in malignant phenotypes of CRC via activating GLUD1.
[Mh] Termos MeSH primário: Carcinogênese/metabolismo
Neoplasias Colorretais/metabolismo
Regulação Neoplásica da Expressão Gênica/fisiologia
Glutamato Desidrogenase/metabolismo
Glutamina/metabolismo
Sirtuínas/metabolismo
[Mh] Termos MeSH secundário: Proliferação Celular
Ciclo do Ácido Cítrico/fisiologia
Regulação Enzimológica da Expressão Gênica/fisiologia
Glutamato Desidrogenase/genética
Células HCT116
Seres Humanos
Interferência de RNA
Sirtuínas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0RH81L854J (Glutamine); EC 1.4.1.2 (Glutamate Dehydrogenase); EC 1.4.1.3 (GLUD1 protein, human); EC 3.5.1.- (SIRT5 protein, human); EC 3.5.1.- (Sirtuins)
[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:180209
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-018-02951-4


  2 / 2383 MEDLINE  
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[PMID]:29317652
[Au] Autor:Santos-Barriopedro I; Bosch-Presegué L; Marazuela-Duque A; de la Torre C; Colomer C; Vazquez BN; Fuhrmann T; Martínez-Pastor B; Lu W; Braun T; Bober E; Jenuwein T; Serrano L; Esteller M; Chen Z; Barceló-Batllori S; Mostoslavsky R; Espinosa L; Vaquero A
[Ad] Endereço:Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Via de l'Hospitalet 199-203, 08908, L'Hospitalet de Llobregat (Barcelona), Spain.
[Ti] Título:SIRT6-dependent cysteine monoubiquitination in the PRE-SET domain of Suv39h1 regulates the NF-κB pathway.
[So] Source:Nat Commun;9(1):101, 2018 01 09.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Sirtuins are NAD -dependent deacetylases that facilitate cellular stress response. They include SirT6, which protects genome stability and regulates metabolic homeostasis through gene silencing, and whose loss induces an accelerated aging phenotype directly linked to hyperactivation of the NF-κB pathway. Here we show that SirT6 binds to the H3K9me3-specific histone methyltransferase Suv39h1 and induces monoubiquitination of conserved cysteines in the PRE-SET domain of Suv39h1. Following activation of NF-κB signaling Suv39h1 is released from the IκBα locus, subsequently repressing the NF-κB pathway. We propose that SirT6 attenuates the NF-κB pathway through IκBα upregulation via cysteine monoubiquitination and chromatin eviction of Suv39h1. We suggest a mechanism based on SirT6-mediated enhancement of a negative feedback loop that restricts the NF-κB pathway.
[Mh] Termos MeSH primário: Cisteína/metabolismo
Metiltransferases/metabolismo
NF-kappa B/metabolismo
Domínios PR-SET
Proteínas Repressoras/metabolismo
Sirtuínas/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Células Cultivadas
Cromatina/metabolismo
Cisteína/genética
Células HCT116
Células HEK293
Células HeLa
Seres Humanos
Metiltransferases/genética
Camundongos
Inibidor de NF-kappaB alfa/metabolismo
Células NIH 3T3
Ligação Proteica
Proteínas Repressoras/genética
Transdução de Sinais
Sirtuínas/genética
Ubiquitinação
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Chromatin); 0 (NF-kappa B); 0 (Repressor Proteins); 139874-52-5 (NF-KappaB Inhibitor alpha); EC 2.1.1. (SUV39H1 protein, human); EC 2.1.1.- (Methyltransferases); EC 3.5.1.- (SIRT6 protein, human); EC 3.5.1.- (Sirtuins); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02586-x


  3 / 2383 MEDLINE  
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[PMID]:29233643
[Au] Autor:Wood M; Rymarchyk S; Zheng S; Cen Y
[Ad] Endereço:Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, 261 Mountain View Drive, Colchester, VT 05446, USA.
[Ti] Título:Trichostatin A inhibits deacetylation of histone H3 and p53 by SIRT6.
[So] Source:Arch Biochem Biophys;638:8-17, 2018 01 15.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:SIRT6 is an epigenetic modification enzyme that regulates gene transcription through its deacetylase activity. In addition to histone protein, SIRT6 also modify other proteins and enzymes, some of which are central players in metabolic reprogramming and aging process. Therefore, SIRT6 has emerged as a therapeutic target for the treatment of metabolic disorder and age-related diseases. Here, we report that SIRT6 deacetylates lysine 382 of p53 in short synthetic peptide sequence and in full length p53. Further studies showed that the deacetylation of H3K9Ac and p53K382Ac are insensitive to nicotinamide inhibition, but are sensitive to trichostatin A (TSA) inhibition. Detailed kinetic analysis revealed that TSA competes with the peptide substrate for inhibition, and this inhibition is unique to SIRT6 in the sirtuin family. Taken together, this study not only suggests potential roles of SIRT6 in regulating apoptosis and stress resistance via direct deacetylation of p53, but also provides lead compound for the development of potent and selective SIRT6 inhibitors.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Histonas
Ácidos Hidroxâmicos/farmacologia
Sirtuínas
Proteína Supressora de Tumor p53
[Mh] Termos MeSH secundário: Acetilação/efeitos dos fármacos
Células HEK293
Histonas/química
Histonas/metabolismo
Seres Humanos
Peptídeos/química
Peptídeos/farmacologia
Sirtuínas/química
Sirtuínas/metabolismo
Proteína Supressora de Tumor p53/química
Proteína Supressora de Tumor p53/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 (Histones); 0 (Hydroxamic Acids); 0 (Peptides); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); 3X2S926L3Z (trichostatin A); EC 3.5.1.- (SIRT6 protein, human); EC 3.5.1.- (Sirtuins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE


  4 / 2383 MEDLINE  
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[PMID]:29374686
[Au] Autor:Song HY; Rellinger EJ; Park SH; Paul P; Qiao J; Vasilopoulos A; Ozden O; Gius D; Chung DH
[Ad] Endereço:Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical Center, Chicago, IL, U.S.A.
[Ti] Título:Inhibition of Sirtuin 6 Induces Neuroblastoma Differentiation.
[So] Source:Anticancer Res;38(2):647-654, 2018 02.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: Sirtuins (SIRTs) play crucial roles in various signaling pathways that modulate differentiation and proliferation. We sought to elucidate the role of SIRTs in differentiation and proliferation of human neuroblastoma (NB). MATERIALS AND METHODS: NB cells were treated with nicotinamide (NAM), a non-specific SIRT inhibitor, SIRT-targeted short hairpin RNAs, and retinoic acid to assess cell growth and differentiation. RESULTS: SIRTs are involved in proliferation and differentiation using NAM in BE(2)-C cells. Specifically, SIRT6 knockdown in BE(2)-C cells reduced cell proliferation, induced neurite extension, corresponding with induction of p21 expression and G cell-cycle arrest. These effects were rescued by forced re-overexpression of SIRT6. SIRT6 expression was reduced in differentiated human NB sections, and RA-induced differentiation in BE(2)-C cells. CONCLUSION: SIRTs have important oncogenic properties in NB beyond its established functions in aging and genome stability. SIRT6 may represent a novel target for developing future therapeutics for the treatment of aggressive NBs.
[Mh] Termos MeSH primário: Diferenciação Celular/efeitos dos fármacos
Neuroblastoma/tratamento farmacológico
Neuroblastoma/metabolismo
Sirtuínas/antagonistas & inibidores
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Técnicas de Silenciamento de Genes
Seres Humanos
Neuroblastoma/patologia
Niacinamida/farmacologia
RNA Interferente Pequeno/farmacologia
Sirtuínas/genética
Tretinoína/administração & dosagem
Tretinoína/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Small Interfering); 25X51I8RD4 (Niacinamide); 5688UTC01R (Tretinoin); EC 3.5.1.- (SIRT6 protein, human); EC 3.5.1.- (Sirtuins)
[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:180129
[St] Status:MEDLINE


  5 / 2383 MEDLINE  
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[PMID]:27777384
[Au] Autor:Bai L; Lin G; Sun L; Liu Y; Huang X; Cao C; Guo Y; Xie C
[Ad] Endereço:Respiratory Department, The First Affiliated Hospital of Sun Yat-Sen University, Institute of Respiratory Diseases of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.
[Ti] Título:Upregulation of SIRT6 predicts poor prognosis and promotes metastasis of non-small cell lung cancer via the ERK1/2/MMP9 pathway.
[So] Source:Oncotarget;7(26):40377-40386, 2016 Jun 28.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sirtuin6 (SIRT6), a member of the sirtuins protein family, plays multiple complex roles in cancer. Here, we report that elevated SIRT6 expression was correlated with clinicopathological parameters such as T and N classification in non-small cell lung cancer (NSCLC) patient tumors. SIRT6 overexpression in NSCLC cell lines increased extracellular signal-regulated kinase (p-ERK)1/2 phosphorylation, activated matrix metalloproteinase 9 (MMP9) and promoted tumor cell migration and invasion. Upon treatment with a specific mitogen-activated protein kinase (MEK) 1/2 inhibitor, these effects were abolished. Our results demonstrate SIRT6 upregulation in NSCLC for the first time and suggest a functional role for SIRT6 in promoting migration and invasion through ERK1/2/MMP9 signaling. SIRT6 may serve as a potential therapeutic target in NSCLC and its utility as a prognostic indicator warrants further study.
[Mh] Termos MeSH primário: Carcinoma Pulmonar de Células não Pequenas/metabolismo
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Neoplasias Pulmonares/metabolismo
Metaloproteinase 9 da Matriz/metabolismo
Sirtuínas/metabolismo
[Mh] Termos MeSH secundário: Células A549
Adulto
Idoso
Idoso de 80 Anos ou mais
Biomarcadores Tumorais
Carcinoma Pulmonar de Células não Pequenas/patologia
Movimento Celular
Feminino
Regulação Neoplásica da Expressão Gênica
Inativação Gênica
Seres Humanos
Neoplasias Pulmonares/patologia
Masculino
Meia-Idade
Invasividade Neoplásica
Metástase Neoplásica
Fosforilação
Prognóstico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 3.4.24.35 (MMP9 protein, human); EC 3.4.24.35 (Matrix Metalloproteinase 9); EC 3.5.1.- (SIRT6 protein, human); EC 3.5.1.- (Sirtuins)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180117
[Lr] Data última revisão:
180117
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.9750


  6 / 2383 MEDLINE  
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[PMID]:27773637
[Au] Autor:Sacconnay L; Carrupt PA; Nurisso A
[Ad] Endereço:School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland.
[Ti] Título:Human sirtuins: Structures and flexibility.
[So] Source:J Struct Biol;196(3):534-542, 2016 Dec.
[Is] ISSN:1095-8657
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In recent years, sirtuins (SIRTs), members of histone deacetylases (HDACs) class III, have been found to modulate cellular processes related to the development of human aging-related pathologies (i.e. cancer, neurodegeneration, metabolic disorders). Several crystallographic structures and computational studies have shed light into their catalytic mechanism of action, identifying also the structural elements for the design of selective drug candidates. In this review, we first aim at summarizing the structural features characterizing human SIRTs. We then describe the observed mass and one-off movements related to conformational changes upon SIRT-mediated recognition events. Such information will be useful not only for rationalizing the design of new SIRT modulators, but also for improving the comprehension of SIRT-related biological roles.
[Mh] Termos MeSH primário: Envelhecimento
Neoplasias/química
Sirtuínas/química
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Seres Humanos
Neoplasias/tratamento farmacológico
Sirtuínas/ultraestrutura
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
EC 3.5.1.- (Sirtuins)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180113
[Lr] Data última revisão:
180113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161030
[St] Status:MEDLINE


  7 / 2383 MEDLINE  
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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


  8 / 2383 MEDLINE  
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[PMID]:28465348
[Au] Autor:Itoh E; Odakura R; Oinuma KI; Shimizu M; Masuo S; Takaya N
[Ad] Endereço:From the Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.
[Ti] Título:Sirtuin E is a fungal global transcriptional regulator that determines the transition from the primary growth to the stationary phase.
[So] Source:J Biol Chem;292(26):11043-11054, 2017 06 30.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In response to limited nutrients, fungal cells exit the primary growth phase, enter the stationary phase, and cease proliferation. Although fundamental to microbial physiology in many environments, the regulation of this transition is poorly understood but likely involves many transcriptional regulators. These may include the sirtuins, which deacetylate acetyllysine residues of histones and epigenetically regulate global transcription. Therefore, we investigated the role of a nuclear sirtuin, sirtuin E (SirE), from the ascomycete fungus An strain with a disrupted gene (SirEΔ) accumulated more acetylated histone H3 during the stationary growth phase when was expressed at increased levels in the wild type. SirEΔ exhibited decreased mycelial autolysis, conidiophore development, sterigmatocystin biosynthesis, and production of extracellular hydrolases. Moreover, the transcription of the genes involved in these processes was also decreased, indicating that SirE is a histone deacetylase that up-regulates these activities in the stationary growth phase. Transcriptome analyses indicated that SirE repressed primary carbon and nitrogen metabolism and cell-wall synthesis. Chromatin immunoprecipitation demonstrated that SirE deacetylates acetylated Lys-9 residues in histone H3 at the gene promoters of α-1,3-glucan synthase ( ), glycolytic phosphofructokinase ( ), and glyceraldehyde 3-phosphate ( ), indicating that SirE represses the expression of these primary metabolic genes. In summary, these results indicate that SirE facilitates the metabolic transition from the primary growth phase to the stationary phase. Because the observed gene expression profiles in stationary phase matched those resulting from carbon starvation, SirE appears to control this metabolic transition via a mechanism associated with the starvation response.
[Mh] Termos MeSH primário: Aspergillus nidulans/metabolismo
Proteínas Fúngicas/metabolismo
Regulação Fúngica da Expressão Gênica/fisiologia
Sirtuínas/metabolismo
Fatores de Transcrição/metabolismo
Transcriptoma/fisiologia
[Mh] Termos MeSH secundário: Aspergillus nidulans/genética
Proteínas Fúngicas/genética
Sirtuínas/genética
Fatores de Transcrição/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Fungal Proteins); 0 (Transcription Factors); EC 3.5.1.- (Sirtuins)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171229
[Lr] Data última revisão:
171229
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.753772


  9 / 2383 MEDLINE  
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[PMID]:28458255
[Au] Autor:Zhang Y; Bharathi SS; Rardin MJ; Lu J; Maringer KV; Sims-Lucas S; Prochownik EV; Gibson BW; Goetzman ES
[Ad] Endereço:From the Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224 and.
[Ti] Título:Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain.
[So] Source:J Biol Chem;292(24):10239-10249, 2017 06 16.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:SIRT5 is a lysine desuccinylase known to regulate mitochondrial fatty acid oxidation and the urea cycle. Here, SIRT5 was observed to bind to cardiolipin via an amphipathic helix on its N terminus. , succinyl-CoA was used to succinylate liver mitochondrial membrane proteins. SIRT5 largely reversed the succinyl-CoA-driven lysine succinylation. Quantitative mass spectrometry of SIRT5-treated membrane proteins pointed to the electron transport chain, particularly Complex I, as being highly targeted for desuccinylation by SIRT5. Correspondingly, SIRT5 HEK293 cells showed defects in both Complex I- and Complex II-driven respiration. In mouse liver, SIRT5 expression was observed to localize strictly to the periportal hepatocytes. However, homogenates prepared from whole SIRT5 liver did show reduced Complex II-driven respiration. The enzymatic activities of Complex II and ATP synthase were also significantly reduced. Three-dimensional modeling of Complex II suggested that several SIRT5-targeted lysine residues lie at the protein-lipid interface of succinate dehydrogenase subunit B. We postulate that succinylation at these sites may disrupt Complex II subunit-subunit interactions and electron transfer. Lastly, SIRT5 mice, like humans with Complex II deficiency, were found to have mild lactic acidosis. Our findings suggest that SIRT5 is targeted to protein complexes on the inner mitochondrial membrane via affinity for cardiolipin to promote respiratory chain function.
[Mh] Termos MeSH primário: Cardiolipinas/metabolismo
Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo
Hepatócitos/enzimologia
Modelos Moleculares
Processamento de Proteína Pós-Traducional
Sirtuínas/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Cardiolipinas/química
Complexo I de Transporte de Elétrons/metabolismo
Complexo II de Transporte de Elétrons/metabolismo
Células HEK293
Hepatócitos/metabolismo
Seres Humanos
Lisina/metabolismo
Camundongos
Camundongos Knockout
Mitocôndrias Hepáticas/enzimologia
Mitocôndrias Hepáticas/metabolismo
Membranas Mitocondriais/enzimologia
Membranas Mitocondriais/metabolismo
Mutação
Transporte Proteico
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Sirtuínas/química
Sirtuínas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Cardiolipins); 0 (Electron Transport Chain Complex Proteins); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); 0 (SIRT5 protein, mouse); EC 1.3.5.1 (Electron Transport Complex II); EC 1.6.5.3 (Electron Transport Complex I); EC 3.5.1.- (SIRT5 protein, human); EC 3.5.1.- (Sirtuins); K3Z4F929H6 (Lysine)
[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:170502
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.785022


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[PMID]:28455447
[Au] Autor:Ye Q; Ji QQ; Yan W; Yang F; Wang ED
[Ad] Endereço:From the State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Science, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China and.
[Ti] Título:Acetylation of lysine ϵ-amino groups regulates aminoacyl-tRNA synthetase activity in .
[So] Source:J Biol Chem;292(25):10709-10722, 2017 06 23.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previous proteomic analyses have shown that aminoacyl-tRNA synthetases in many organisms can be modified by acetylation of Lys. In this present study, leucyl-tRNA synthetase and arginyl-tRNA synthetase from ( LeuRS and ArgRS) were overexpressed and purified and found to be acetylated on Lys residues by MS. Gln scanning mutagenesis revealed that Lys , Lys , and Lys in LeuRS and Lys and Lys in ArgRS might play important roles in enzyme activity. Furthermore, we utilized a novel protein expression system to obtain enzymes harboring acetylated Lys at specific sites and investigated their catalytic activity. Acetylation of these Lys residues could affect their aminoacylation activity by influencing amino acid activation and/or the affinity for tRNA. assays showed that acetyl-phosphate nonenzymatically acetylates LeuRS and ArgRS and suggested that the sirtuin class deacetylase CobB might regulate acetylation of these two enzymes. These findings imply a potential regulatory role for Lys acetylation in controlling the activity of aminoacyl-tRNA synthetases and thus protein synthesis.
[Mh] Termos MeSH primário: Arginina-tRNA Ligase/química
Proteínas de Escherichia coli/química
Escherichia coli/enzimologia
Leucina-tRNA Ligase/química
Sirtuínas/química
[Mh] Termos MeSH secundário: Acetilação
Arginina-tRNA Ligase/genética
Arginina-tRNA Ligase/metabolismo
Ativação Enzimática
Escherichia coli/genética
Proteínas de Escherichia coli/genética
Proteínas de Escherichia coli/metabolismo
Leucina-tRNA Ligase/genética
Leucina-tRNA Ligase/metabolismo
Lisina/química
Lisina/genética
Lisina/metabolismo
Sirtuínas/genética
Sirtuínas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Escherichia coli Proteins); EC 3.5.1.- (Sirtuins); EC 3.5.1.- (cobB protein, E Coli); EC 6.1.1.19 (Arginine-tRNA Ligase); EC 6.1.1.4 (Leucine-tRNA Ligase); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171229
[Lr] Data última revisão:
171229
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.770826



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