Base de dados : MEDLINE
Pesquisa : G02.111.210 [Categoria DeCS]
Referências encontradas : 1345 [refinar]
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[PMID]:29335211
[Au] Autor:Li PH; Jiang H; Zhang WJ; Li YL; Zhao MC; Zhou W; Zhang LY; Tang YD; Dong CZ; Huang ZS; Chen HX; Du ZY
[Ad] Endereço:Institute of Natural Medicine & Green Chemistry, School of Chemical Engineering and Light Industry, Guandong University of Technology, Guangzhou, 510006, China.
[Ti] Título:Synthesis of carbazole derivatives containing chalcone analogs as non-intercalative topoisomerase II catalytic inhibitors and apoptosis inducers.
[So] Source:Eur J Med Chem;145:498-510, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Novel topoisomerase II (Topo II) inhibitors have gained considerable interest for the development of anticancer agents. In this study, a series of carbazole derivatives containing chalcone analogs (CDCAs) were synthesized and investigated for their Topo II inhibition and cytotoxic activities. The results from Topo II mediated DNA relaxation assay showed that CDCAs could significantly inhibit the activity of Topo II, and the structure-activity relationship indicated the halogen substituent in phenyl ring play an important role in the activity. Further mechanism studies revealed that CDCAs function as non-intercalative Topo II catalytic inhibitors. Moreover, some CDCAs showed micromolar cytotoxic activities. The most potent compound 3h exhibited notable growth inhibition against four human cancer cell lines. Flow cytometric analysis revealed that compounds 3d and 3h arrested the HL-60 cells in sub G1 phase by induction of apoptosis. It was further confirmed by Annexin-V-FITC binding assay. Western blot analysis revealed that compound 3h induces apoptosis likely through the activation of caspase proteins.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Carbazóis/farmacologia
Chalcona/farmacologia
DNA Topoisomerases Tipo II/metabolismo
Inibidores da Topoisomerase II/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Biocatálise
Carbazóis/síntese química
Carbazóis/química
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Chalcona/química
Clivagem do DNA/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Células HL-60
Seres Humanos
Estrutura Molecular
Plasmídeos
Relação Estrutura-Atividade
Inibidores da Topoisomerase II/síntese química
Inibidores da Topoisomerase II/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Carbazoles); 0 (Topoisomerase II Inhibitors); 0P2197HHHN (carbazole); 5S5A2Q39HX (Chalcone); EC 5.99.1.3 (DNA Topoisomerases, Type II)
[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:180117
[St] Status:MEDLINE


  2 / 1345 MEDLINE  
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[PMID]:29321179
[Au] Autor:Reginato G; Cannavo E; Cejka P
[Ad] Endereço:Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland.
[Ti] Título:Physiological protein blocks direct the Mre11-Rad50-Xrs2 and Sae2 nuclease complex to initiate DNA end resection.
[So] Source:Genes Dev;31(23-24):2325-2330, 2017 12 01.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:DNA double-strand break repair by homologous recombination is initiated by DNA end resection, which is commenced by the Mre11-Rad50-Xrs2 complex and Sae2 in yeast. Here we report that the nonhomologous end joining factor Ku limits the exonuclease activity of Mre11 and promotes its endonuclease to cleave 5'-terminated DNA strands at break sites. Following initial endonucleolytic cleavage past the obstacle, Exo1 specifically extends the resection track, leading to the generation of long 3' overhangs that are required for homologous recombination. These experiments provide mechanistic insights into how short-range and long-range DNA end resection enzymes overcome obstacles near broken DNA ends to initiate recombination.
[Mh] Termos MeSH primário: Reparo do DNA por Junção de Extremidades
Endonucleases/metabolismo
Exonucleases/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/fisiologia
[Mh] Termos MeSH secundário: Animais
Clivagem do DNA
Proteínas de Ligação a DNA/metabolismo
Endodesoxirribonucleases/metabolismo
Ativação Enzimática/genética
Exodesoxirribonucleases/metabolismo
Complexos Multiproteicos/metabolismo
Saccharomyces cerevisiae/enzimologia
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/genética
Células Sf9
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (Multiprotein Complexes); 0 (RAD50 protein, S cerevisiae); 0 (SAE2 protein, S cerevisiae); 0 (Saccharomyces cerevisiae Proteins); 0 (XRS2 protein, S cerevisiae); 0 (high affinity DNA-binding factor, S cerevisiae); EC 3.1.- (Endodeoxyribonucleases); EC 3.1.- (Endonucleases); EC 3.1.- (Exodeoxyribonucleases); EC 3.1.- (Exonucleases); EC 3.1.- (MRE11 protein, S cerevisiae); EC 3.1.11.1 (exodeoxyribonuclease I)
[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:180112
[St] Status:MEDLINE
[do] DOI:10.1101/gad.308254.117


  3 / 1345 MEDLINE  
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[PMID]:29321177
[Au] Autor:Wang W; Daley JM; Kwon Y; Krasner DS; Sung P
[Ad] Endereço:Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
[Ti] Título:Plasticity of the Mre11-Rad50-Xrs2-Sae2 nuclease ensemble in the processing of DNA-bound obstacles.
[So] Source:Genes Dev;31(23-24):2331-2336, 2017 12 01.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The budding yeast Mre11-Rad50-Xrs2 (MRX) complex and Sae2 function together in DNA end resection during homologous recombination. Here we show that the Ku complex shields DNA ends from exonucleolytic digestion but facilitates endonucleolytic scission by MRX with a dependence on ATP and Sae2. The incision site is enlarged into a DNA gap via the exonuclease activity of MRX, which is stimulated by Sae2 without ATP being present. RPA renders a partially resected or palindromic DNA structure susceptible to MRX-Sae2, and internal protein blocks also trigger DNA cleavage. We present models for how MRX-Sae2 creates entry sites for the long-range resection machinery.
[Mh] Termos MeSH primário: Reparo do DNA por Junção de Extremidades
Reparo do DNA/fisiologia
Endonucleases/metabolismo
Exonucleases/metabolismo
Complexos Multienzimáticos/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/fisiologia
[Mh] Termos MeSH secundário: Clivagem do DNA
Proteínas de Ligação a DNA/metabolismo
Endodesoxirribonucleases/metabolismo
Ativação Enzimática/genética
Exodesoxirribonucleases/metabolismo
Complexos Multiproteicos/metabolismo
Saccharomyces cerevisiae/enzimologia
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (Multienzyme Complexes); 0 (Multiprotein Complexes); 0 (RAD50 protein, S cerevisiae); 0 (SAE2 protein, S cerevisiae); 0 (Saccharomyces cerevisiae Proteins); 0 (XRS2 protein, S cerevisiae); 0 (high affinity DNA-binding factor, S cerevisiae); EC 3.1.- (Endodeoxyribonucleases); EC 3.1.- (Endonucleases); EC 3.1.- (Exodeoxyribonucleases); EC 3.1.- (Exonucleases); EC 3.1.- (MRE11 protein, S cerevisiae); EC 3.1.11.1 (exodeoxyribonuclease I)
[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:180112
[St] Status:MEDLINE
[do] DOI:10.1101/gad.307900.117


  4 / 1345 MEDLINE  
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[PMID]:28745489
[Au] Autor:Wani TH; Chakrabarty A; Shibata N; Yamazaki H; Guengerich FP; Chowdhury G
[Ad] Endereço:Departments of Chemistry and Life Sciences, SONS, Shiv Nadar University , Greater Noida, Uttar Pradesh 201314, India.
[Ti] Título:The Dihydroxy Metabolite of the Teratogen Thalidomide Causes Oxidative DNA Damage.
[So] Source:Chem Res Toxicol;30(8):1622-1628, 2017 08 21.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Thalidomide [α-(N-phthalimido)glutarimide] (1) is a sedative and antiemetic drug originally introduced into the clinic in the 1950s for the treatment of morning sickness. Although marketed as entirely safe, more than 10 000 babies were born with severe birth defects. Thalidomide was banned and subsequently approved for the treatment of multiple myeloma and complications associated with leprosy. Although known for more than 5 decades, the mechanism of teratogenicity remains to be conclusively understood. Various theories have been proposed in the literature including DNA damage and ROS and inhibition of angiogenesis and cereblon. All of the theories have their merits and limitations. Although the recently proposed cereblon theory has gained wide acceptance, it fails to explain the metabolism and low-dose requirement reported by a number of groups. Recently, we have provided convincing structural evidence in support of the presence of arene oxide and the quinone-reactive intermediates. However, the ability of these reactive intermediates to impart toxicity/teratogenicity needs investigation. Herein we report that the oxidative metabolite of thalidomide, dihydroxythalidomide, is responsible for generating ROS and causing DNA damage. We show, using cell lines, the formation of comet (DNA damage) and ROS. Using DNA-cleavage assays, we also show that catalase, radical scavengers, and desferal are capable of inhibiting DNA damage. A mechanism of teratogenicity is proposed that not only explains the DNA-damaging property but also the metabolism, low concentration, and species-specificity requirements of thalidomide.
[Mh] Termos MeSH primário: Dano ao DNA/efeitos dos fármacos
Talidomida/toxicidade
[Mh] Termos MeSH secundário: Catalase/metabolismo
Clivagem do DNA
Depuradores de Radicais Livres/química
Células HEK293
Células Hep G2
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Microscopia de Fluorescência
Plasmídeos/metabolismo
Poli(ADP-Ribose) Polimerases/metabolismo
Espécies Reativas de Oxigênio/análise
Espécies Reativas de Oxigênio/metabolismo
Teratogênios/química
Teratogênios/metabolismo
Teratogênios/toxicidade
Talidomida/química
Talidomida/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 (Free Radical Scavengers); 0 (Reactive Oxygen Species); 0 (Teratogens); 4Z8R6ORS6L (Thalidomide); EC 1.11.1.6 (Catalase); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180127
[Lr] Data última revisão:
180127
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1021/acs.chemrestox.7b00127


  5 / 1345 MEDLINE  
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[PMID]:29235857
[Au] Autor:Camargo TP; Neves A; Peralta RA; Chaves C; Maia ECP; Lizarazo-Jaimes EH; Gomes DA; Bortolotto T; Norberto DR; Terenzi H; Tierney DL; Schenk G
[Ti] Título:Second-Sphere Effects in Dinuclear Fe Zn Hydrolase Biomimetics: Tuning Binding and Reactivity Properties.
[So] Source:Inorg Chem;57(1):187-203, 2018 Jan 02.
[Is] ISSN:1520-510X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Herein, we report the synthesis and characterization of two dinuclear Fe Zn complexes [Fe Zn LP1] (1) and [Fe Zn LP2] (2), in which LP1 and LP2 are conjugated systems containing one and two pyrene groups, respectively, connected via the diamine -HN(CH ) NH- spacer to the well-known N O -donor H L ligand (H L = 2-bis{[(2-pyridylmethyl)aminomethyl]-6-[(2-hydroxybenzyl)(2-pyridylmethyl)]aminomethyl}-4-methylphenol). The complex [Fe Zn L1] (3), in which H L was modified to H L1, with a carbonyl group attached to the terminal phenol group, was included in this study for comparison purposes. Both complexes 1 and 2 were satisfactorily characterized in the solid state and in solution. Extended X-ray absorption fine structure data for 1 and 3 in an acetonitrile solution show that the multiply bridged structure seen in the solid state of 3 is retained in solution. Potentiometric and UV-vis titration of 1 and 2 show that electrostatic interaction between the protonated amino groups and coordinated water molecules significantly decreases the pK of the iron(III)-bound water compared to those of 3. On the other hand, catalytic activity studies using 1 and 2 in the hydrolysis of the activated substrate bis(2,4-dinitrophenyl)phosphate (BDNPP) resulted in a significant increase in the association of the substrate (K ≅ 1/K ) compared to that of 3 because of electrostatic and hydrophobic interactions between BDNPP and the side-chain diaminopyrene of the ligands H LP1 and H LP2. In addition, the introduction of the pyrene motifs in 1 and 2 enhanced their activity toward DNA and as effective antitumor drugs, although the biochemical mechanism of the latter effect is currently under investigation. These complexes represent interesting examples of how to promote an increase in the activity of traditional artificial metal nucleases by introducing second-coordination-sphere effects.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Biomimética
DNA/efeitos dos fármacos
Compostos Férricos/farmacologia
Hidrolases/metabolismo
Compostos Organometálicos/farmacologia
Zinco/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/química
Antineoplásicos/metabolismo
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Cristalografia por Raios X
Clivagem do DNA/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Compostos Férricos/química
Compostos Férricos/metabolismo
Seres Humanos
Hidrolases/química
Ligantes
Modelos Moleculares
Conformação Molecular
Compostos Organometálicos/química
Compostos Organometálicos/metabolismo
Relação Estrutura-Atividade
Células Tumorais Cultivadas
Zinco/química
Zinco/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Ferric Compounds); 0 (Ligands); 0 (Organometallic Compounds); 9007-49-2 (DNA); EC 3.- (Hydrolases); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180109
[Lr] Data última revisão:
180109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE
[do] DOI:10.1021/acs.inorgchem.7b02384


  6 / 1345 MEDLINE  
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[PMID]:28973448
[Au] Autor:Zarnegar MA; Reinitz F; Newman AM; Clarke MF
[Ad] Endereço:Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
[Ti] Título:Targeted chromatin ligation, a robust epigenetic profiling technique for small cell numbers.
[So] Source:Nucleic Acids Res;45(17):e153, 2017 Sep 29.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The complexity and inefficiency of chromatin immunoprecipitation strategies restrict their sensitivity and application when examining rare cell populations. We developed a new technique that replaces immunoprecipitation with a simplified chromatin fragmentation and proximity ligation step that eliminates bead purification and washing steps. We present a simple single tube proximity ligation technique, targeted chromatin ligation, that captures histone modification patterns with only 200 cells. Our technique eliminates loss of material and sensitivity due to multiple inefficient steps, while simplifying the workflow to enhance sensitivity and create the potential for novel applications.
[Mh] Termos MeSH primário: Técnicas de Química Analítica
Cromatina/metabolismo
Epigênese Genética
Histonas/genética
Neurônios/metabolismo
[Mh] Termos MeSH secundário: Animais
Contagem de Células
Cromatina/química
Imunoprecipitação da Cromatina
Clivagem do DNA
Histonas/metabolismo
Seres Humanos
Células MCF-7
Camundongos
Camundongos Endogâmicos C57BL
Neurônios/citologia
Cultura Primária de Células
Proteólise
Reprodutibilidade dos Testes
Sensibilidade e Especificidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chromatin); 0 (Histones)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx648


  7 / 1345 MEDLINE  
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[PMID]:28934493
[Au] Autor:Sasnauskas G; Tamulaitiene G; Tamulaitis G; Calyseva J; Laime M; Rimseliene R; Lubys A; Siksnys V
[Ad] Endereço:Institute of Biotechnology, Vilnius University, Sauletekio av. 7, LT-10257 Vilnius, Lithuania.
[Ti] Título:UbaLAI is a monomeric Type IIE restriction enzyme.
[So] Source:Nucleic Acids Res;45(16):9583-9594, 2017 Sep 19.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Type II restriction endonucleases (REases) form a large and highly diverse group of enzymes. Even REases specific for a common recognition site often vary in their oligomeric structure, domain organization and DNA cleavage mechanisms. Here we report biochemical and structural characterization of the monomeric restriction endonuclease UbaLAI, specific for the pseudosymmetric DNA sequence 5'-CC/WGG-3' (where W = A/T, and '/' marks the cleavage position). We present a 1.6 Å co-crystal structure of UbaLAI N-terminal domain (UbaLAI-N) and show that it resembles the B3-family domain of EcoRII specific for the 5'-CCWGG-3' sequence. We also find that UbaLAI C-terminal domain (UbaLAI-C) is closely related to the monomeric REase MvaI, another enzyme specific for the 5'-CCWGG-3' sequence. Kinetic studies of UbaLAI revealed that it requires two recognition sites for optimal activity, and, like other type IIE enzymes, uses one copy of a recognition site to stimulate cleavage of a second copy. We propose that during the reaction UbaLAI-N acts as a handle that tethers the monomeric UbaLAI-C domain to the DNA, thereby helping UbaLAI-C to perform two sequential DNA nicking reactions on the second recognition site during a single DNA-binding event. A similar reaction mechanism may be characteristic to other monomeric two-domain REases.
[Mh] Termos MeSH primário: Desoxirribonucleases de Sítio Específico do Tipo II/química
Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo
[Mh] Termos MeSH secundário: Cristalografia por Raios X
DNA/química
DNA/metabolismo
Clivagem do DNA
Desoxirribonucleases de Sítio Específico do Tipo II/genética
Modelos Moleculares
Domínios Proteicos
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9007-49-2 (DNA); EC 3.1.21.4 (Deoxyribonucleases, Type II Site-Specific)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx634


  8 / 1345 MEDLINE  
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[PMID]:28934480
[Au] Autor:Shaytan AK; Xiao H; Armeev GA; Wu C; Landsman D; Panchenko AR
[Ad] Endereço:National Center for Biotechnology Information, NLM, NIH, Bethesda, MD 20894, USA.
[Ti] Título:Hydroxyl-radical footprinting combined with molecular modeling identifies unique features of DNA conformation and nucleosome positioning.
[So] Source:Nucleic Acids Res;45(16):9229-9243, 2017 Sep 19.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Nucleosomes are the most abundant protein-DNA complexes in eukaryotes that provide compaction of genomic DNA and are implicated in regulation of transcription, DNA replication and repair. The details of DNA positioning on the nucleosome and the DNA conformation can provide key regulatory signals. Hydroxyl-radical footprinting (HRF) of protein-DNA complexes is a chemical technique that probes nucleosome organization in solution with a high precision unattainable by other methods. In this work we propose an integrative modeling method for constructing high-resolution atomistic models of nucleosomes based on HRF experiments. Our method precisely identifies DNA positioning on nucleosome by combining HRF data for both DNA strands with the pseudo-symmetry constraints. We performed high-resolution HRF for Saccharomyces cerevisiae centromeric nucleosome of unknown structure and characterized it using our integrative modeling approach. Our model provides the basis for further understanding the cooperative engagement and interplay between Cse4p protein and the A-tracts important for centromere function.
[Mh] Termos MeSH primário: Pegada de DNA/métodos
DNA/química
Modelos Moleculares
Nucleossomos/química
[Mh] Termos MeSH secundário: Algoritmos
Centrômero/química
Proteínas Cromossômicas não Histona
Clivagem do DNA
Proteínas de Ligação a DNA
Radical Hidroxila
Conformação de Ácido Nucleico
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CSE4 protein, S cerevisiae); 0 (Chromosomal Proteins, Non-Histone); 0 (DNA-Binding Proteins); 0 (Nucleosomes); 0 (Saccharomyces cerevisiae Proteins); 3352-57-6 (Hydroxyl Radical); 9007-49-2 (DNA)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx616


  9 / 1345 MEDLINE  
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[PMID]:28921956
[Au] Autor:Ashley RE; Blower TR; Berger JM; Osheroff N
[Ti] Título:Recognition of DNA Supercoil Geometry by Mycobacterium tuberculosis Gyrase.
[So] Source:Biochemistry;56(40):5440-5448, 2017 Oct 10.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mycobacterium tuberculosis encodes only a single type II topoisomerase, gyrase. As a result, this enzyme likely carries out the cellular functions normally performed by canonical gyrase and topoisomerase IV, both in front of and behind the replication fork. In addition, it is the sole target for quinolone antibacterials in this species. Because quinolone-induced DNA strand breaks generated on positively supercoiled DNA ahead of replication forks and transcription complexes are most likely to result in permanent genomic damage, the actions of M. tuberculosis gyrase on positively supercoiled DNA were investigated. Results indicate that the enzyme acts rapidly on overwound DNA and removes positive supercoils much faster than it introduces negative supercoils into relaxed DNA. Canonical gyrase and topoisomerase IV distinguish supercoil handedness differently during the DNA cleavage reaction: while gyrase maintains lower levels of cleavage complexes on overwound DNA, topoisomerase IV maintains similar levels of cleavage complexes on both over- and underwound substrates. M. tuberculosis gyrase maintained lower levels of cleavage complexes on positively supercoiled DNA in the absence and presence of quinolone-based drugs. By retaining this important feature of canonical gyrase, the dual function M. tuberculosis type II enzyme remains a safe enzyme to act in front of replication forks and transcription complexes. Finally, the N-terminal gate region of the enzyme appears to be necessary to distinguish supercoil handedness during DNA cleavage, suggesting that the capture of the transport segment may influence how gyrase maintains cleavage complexes on substrates with different topological states.
[Mh] Termos MeSH primário: DNA Girase/metabolismo
DNA Super-Helicoidal/química
DNA Super-Helicoidal/metabolismo
Mycobacterium tuberculosis/enzimologia
[Mh] Termos MeSH secundário: Clivagem do DNA
DNA Girase/química
Ligação Proteica
Domínios Proteicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Superhelical); EC 5.99.1.3 (DNA Gyrase)
[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:170919
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00681


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[PMID]:28919339
[Au] Autor:Minniti E; Byl JAW; Riccardi L; Sissi C; Rosini M; De Vivo M; Minarini A; Osheroff N
[Ad] Endereço:Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy; Laboratory of Molecular Modeling and Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy.
[Ti] Título:Novel xanthone-polyamine conjugates as catalytic inhibitors of human topoisomerase IIα.
[So] Source:Bioorg Med Chem Lett;27(20):4687-4693, 2017 10 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:It has been proposed that xanthone derivatives with anticancer potential act as topoisomerase II inhibitors because they interfere with the ability of the enzyme to bind its ATP cofactor. In order to further characterize xanthone mechanism and generate compounds with potential as anticancer drugs, we synthesized a series of derivatives in which position 3 was substituted with different polyamine chains. As determined by DNA relaxation and decatenation assays, the resulting compounds are potent topoisomerase IIα inhibitors. Although xanthone derivatives inhibit topoisomerase IIα-catalyzed ATP hydrolysis, mechanistic studies indicate that they do not act at the ATPase site. Rather, they appear to function by blocking the ability of DNA to stimulate ATP hydrolysis. On the basis of activity, competition, and modeling studies, we propose that xanthones interact with the DNA cleavage/ligation active site of topoisomerase IIα and inhibit the catalytic activity of the enzyme by interfering with the DNA strand passage step.
[Mh] Termos MeSH primário: Proteínas de Ligação a DNA/antagonistas & inibidores
Poliaminas/farmacologia
Inibidores da Topoisomerase II/química
Inibidores da Topoisomerase II/farmacologia
Xantonas/farmacologia
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Antígenos de Neoplasias/metabolismo
Antineoplásicos/síntese química
Antineoplásicos/química
Antineoplásicos/farmacologia
Sítios de Ligação
Catálise
Domínio Catalítico
DNA/metabolismo
Clivagem do DNA/efeitos dos fármacos
DNA Topoisomerases Tipo II/metabolismo
Proteínas de Ligação a DNA/metabolismo
Seres Humanos
Simulação de Acoplamento Molecular
Conformação de Ácido Nucleico
Poliaminas/química
Inibidores da Topoisomerase II/síntese química
Xantonas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antigens, Neoplasm); 0 (Antineoplastic Agents); 0 (DNA-Binding Proteins); 0 (Polyamines); 0 (Topoisomerase II Inhibitors); 0 (Xanthones); 8L70Q75FXE (Adenosine Triphosphate); 9007-49-2 (DNA); 9749WEV0CA (xanthone); EC 5.99.1.3 (DNA Topoisomerases, Type II)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170919
[St] Status:MEDLINE



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