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  1 / 10 MEDLINE  
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[PMID]:29287247
[Au] Autor:Beloborodov SS; Bao J; Krylova SM; Shala-Lawrence A; Johnson PE; Krylov SN
[Ad] Endereço:Department of Chemistry and Centre for Research on Biomolecular Interactions, York University, Toronto, Ontario M3J 1P3, Canada.
[Ti] Título:Aptamer facilitated purification of functional proteins.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1073:201-206, 2018 Jan 15.
[Is] ISSN:1873-376X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:DNA aptamers are attractive capture probes for affinity chromatography since, in contrast to antibodies, they can be chemically synthesized and, in contrast to tag-specific capture probes (such as Nickel-NTA or Glutathione), they can be used for purification of proteins free of genetic modifications (such as His or GST tags). Despite these attractive features of aptamers as capture probes, there are only a few reports on aptamer-based protein purification and none of them includes a test of the purified protein's activity, thus, leaving discouraging doubts about method's ability to purify proteins in their active state. The goal of this work was to prove that aptamers could facilitate isolation of active proteins. We refined a complete aptamer-based affinity purification procedure, which takes 4 h to complete. We further applied this procedure to purify two recombinant proteins, MutS and AlkB, from bacterial cell culture: 0.21 mg of 85%-pure AlkB from 4 mL of culture and 0.24 mg of 82%-pure MutS from 0.5 mL of culture. Finally, we proved protein activity by two capillary electrophoresis based assays: an enzymatic assay for AlkB and a DNA-binding assay for MutS. We suggest that in combination with aptamer selection for non-purified protein targets in crude cell lysate, aptamer-based purification provides a means of fast isolation of tag-free recombinant proteins in their native state without the use of antibodies.
[Mh] Termos MeSH primário: Aptâmeros de Nucleotídeos/química
Cromatografia de Afinidade/métodos
Ácidos Nucleicos Imobilizados/química
Proteínas Recombinantes/isolamento & purificação
[Mh] Termos MeSH secundário: Enzimas AlkB/química
Enzimas AlkB/genética
Enzimas AlkB/isolamento & purificação
Enzimas AlkB/metabolismo
Aptâmeros de Nucleotídeos/metabolismo
Eletroforese Capilar
Eletroforese em Gel de Poliacrilamida
Escherichia coli/genética
Ácidos Nucleicos Imobilizados/metabolismo
Metilação
Proteína MutS de Ligação de DNA com Erro de Pareamento/química
Proteína MutS de Ligação de DNA com Erro de Pareamento/genética
Proteína MutS de Ligação de DNA com Erro de Pareamento/isolamento & purificação
Proteína MutS de Ligação de DNA com Erro de Pareamento/metabolismo
Ligação Proteica
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aptamers, Nucleotide); 0 (Immobilized Nucleic Acids); 0 (Recombinant Proteins); EC 1.14.11.33 (AlkB Enzymes); EC 3.6.1.3 (MutS DNA Mismatch-Binding Protein)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171230
[St] Status:MEDLINE


  2 / 10 MEDLINE  
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[PMID]:29107960
[Au] Autor:Tran TQ; Ishak Gabra MB; Lowman XH; Yang Y; Reid MA; Pan M; O'Connor TR; Kong M
[Ad] Endereço:Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
[Ti] Título:Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes.
[So] Source:PLoS Biol;15(11):e2002810, 2017 Nov.
[Is] ISSN:1545-7885
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death. In addition, low glutamine-induced DNA damage is abolished in ALKBH deficient cells. Importantly, we show that glutaminase inhibitors, 6-Diazo-5-oxo-L-norleucine (DON) or CB-839, hypersensitize cancer cells to alkylating agents both in vitro and in vivo. Together, the crosstalk between glutamine metabolism and the DNA repair pathway identified in this study highlights a potential role of metabolic stress in genomic instability and therapeutic response in cancer.
[Mh] Termos MeSH primário: Enzimas AlkB/antagonistas & inibidores
Antineoplásicos Alquilantes/uso terapêutico
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Inibidores Enzimáticos/uso terapêutico
Glutaminase/antagonistas & inibidores
Proteínas de Neoplasias/antagonistas & inibidores
Neoplasias/tratamento farmacológico
[Mh] Termos MeSH secundário: Enzimas AlkB/genética
Enzimas AlkB/metabolismo
Homólogo AlkB 3 da Dioxigenase Dependente de alfa-Cetoglutarato/antagonistas & inibidores
Homólogo AlkB 3 da Dioxigenase Dependente de alfa-Cetoglutarato/genética
Homólogo AlkB 3 da Dioxigenase Dependente de alfa-Cetoglutarato/metabolismo
Alquilação/efeitos dos fármacos
Animais
Antineoplásicos Alquilantes/farmacologia
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Dano ao DNA
Inibidores Enzimáticos/farmacologia
Glutaminase/metabolismo
Seres Humanos
Masculino
Camundongos
Camundongos Nus
Proteínas de Neoplasias/genética
Proteínas de Neoplasias/metabolismo
Neoplasias/metabolismo
Neoplasias/patologia
Interferência de RNA
Distribuição Aleatória
Carga Tumoral/efeitos dos fármacos
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Alkylating); 0 (Enzyme Inhibitors); 0 (Neoplasm Proteins); EC 1.14.11.- (ALKBH3 protein, human); EC 1.14.11.- (AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase); EC 1.14.11.33 (AlkB Enzymes); EC 3.5.1.2 (Glutaminase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171119
[Lr] Data última revisão:
171119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171107
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pbio.2002810


  3 / 10 MEDLINE  
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[PMID]:28408432
[Au] Autor:Dylewska M; Kusmierek JT; Pilzys T; Poznanski J; Maciejewska AM
[Ad] Endereço:Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A, Warszawa 02-106, Poland.
[Ti] Título:1,N -α-hydroxypropanoadenine, the acrolein adduct to adenine, is a substrate for AlkB dioxygenase.
[So] Source:Biochem J;474(11):1837-1852, 2017 May 16.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:1,N -α-hydroxypropanoadenine (HPA) is an exocyclic DNA adduct of acrolein - an environmental pollutant and endocellular oxidative stress product. AlkB dioxygenase belongs to the superfamily of α-ketoglutarate (αKG)- and iron-dependent dioxygenases which remove alkyl lesions from bases via an oxidative mechanism, thereby restoring native DNA structure. Here, we provide and evidence that HPA is mutagenic and is effectively repaired by AlkB dioxygenase. HPA generated in plasmid DNA caused A → C and A → T transversions and, less frequently, A → G transitions. The lesion was efficiently repaired by purified AlkB protein; the optimal pH, Fe(II), and αKG concentrations for this reaction were determined. kinetic data show that the protonated form of HPA is preferentially repaired by AlkB, albeit the reaction is stereoselective. Moreover, the number of reaction cycles carried out by an AlkB molecule remains limited. Molecular modeling of the T(HPA)T/AlkB complex demonstrated that the R stereoisomer in the equatorial conformation of the HPA hydroxyl group is strongly preferred, while the S stereoisomer seems to be susceptible to AlkB-directed oxidative hydroxylation only when HPA adopts the conformation around the glycosidic bond. In addition to the biochemical activity assays, substrate binding to the protein was monitored by differential scanning fluorimetry allowing identification of the active protein form, with cofactor and cosubstrate bound, and monitoring of substrate binding. In contrast FTO, a human AlkB homolog, failed to bind an ssDNA trimer carrying HPA.
[Mh] Termos MeSH primário: Adenina/análogos & derivados
Enzimas AlkB/metabolismo
Carcinógenos Ambientais/metabolismo
Adutos de DNA/metabolismo
Reparo do DNA
Proteínas de Escherichia coli/metabolismo
Modelos Moleculares
Mutagênicos/metabolismo
[Mh] Termos MeSH secundário: Adenina/química
Adenina/metabolismo
Adenina/toxicidade
Enzimas AlkB/química
Enzimas AlkB/genética
Sítios de Ligação
Biocatálise
Carcinógenos Ambientais/química
Carcinógenos Ambientais/toxicidade
Adutos de DNA/química
Adutos de DNA/toxicidade
DNA Bacteriano/química
DNA Bacteriano/efeitos dos fármacos
DNA Bacteriano/metabolismo
Estabilidade Enzimática
Escherichia coli/efeitos dos fármacos
Escherichia coli/crescimento & desenvolvimento
Escherichia coli/metabolismo
Proteínas de Escherichia coli/química
Proteínas de Escherichia coli/genética
Hidroxilação
Conformação Molecular
Simulação de Dinâmica Molecular
Mutagênese/efeitos dos fármacos
Mutagênicos/química
Mutagênicos/toxicidade
Oxirredução
Conformação Proteica
Teoria Quântica
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Estereoisomerismo
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1,N6-alpha-hydroxypropanoadenine); 0 (Carcinogens, Environmental); 0 (DNA Adducts); 0 (DNA, Bacterial); 0 (Escherichia coli Proteins); 0 (Mutagens); 0 (Recombinant Proteins); EC 1.14.11.33 (AlkB Enzymes); JAC85A2161 (Adenine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170623
[Lr] Data última revisão:
170623
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170415
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20161008


  4 / 10 MEDLINE  
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[PMID]:28231280
[Au] Autor:Walker AR; Silvestrov P; Müller TA; Podolsky RH; Dyson G; Hausinger RP; Cisneros GA
[Ad] Endereço:Department of Chemistry, Wayne State University, Detroit, MI, United States of America.
[Ti] Título:ALKBH7 Variant Related to Prostate Cancer Exhibits Altered Substrate Binding.
[So] Source:PLoS Comput Biol;13(2):e1005345, 2017 Feb.
[Is] ISSN:1553-7358
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The search for prostate cancer biomarkers has received increased attention and several DNA repair related enzymes have been linked to this dysfunction. Here we report a targeted search for single nucleotide polymorphisms (SNPs) and functional impact characterization of human ALKBH family dioxygenases related to prostate cancer. Our results uncovered a SNP of ALKBH7, rs7540, which is associated with prostate cancer disease in a statistically significantly manner in two separate cohorts, and maintained in African American men. Comparisons of molecular dynamics (MD) simulations on the wild-type and variant protein structures indicate that the resulting alteration in the enzyme induces a significant structural change that reduces ALKBH7's ability to bind its cosubstrate. Experimental spectroscopy studies with purified proteins validate our MD predictions and corroborate the conclusion that this cancer-associated mutation affects productive cosubstrate binding in ALKBH7.
[Mh] Termos MeSH primário: Enzimas AlkB/genética
Ácidos Cetoglutáricos/química
Proteínas Mitocondriais/genética
Polimorfismo de Nucleotídeo Único/genética
Neoplasias da Próstata/etnologia
Neoplasias da Próstata/genética
[Mh] Termos MeSH secundário: Afroamericanos/estatística & dados numéricos
Sítios de Ligação
Biomarcadores Tumorais/química
Biomarcadores Tumorais/genética
Ativação Enzimática
Marcadores Genéticos/genética
Predisposição Genética para Doença/etnologia
Predisposição Genética para Doença/genética
Seres Humanos
Masculino
Simulação de Dinâmica Molecular
Oxigênio/química
Prevalência
Ligação Proteica
Fatores de Risco
Especificidade por Substrato
Estados Unidos/epidemiologia
Estados Unidos/etnologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Genetic Markers); 0 (Ketoglutaric Acids); 0 (Mitochondrial Proteins); 8ID597Z82X (alpha-ketoglutaric acid); EC 1.14.11.33 (ALKBH7 protein, human); EC 1.14.11.33 (AlkB Enzymes); S88TT14065 (Oxygen)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170224
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pcbi.1005345


  5 / 10 MEDLINE  
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[PMID]:28137747
[Au] Autor:Willemsen A; Zwart MP; Ambrós S; Carrasco JL; Elena SF
[Ad] Endereço:Instituto de Biología Molecular y Celular de Plantas (IBMCP), Consejo Superior de Investigaciones Científicas-Universidad Politécnica de Valencia, València, Spain.
[Ti] Título:2b or Not 2b: Experimental Evolution of Functional Exogenous Sequences in a Plant RNA Virus.
[So] Source:Genome Biol Evol;9(2):297-310, 2017 Feb 01.
[Is] ISSN:1759-6653
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Horizontal gene transfer (HGT) is pervasive in viruses and thought to be a key mechanism in their evolution. On the other hand, strong selective constraints against increasing genome size are an impediment for HGT, rapidly purging horizontally transferred sequences and thereby potentially hindering evolutionary innovation. Here, we explore experimentally the evolutionary fate of viruses with simulated HGT events, using the plant RNA virus Tobacco etch virus (TEV), by separately introducing two functional, exogenous sequences to its genome. One of the events simulates the acquisition of a new function though HGT of a conserved AlkB domain, responsible for the repair of alkylation or methylation damage in many organisms. The other event simulates the acquisition of a sequence that duplicates an existing function, through HGT of the 2b RNA silencing suppressor from Cucumber mosaic virus. We then evolved these two viruses, tracked the maintenance of the horizontally transferred sequences over time, and for the final virus populations, sequenced their genome and measured viral fitness. We found that the AlkB domain was rapidly purged from the TEV genome, restoring fitness to wild-type levels. Conversely, the 2b gene was stably maintained and did not have a major impact on viral fitness. Moreover, we found that 2b is functional in TEV, as it provides a replicative advantage when the RNA silencing suppression domain of HC-Pro is mutated. These observations suggest a potentially interesting role for HGT of short functional sequences in ameliorating evolutionary constraints on viruses, through the duplication of functions.
[Mh] Termos MeSH primário: Evolução Molecular
Transferência Genética Horizontal
Potyvirus/genética
[Mh] Termos MeSH secundário: Enzimas AlkB/química
Enzimas AlkB/genética
Cucumovirus/genética
Genoma Viral
Domínios Proteicos
RNA Viral/genética
Tabaco/virologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Viral); EC 1.14.11.33 (AlkB Enzymes)
[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:170201
[St] Status:MEDLINE
[do] DOI:10.1093/gbe/evw300


  6 / 10 MEDLINE  
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[PMID]:27378775
[Au] Autor:Shivange G; Monisha M; Nigam R; Kodipelli N; Anindya R
[Ad] Endereço:Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, 502285 Hyderabad, Telangana, India.
[Ti] Título:RecA stimulates AlkB-mediated direct repair of DNA adducts.
[So] Source:Nucleic Acids Res;44(18):8754-8763, 2016 Oct 14.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The Escherichia coli AlkB protein is a 2-oxoglutarate/Fe(II)-dependent demethylase that repairs alkylated single stranded and double stranded DNA. Immunoaffinity chromatography coupled with mass spectrometry identified RecA, a key factor in homologous recombination, as an AlkB-associated protein. The interaction between AlkB and RecA was validated by yeast two-hybrid assay; size-exclusion chromatography and standard pull down experiment and was shown to be direct and mediated by the N-terminal domain of RecA. RecA binding results AlkB-RecA heterodimer formation and RecA-AlkB repairs alkylated DNA with higher efficiency than AlkB alone.
[Mh] Termos MeSH primário: Enzimas AlkB/metabolismo
Adutos de DNA
Reparo do DNA
Recombinases Rec A/metabolismo
[Mh] Termos MeSH secundário: Enzimas AlkB/química
Proteínas de Transporte/química
Proteínas de Transporte/metabolismo
Metilação de DNA
Escherichia coli/genética
Escherichia coli/metabolismo
Modelos Moleculares
Conformação Molecular
Oxirredução
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Recombinases Rec A/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (DNA Adducts); EC 1.14.11.33 (AlkB Enzymes); EC 2.7.7.- (Rec A Recombinases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170606
[Lr] Data última revisão:
170606
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160706
[St] Status:MEDLINE


  7 / 10 MEDLINE  
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[PMID]:27237585
[Au] Autor:A Alemu E; He C; Klungland A
[Ad] Endereço:Department of Microbiology, Division of Diagnostics and Intervention, Institute of Clinical Medicine, Oslo University Hospital, Rikshospitalet, Oslo NO-0027, Norway; Department of Molecular Medicine, Faculty of Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo NO-0027, Norway.
[Ti] Título:ALKBHs-facilitated RNA modifications and de-modifications.
[So] Source:DNA Repair (Amst);44:87-91, 2016 Aug.
[Is] ISSN:1568-7856
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The AlkB gene that protects E.coli against methylation damage to DNA was identified more than 3 decades ago. 20 years later, the AlkB protein was shown to catalyze repair of methylated DNA base lesions by oxidative demethylation. Two human AlkB homologs were characterized with similar DNA repair activities and seven additional human AlkB homologs were identified based on sequence homology. All these dioxygenases, ALKBH1-8 and FTO, contain a conserved α-ketoglutarate/iron-dependent domain for methyl modifications and de-modifications. Well-designed research over the last 10 years has identified unforeseen substrate heterogeneity for the AlkB homologs, including novel reversible methyl modifications in RNA. The discoveries of RNA demethylation catalyzed by AlkB family enzymes initiated a new realm of gene expression regulation, although the understanding of precise endogenous activities and roles of these RNA demethylases are still undeveloped. It is worth mentioning that the AlkB mechanism and use of α-ketoglutarate have also emerged to be essential for many enzymes in epigenetic reprogramming that modify and de-modify methylated bases in DNA and methylated amino acids in histones.
[Mh] Termos MeSH primário: Enzimas AlkB/genética
Reparo do DNA
DNA/genética
Epigênese Genética
RNA/genética
[Mh] Termos MeSH secundário: Enzimas AlkB/metabolismo
DNA/metabolismo
Dano ao DNA
Metilação de DNA
Escherichia coli/genética
Escherichia coli/metabolismo
Histonas/genética
Histonas/metabolismo
Seres Humanos
Ferro/metabolismo
Ácidos Cetoglutáricos/metabolismo
Família Multigênica
RNA/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Histones); 0 (Ketoglutaric Acids); 63231-63-0 (RNA); 8ID597Z82X (alpha-ketoglutaric acid); 9007-49-2 (DNA); E1UOL152H7 (Iron); EC 1.14.11.33 (AlkB Enzymes)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170813
[Lr] Data última revisão:
170813
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160531
[St] Status:MEDLINE


  8 / 10 MEDLINE  
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[PMID]:27074833
[Au] Autor:Yang T; Cheong A; Mai X; Zou S; Woon EC
[Ad] Endereço:Department of Pharmacy, National University of Singapore, 18 Science Drive 4, 117 543, Singapore. esther.woon@nus.edu.sg.
[Ti] Título:A methylation-switchable conformational probe for the sensitive and selective detection of RNA demethylase activity.
[So] Source:Chem Commun (Camb);52(36):6181-4, 2016 05 04.
[Is] ISSN:1364-548X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We describe a novel methylation-sensitive nucleic acid (RNA) probe which switches conformation according to its methylation status. When combined with a differential scanning fluorimetry technique, it enables highly sensitive and selective detection of demethylase activity at a single methylated-base level. The approach is highly versatile and may be adapted to a broad range of RNA demethylases.
[Mh] Termos MeSH primário: Enzimas AlkB/metabolismo
RNA/metabolismo
[Mh] Termos MeSH secundário: Sequência de Bases
Dicroísmo Circular
Fluorometria
Cinética
Espectroscopia de Ressonância Magnética
Metilação
Conformação de Ácido Nucleico
RNA/química
RNA de Cadeia Dupla/química
RNA de Cadeia Dupla/metabolismo
Temperatura de Transição
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (RNA, Double-Stranded); 63231-63-0 (RNA); EC 1.14.11.33 (AlkB Enzymes)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160415
[St] Status:MEDLINE
[do] DOI:10.1039/c6cc01045h


  9 / 10 MEDLINE  
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[PMID]:25122757
[Au] Autor:Wang G; He Q; Feng C; Liu Y; Deng Z; Qi X; Wu W; Mei P; Chen Z
[Ad] Endereço:From the State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193 and.
[Ti] Título:The atomic resolution structure of human AlkB homolog 7 (ALKBH7), a key protein for programmed necrosis and fat metabolism.
[So] Source:J Biol Chem;289(40):27924-36, 2014 Oct 03.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:ALKBH7 is the mitochondrial AlkB family member that is required for alkylation- and oxidation-induced programmed necrosis. In contrast to the protective role of other AlkB family members after suffering alkylation-induced DNA damage, ALKBH7 triggers the collapse of mitochondrial membrane potential and promotes cell death. Moreover, genetic ablation of mouse Alkbh7 dramatically increases body weight and fat mass. Here, we present crystal structures of human ALKBH7 in complex with Mn(II) and α-ketoglutarate at 1.35 Å or N-oxalylglycine at 2.0 Å resolution. ALKBH7 possesses the conserved double-stranded ß-helix fold that coordinates a catalytically active iron by a conserved HX(D/E) … Xn … H motif. Self-hydroxylation of Leu-110 was observed, indicating that ALKBH7 has the potential to catalyze hydroxylation of its substrate. Unlike other AlkB family members whose substrates are DNA or RNA, ALKBH7 is devoid of the "nucleotide recognition lid" which is essential for binding nucleobases, and thus exhibits a solvent-exposed active site; two loops between ß-strands ß6 and ß7 and between ß9 and ß10 create a special outer wall of the minor ß-sheet of the double-stranded ß-helix and form a negatively charged groove. These distinct features suggest that ALKBH7 may act on protein substrate rather than nucleic acids. Taken together, our findings provide a structural basis for understanding the distinct function of ALKBH7 in the AlkB family and offer a foundation for drug design in treating cell death-related diseases and metabolic diseases.
[Mh] Termos MeSH primário: Proteínas Mitocondriais/química
[Mh] Termos MeSH secundário: Enzimas AlkB
Sequência de Aminoácidos
Domínio Catalítico
Cristalografia por Raios X
Gorduras/metabolismo
Seres Humanos
Ácidos Cetoglutáricos
Manganês/química
Manganês/metabolismo
Proteínas Mitocondriais/genética
Proteínas Mitocondriais/metabolismo
Modelos Moleculares
Dados de Sequência Molecular
Necrose
Multimerização Proteica
Estrutura Secundária de Proteína
Alinhamento de Sequência
Difração de Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Fats); 0 (Ketoglutaric Acids); 0 (Mitochondrial Proteins); 42Z2K6ZL8P (Manganese); EC 1.14.11.33 (ALKBH7 protein, human); EC 1.14.11.33 (AlkB Enzymes)
[Em] Mês de entrada:1412
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140815
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M114.590505


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[PMID]:23666923
[Au] Autor:Fu D; Jordan JJ; Samson LD
[Ad] Endereço:Department of Biological Engineering, Department of Biology, Center for Environmental Health Sciences, David H. Koch Center for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
[Ti] Título:Human ALKBH7 is required for alkylation and oxidation-induced programmed necrosis.
[So] Source:Genes Dev;27(10):1089-100, 2013 May 15.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Programmed necrosis has emerged as a crucial modulator of cell death in response to several forms of cellular stress. In one form of programmed necrotic cell death, induced by cytotoxic alkylating agents, hyperactivation of poly-ADP-ribose polymerase (PARP) leads to cellular NAD and ATP depletion, mitochondrial dysfunction, reactive oxygen species formation, and ensuing cell death. Here, we show that the protein encoded by the human AlkB homolog 7 (ALKBH7) gene plays a pivotal role in DNA-damaging agent-induced programmed necrosis by triggering the collapse of mitochondrial membrane potential and large-scale loss of mitochondrial function that lead to energy depletion and cellular demise. Depletion of ALKBH7 suppresses necrotic cell death induced by numerous alkylating and oxidizing agents while having no effect on apoptotic cell death. Like wild-type cells, ALKBH7-depleted cells undergo PARP hyperactivation and NAD depletion after severe DNA damage but, unlike wild-type cells, exhibit rapid recovery of intracellular NAD and ATP levels. Consistent with the recovery of cellular bioenergetics, ALKBH7-depleted cells maintain their mitochondrial membrane potential, plasma membrane integrity, and viability. Our results uncover a novel role for a mammalian AlkB homolog in programmed necrosis, presenting a new target for therapeutic intervention in cancer cells that are resistant to apoptotic cell death.
[Mh] Termos MeSH primário: Apoptose
Dano ao DNA
Proteínas Mitocondriais/metabolismo
Proteínas Nucleares/metabolismo
Estresse Oxidativo
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Enzimas AlkB
Alquilação
Apoptose/efeitos dos fármacos
Linhagem Celular
Dano ao DNA/efeitos dos fármacos
Resistência a Medicamentos
Metabolismo Energético
Ativação Enzimática
Seres Humanos
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Mitocôndrias/patologia
Proteínas Mitocondriais/deficiência
NAD/metabolismo
Necrose/metabolismo
Necrose/patologia
Proteínas Nucleares/deficiência
Oxirredução
Poli(ADP-Ribose) Polimerases/metabolismo
Transporte Proteico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Mitochondrial Proteins); 0 (Nuclear Proteins); 0U46U6E8UK (NAD); 8L70Q75FXE (Adenosine Triphosphate); EC 1.14.11.33 (ALKBH7 protein, human); EC 1.14.11.33 (AlkB Enzymes); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
[Em] Mês de entrada:1307
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130514
[St] Status:MEDLINE
[do] DOI:10.1101/gad.215533.113



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