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Pesquisa : D03.633.100.079.080.070.050 [Categoria DeCS]
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  1 / 97 MEDLINE  
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[PMID]:28941814
[Au] Autor:Basher MA; Rahman KM; Jackson PJM; Thurston DE; Fox KR
[Ad] Endereço:Biological Sciences, Life Sciences Building 85, University of Southampton, Southampton SO17 1BJ, UK.
[Ti] Título:Sequence-selective binding of C8-conjugated pyrrolobenzodiazepines (PBDs) to DNA.
[So] Source:Biophys Chem;230:53-61, 2017 Nov.
[Is] ISSN:1873-4200
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:DNA footprinting and melting experiments have been used to examine the sequence-specific binding of C8-conjugates of pyrrolobenzodiazepines (PBDs) and benzofused rings including benzothiophene and benzofuran, which are attached using pyrrole- or imidazole-containing linkers. The conjugates modulate the covalent attachment points of the PBDs, so that they bind best to guanines flanked by A/T-rich sequences on either the 5'- or 3'-side. The linker affects the binding, and pyrrole produces larger changes than imidazole. Melting studies with 14-mer oligonucleotide duplexes confirm covalent attachment of the conjugates, which show a different selectivity to anthramycin and reveal that more than one ligand molecule can bind to each duplex.
[Mh] Termos MeSH primário: Benzodiazepinas/química
DNA/química
Pirróis/química
[Mh] Termos MeSH secundário: Antramicina/química
Antramicina/metabolismo
Sequência de Bases
Benzodiazepinas/metabolismo
Sítios de Ligação
DNA/metabolismo
Pegada de DNA
Desoxirribonuclease I/metabolismo
Guanina/química
Simulação de Dinâmica Molecular
Conformação de Ácido Nucleico
Desnaturação de Ácido Nucleico
Oligonucleotídeos/química
Oligonucleotídeos/metabolismo
Pirróis/metabolismo
Espectrometria de Fluorescência
Temperatura Ambiente
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Oligonucleotides); 0 (Pyrroles); 0 (pyrrolo(2,1-c)(1,4)benzodiazepine); 0WZD9Y66WN (Anthramycin); 12794-10-4 (Benzodiazepines); 5Z93L87A1R (Guanine); 9007-49-2 (DNA); EC 3.1.21.1 (Deoxyribonuclease I)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170925
[St] Status:MEDLINE


  2 / 97 MEDLINE  
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[PMID]:27055050
[Au] Autor:Mantaj J; Jackson PJ; Karu K; Rahman KM; Thurston DE
[Ad] Endereço:Institute of Pharmaceutical Science, King's College London, 7 Trinity Street, London, SE1 1DB, United Kingdom.
[Ti] Título:Covalent Bonding of Pyrrolobenzodiazepines (PBDs) to Terminal Guanine Residues within Duplex and Hairpin DNA Fragments.
[So] Source:PLoS One;11(4):e0152303, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pyrrolobenzodiazepines (PBDs) are covalent-binding DNA-interactive agents with growing importance as payloads in Antibody Drug Conjugates (ADCs). Until now, PBDs were thought to covalently bond to C2-NH2 groups of guanines in the DNA-minor groove across a three-base-pair recognition sequence. Using HPLC/MS methodology with designed hairpin and duplex oligonucleotides, we have now demonstrated that the PBD Dimer SJG-136 and the C8-conjugated PBD Monomer GWL-78 can covalently bond to a terminal guanine of DNA, with the PBD skeleton spanning only two base pairs. Control experiments with the non-C8-conjugated anthramycin along with molecular dynamics simulations suggest that the C8-substituent of a PBD Monomer, or one-half of a PBD Dimer, may provide stability for the adduct. This observation highlights the importance of PBD C8-substituents, and also suggests that PBDs may bind to terminal guanines within stretches of DNA in cells, thus representing a potentially novel mechanism of action at the end of DNA strand breaks.
[Mh] Termos MeSH primário: Benzodiazepinas/química
Quebras de DNA
DNA/química
Guanina/química
Simulação de Dinâmica Molecular
Conformação de Ácido Nucleico
Pirróis/química
[Mh] Termos MeSH secundário: Antramicina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Pyrroles); 0 (pyrrolo(2,1-c)(1,4)benzodiazepine); 0WZD9Y66WN (Anthramycin); 12794-10-4 (Benzodiazepines); 5Z93L87A1R (Guanine); 9007-49-2 (DNA)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160408
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0152303


  3 / 97 MEDLINE  
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[PMID]:25564379
[Au] Autor:Saha S; Li W; Gerratana B; Rokita SE
[Ad] Endereço:Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA. Electronic address: ssaha1@umd.edu.
[Ti] Título:Identification of the dioxygenase-generated intermediate formed during biosynthesis of the dihydropyrrole moiety common to anthramycin and sibiromycin.
[So] Source:Bioorg Med Chem;23(3):449-54, 2015 Feb 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A description of pyrrolo[1,4]benzodiazepine (PBD) biosynthesis is a prerequisite for engineering production of analogs with enhanced antitumor activity. Predicted dioxygenases Orf12 and SibV associated with dihydropyrrole biosynthesis in PBDs anthramycin and sibiromycin, respectively, were expressed and purified for activity studies. UV-visible spectroscopy revealed that these enzymes catalyze the regiospecific 2,3-extradiol dioxygenation of l-3,4-dihydroxyphenylalanine (l-DOPA) to form l-2,3-secodopa (λmax=368 nm). (1)H NMR spectroscopy indicates that l-2,3-secodopa cyclizes into the α-keto acid tautomer of l-4-(2-oxo-3-butenoic-acid)-4,5-dihydropyrrole-2-carboxylic acid (λmax=414 nm). Thus, the dioxygenases are key for establishing the scaffold of the dihydropyrrole moiety. Kinetic studies suggest the dioxygenase product is relatively labile and is likely consumed rapidly by subsequent biosynthetic steps. The enzymatic product and dimeric state of these dioxygenases are conserved in dioxygenases involved in dihydropyrrole and pyrrolidine biosynthesis within both PBD and non-PBD pathways.
[Mh] Termos MeSH primário: Aminoglicosídeos/química
Antramicina/química
Dioxigenases/química
Pirróis/metabolismo
[Mh] Termos MeSH secundário: Aminoglicosídeos/metabolismo
Antramicina/metabolismo
Dioxigenases/metabolismo
Espectroscopia de Ressonância Magnética
Estrutura Molecular
Pirróis/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Aminoglycosides); 0 (Pyrroles); 0WZD9Y66WN (Anthramycin); 12684-33-2 (sibiromycin); 28350-87-0 (pyrroline); EC 1.13.11.- (Dioxygenases)
[Em] Mês de entrada:1510
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150108
[St] Status:MEDLINE


  4 / 97 MEDLINE  
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[PMID]:25128200
[Au] Autor:Najmanova L; Ulanova D; Jelinkova M; Kamenik Z; Kettnerova E; Koberska M; Gazak R; Radojevic B; Janata J
[Ad] Endereço:Institute of Microbiology AS CR, Videnska 1083, 142 20, Prague 4, Czech Republic, lucie.najmanova@biomed.cas.cz.
[Ti] Título:Sequence analysis of porothramycin biosynthetic gene cluster.
[So] Source:Folia Microbiol (Praha);59(6):543-52, 2014 Nov.
[Is] ISSN:1874-9356
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The biosynthetic gene cluster of porothramycin, a sequence-selective DNA alkylating compound, was identified in the genome of producing strain Streptomyces albus subsp. albus (ATCC 39897) and sequentially characterized. A 39.7 kb long DNA region contains 27 putative genes, 18 of them revealing high similarity with homologous genes from biosynthetic gene cluster of closely related pyrrolobenzodiazepine (PBD) compound anthramycin. However, considering the structures of both compounds, the number of differences in the gene composition of compared biosynthetic gene clusters was unexpectedly high, indicating participation of alternative enzymes in biosynthesis of both porothramycin precursors, anthranilate, and branched L-proline derivative. Based on the sequence analysis of putative NRPS modules Por20 and Por21, we suppose that in porothramycin biosynthesis, the methylation of anthranilate unit occurs prior to the condensation reaction, while modifications of branched proline derivative, oxidation, and dimethylation of the side chain occur on already condensed PBD core. Corresponding two specific methyltransferase encoding genes por26 and por25 were identified in the porothramycin gene cluster. Surprisingly, also methyltransferase gene por18 homologous to orf19 from anthramycin biosynthesis was detected in porothramycin gene cluster even though the appropriate biosynthetic step is missing, as suggested by ultra high-performance liquid chromatography-diode array detection-mass spectrometry (UHPLC-DAD-MS) analysis of the product in the S. albus culture broth.
[Mh] Termos MeSH primário: Antramicina/análogos & derivados
Proteínas de Bactérias/genética
Família Multigênica
Streptomyces/genética
Streptomyces/metabolismo
[Mh] Termos MeSH secundário: Antramicina/biossíntese
Antramicina/química
Proteínas de Bactérias/metabolismo
Dados de Sequência Molecular
Estrutura Molecular
Análise de Sequência
Streptomyces/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0WZD9Y66WN (Anthramycin); 110652-73-8 (porothramycin A)
[Em] Mês de entrada:1506
[Cu] Atualização por classe:150804
[Lr] Data última revisão:
150804
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140817
[St] Status:MEDLINE
[do] DOI:10.1007/s12223-014-0339-x


  5 / 97 MEDLINE  
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[PMID]:24116648
[Au] Autor:Zheng W; Vargiu AV; Vargiu AV; Rohrdanz MA; Carloni P; Clementi C
[Ad] Endereço:Department of Chemistry, Rice University, Houston, Texas 77005, USA.
[Ti] Título:Molecular recognition of DNA by ligands: roughness and complexity of the free energy profile.
[So] Source:J Chem Phys;139(14):145102, 2013 Oct 14.
[Is] ISSN:1089-7690
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Understanding the molecular mechanism by which probes and chemotherapeutic agents bind to nucleic acids is a fundamental issue in modern drug design. From a computational perspective, valuable insights are gained by the estimation of free energy landscapes as a function of some collective variables (CVs), which are associated with the molecular recognition event. Unfortunately the choice of CVs is highly non-trivial because of DNA's high flexibility and the presence of multiple association-dissociation events at different locations and/or sliding within the grooves. Here we have applied a modified version of Locally-Scaled Diffusion Map (LSDMap), a nonlinear dimensionality reduction technique for decoupling multiple-timescale dynamics in macromolecular systems, to a metadynamics-based free energy landscape calculated using a set of intuitive CVs. We investigated the binding of the organic drug anthramycin to a DNA 14-mer duplex. By performing an extensive set of metadynamics simulations, we observed sliding of anthramycin along the full-length DNA minor groove, as well as several detachments from multiple sites, including the one identified by X-ray crystallography. As in the case of equilibrium processes, the LSDMap analysis is able to extract the most relevant collective motions, which are associated with the slow processes within the system, i.e., ligand diffusion along the minor groove and dissociation from it. Thus, LSDMap in combination with metadynamics (and possibly every equivalent method) emerges as a powerful method to describe the energetics of ligand binding to DNA without resorting to intuitive ad hoc reaction coordinates.
[Mh] Termos MeSH primário: Antramicina/química
DNA/química
Simulação de Dinâmica Molecular
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Ligantes
Modelos Moleculares
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Ligands); 0WZD9Y66WN (Anthramycin); 9007-49-2 (DNA)
[Em] Mês de entrada:1405
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131015
[St] Status:MEDLINE
[do] DOI:10.1063/1.4824106


  6 / 97 MEDLINE  
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[PMID]:20544978
[Au] Autor:Gerratana B
[Ad] Endereço:Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, USA. bgerrata@umd.edu
[Ti] Título:Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines.
[So] Source:Med Res Rev;32(2):254-93, 2012 Mar.
[Is] ISSN:1098-1128
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pyrrolobenzodiazepines (PBDs) are sequence selective DNA alkylating agents with remarkable antineoplastic activity. They are either naturally produced by actinomycetes or synthetically produced. The remarkable broad spectrum of activities of the naturally produced PBDs encouraged the synthesis of several PBDs, including dimeric and hybrid PBDs yielding to an improvement in the DNA-binding sequence specificity and in the potency of this class of compounds. However, limitation in the chemical synthesis prevented the testing of one of the most potent PBDs, sibiromycin, a naturally produced glycosylated PBDs. Only recently, the biosynthetic gene clusters for PBDs have been identified opening the doors to the production of glycosylated PBDs by mutasynthesis and biosynthetic engineering. This review describes the recent studies on the biosynthesis of naturally produced pyrrolobenzodiazepines. In addition, it provides an overview on the isolation and characterization of naturally produced PBDs, chemical synthesis of PBDs, mechanism of DNA alkylation, and DNA-binding affinity and cytotoxic properties of both naturally produced and synthetic pyrrolobenzodiazepines.
[Mh] Termos MeSH primário: Actinobacteria/metabolismo
Antineoplásicos Alquilantes/metabolismo
Benzodiazepinas/síntese química
Benzodiazepinas/farmacologia
DNA/metabolismo
Pirróis/síntese química
Pirróis/farmacologia
[Mh] Termos MeSH secundário: Actinobacteria/genética
Aminoglicosídeos/biossíntese
Antramicina/biossíntese
Antineoplásicos Alquilantes/síntese química
Antineoplásicos Alquilantes/farmacologia
Benzodiazepinas/metabolismo
Modelos Moleculares
Família Multigênica
Pirróis/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Aminoglycosides); 0 (Antineoplastic Agents, Alkylating); 0 (Pyrroles); 0 (pyrrolo(2,1-c)(1,4)benzodiazepine); 0WZD9Y66WN (Anthramycin); 12684-33-2 (sibiromycin); 12794-10-4 (Benzodiazepines); 9007-49-2 (DNA)
[Em] Mês de entrada:1206
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:100615
[St] Status:MEDLINE
[do] DOI:10.1002/med.20212


  7 / 97 MEDLINE  
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[PMID]:22001031
[Au] Autor:Sato S; Iwata F; Yamada S; Kawahara H; Katayama M
[Ad] Endereço:Central Research Laboratory, Tokyo Innovation Center, Nippon Suisan Kaisha, Ltd, Hachioji, Tokyo, Japan. s-satou@nissui.co.jp
[Ti] Título:Usabamycins A-C: new anthramycin-type analogues from a marine-derived actinomycete.
[So] Source:Bioorg Med Chem Lett;21(23):7099-101, 2011 Dec 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:New anthramycin-type analogues, designated usabamycin A-C (1, 2 and 3), have been isolated from cultures of Streptomyces sp. NPS853, a bacterium found in marine sediments. The structures of the new compounds were established on the basis of extensive spectroscopic analyses including 1D- and 2D-NMR ((1)H-(1)H COSY, HSQC, and HMBC) experiments. The usabamycins show weak inhibition of HeLa cell growth and selective inhibition of serotonin (5-hydroxytrypamine) 5-HT(2B) uptake.
[Mh] Termos MeSH primário: Actinobacteria/química
Antramicina/análogos & derivados
Antramicina/química
[Mh] Termos MeSH secundário: Antramicina/farmacologia
Antineoplásicos/síntese química
Antineoplásicos/química
Antineoplásicos/farmacologia
Proliferação Celular/efeitos dos fármacos
Células HeLa
Seres Humanos
Concentração Inibidora 50
Espectroscopia de Ressonância Magnética
Estrutura Molecular
Antagonistas da Serotonina/síntese química
Antagonistas da Serotonina/química
Antagonistas da Serotonina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Serotonin Antagonists); 0 (usabamycin A); 0 (usabamycin B); 0 (usabamycin C); 0WZD9Y66WN (Anthramycin)
[Em] Mês de entrada:1204
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:111018
[St] Status:MEDLINE
[do] DOI:10.1016/j.bmcl.2011.09.086


  8 / 97 MEDLINE  
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[PMID]:21919439
[Au] Autor:Connor KL; Colabroy KL; Gerratana B
[Ad] Endereço:Department of Chemistry and Biochemistry, University of Maryland, Maryland 20742, USA.
[Ti] Título:A heme peroxidase with a functional role as an L-tyrosine hydroxylase in the biosynthesis of anthramycin.
[So] Source:Biochemistry;50(41):8926-36, 2011 Oct 18.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We report the first characterization and classification of Orf13 (S. refuineus) as a heme-dependent peroxidase catalyzing the ortho-hydroxylation of L-tyrosine to L-DOPA. The putative tyrosine hydroxylase coded by orf13 of the anthramycin biosynthesis gene cluster has been expressed and purified. Heme b has been identified as the required cofactor for catalysis, and maximal L-tyrosine conversion to L-DOPA is observed in the presence of hydrogen peroxide. Preincubation of L-tyrosine with Orf13 prior to the addition of hydrogen peroxide is required for L-DOPA production. However, the enzyme becomes inactivated by hydrogen peroxide during catalysis. Steady-state kinetic analysis of L-tyrosine hydroxylation revealed similar catalytic efficiency for both L-tyrosine and hydrogen peroxide. Spectroscopic data from a reduced-CO(g) UV-vis spectrum of Orf13 and electron paramagnetic resonance of ferric heme Orf13 are consistent with heme peroxidases that have a histidyl-ligated heme iron. Contrary to the classical heme peroxidase oxidation reaction with hydrogen peroxide that produces coupled aromatic products such as o,o'-dityrosine, Orf13 is novel in its ability to catalyze aromatic amino acid hydroxylation with hydrogen peroxide, in the substrate addition order and for its substrate specificity for L-tyrosine. Peroxygenase activity of Orf13 for the ortho-hydroxylation of L-tyrosine to L-DOPA by a molecular oxygen dependent pathway in the presence of dihydroxyfumaric acid is also observed. This reaction behavior is consistent with peroxygenase activity reported with horseradish peroxidase for the hydroxylation of phenol. Overall, the putative function of Orf13 as a tyrosine hydroxylase has been confirmed and establishes the first bacterial class of tyrosine hydroxylases.
[Mh] Termos MeSH primário: Antramicina/química
Heme/química
Peroxidases/química
Streptomyces/enzimologia
Tirosina 3-Mono-Oxigenase/química
[Mh] Termos MeSH secundário: Clonagem Molecular
Espectroscopia de Ressonância de Spin Eletrônica/métodos
Escherichia coli/metabolismo
Peróxido de Hidrogênio/química
Cinética
Levodopa/química
Modelos Químicos
Oxigênio/química
Espectrofotometria Ultravioleta/métodos
Tirosina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0WZD9Y66WN (Anthramycin); 42HK56048U (Tyrosine); 42VZT0U6YR (Heme); 46627O600J (Levodopa); BBX060AN9V (Hydrogen Peroxide); EC 1.11.1.- (Peroxidases); EC 1.14.16.2 (Tyrosine 3-Monooxygenase); S88TT14065 (Oxygen)
[Em] Mês de entrada:1112
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110928
[St] Status:MEDLINE
[do] DOI:10.1021/bi201148a


  9 / 97 MEDLINE  
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[PMID]:20527899
[Au] Autor:Michels TD; Kier MJ; Kearney AM; Vanderwal CD
[Ad] Endereço:Department of Chemistry, The University of California, Irvine, California 92697-2025, USA.
[Ti] Título:Concise formal synthesis of porothramycins A and B via Zincke pyridinium ring-opening/ring-closing cascade.
[So] Source:Org Lett;12(13):3093-5, 2010 Jul 02.
[Is] ISSN:1523-7052
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Short formal syntheses of the antitumor antibiotics porothramycins A and B from a commercially available ester of the unnatural amino acid 3-(3-pyridyl)alanine are presented. A rearrangement cascade that presumably involves a Zincke-type pyridinium ring-opening followed by cyclization of a pendant nucleophilic amide generates the salient pyrroline ring of the alkaloids.
[Mh] Termos MeSH primário: Antramicina/análogos & derivados
Compostos de Piridínio/química
[Mh] Termos MeSH secundário: Antramicina/síntese química
Antramicina/química
Ciclização
Conformação Molecular
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Pyridinium Compounds); 0WZD9Y66WN (Anthramycin); 110652-72-7 (porothramycin B); 110652-73-8 (porothramycin A)
[Em] Mês de entrada:1009
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:100610
[St] Status:MEDLINE
[do] DOI:10.1021/ol101035p


  10 / 97 MEDLINE  
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[PMID]:19477411
[Au] Autor:Phelan VV; Du Y; McLean JA; Bachmann BO
[Ad] Endereço:Department of Chemistry, Vanderbilt University, Nashville, TN 37204, USA.
[Ti] Título:Adenylation enzyme characterization using gamma -(18)O(4)-ATP pyrophosphate exchange.
[So] Source:Chem Biol;16(5):473-8, 2009 May 29.
[Is] ISSN:1879-1301
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We present here a rapid, highly sensitive nonradioactive assay for adenylation enzyme selectivity determination and characterization. This method measures the isotopic back exchange of unlabeled pyrophosphate into gamma-(18)O(4)-labeled ATP via matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MS), electrospray ionization liquid chromatography MS, or electrospray ionization liquid chromatography-tandem MS and is demonstrated for both nonribosomal (TycA, ValA) and ribosomal synthetases (TrpRS, LysRS) of known specificity. This low-volume (6 microl) method detects as little as 0.01% (600 fmol) exchange, comparable in sensitivity to previously reported radioactive assays and readily adaptable to kinetics measurements and high throughput analysis of a wide spectrum of synthetases. Finally, a previously uncharacterized A-T didomain from anthramycin biosynthesis in the thermophile S. refuinius was demonstrated to selectively activate 4-methyl-3-hydroxyanthranilic acid at 47 degrees C, providing biochemical evidence for a new aromatic beta-amino acid activating adenylation domain and the first functional analysis of the anthramycin biosynthetic gene cluster.
[Mh] Termos MeSH primário: Trifosfato de Adenosina/química
Aminoacil-tRNA Sintetases/metabolismo
Difosfatos/química
Peptídeo Sintases/metabolismo
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/síntese química
Aminoacil-tRNA Sintetases/química
Antramicina/biossíntese
Antramicina/química
Biocatálise
Cromatografia Líquida de Alta Pressão
Cinética
Família Multigênica
Radioisótopos de Oxigênio
Peptídeo Sintases/química
Espectrometria de Massas por Ionização por Electrospray
Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
ortoaminobenzoatos/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 (Diphosphates); 0 (Oxygen Radioisotopes); 0 (ortho-Aminobenzoates); 0WZD9Y66WN (Anthramycin); 552-14-7 (4-methyl-3-hydroxyanthranilic acid); 8L70Q75FXE (Adenosine Triphosphate); EC 6.1.1.- (Amino Acyl-tRNA Synthetases); EC 6.3.2.- (Peptide Synthases); EC 6.3.2.- (non-ribosomal peptide synthase)
[Em] Mês de entrada:0908
[Cu] Atualização por classe:161122
[Lr] Data última revisão:
161122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:090530
[St] Status:MEDLINE
[do] DOI:10.1016/j.chembiol.2009.04.007



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