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[PMID]:29216817
[Au] Autor:Nivala O; Faccio G; Arvas M; Permi P; Buchert J; Kruus K; Mattinen ML
[Ad] Endereço:VTT Technical Research Centre of Finland, Ltd., P.O. Box 1000, FI-02044, Espoo, Finland. outi.nivala@helsinki.fi.
[Ti] Título:Characterization of sulfhydryl oxidase from Aspergillus tubingensis.
[So] Source:BMC Biochem;18(1):15, 2017 12 08.
[Is] ISSN:1471-2091
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Despite of the presence of sulfhydryl oxidases (SOXs) in the secretomes of industrially relevant organisms and their many potential applications, only few of these enzymes have been biochemically characterized. In addition, basic functions of most of the SOX enzymes reported so far are not fully understood. In particular, the physiological role of secreted fungal SOXs is unclear. RESULTS: The recently identified SOX from Aspergillus tubingensis (AtSOX) was produced, purified and characterized in the present work. AtSOX had a pH optimum of 6.5, and showed a good pH stability retaining more than 80% of the initial activity in a pH range 4-8.5 within 20 h. More than 70% of the initial activity was retained after incubation at 50 °C for 20 h. AtSOX contains a non-covalently bound flavin cofactor. The enzyme oxidised a sulfhydryl group of glutathione to form a disulfide bond, as verified by nuclear magnetic resonance spectroscopy. AtSOX preferred glutathione as a substrate over cysteine and dithiothreitol. The activity of the enzyme was totally inhibited by 10 mM zinc sulphate. Peptide- and protein-bound sulfhydryl groups in bikunin, gliotoxin, holomycin, insulin B chain, and ribonuclease A, were not oxidised by the enzyme. Based on the analysis of 33 fungal genomes, SOX enzyme encoding genes were found close to nonribosomal peptide synthetases (NRPS) but not with polyketide synthases (PKS). In the phylogenetic tree, constructed from 25 SOX and thioredoxin reductase sequences from IPR000103 InterPro family, AtSOX was evolutionary closely related to other Aspergillus SOXs. Oxidoreductases involved in the maturation of nonribosomal peptides of fungal and bacterial origin, namely GliT, HlmI and DepH, were also evolutionary closely related to AtSOX whereas fungal thioreductases were more distant. CONCLUSIONS: AtSOX (55 kDa) is a fungal secreted flavin-dependent enzyme with good stability to both pH and temperature. A Michaelis-Menten behaviour was observed with reduced glutathione as a substrate. Based on the location of SOX enzyme encoding genes close to NRPSs, SOXs could be involved in the secondary metabolism and act as an accessory enzyme in the production of nonribosomal peptides.
[Mh] Termos MeSH primário: Aspergillus/enzimologia
Oxirredutases/metabolismo
[Mh] Termos MeSH secundário: Dissulfetos
Estabilidade Enzimática
Glutationa/metabolismo
Concentração de Íons de Hidrogênio
Oxirredutases/química
Oxirredutases/genética
Oxirredutases/isolamento & purificação
Peptídeo Sintases
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Disulfides); EC 1.- (Oxidoreductases); EC 1.8.3.- (sulfhydryl oxidase); EC 6.3.2.- (Peptide Synthases); EC 6.3.2.- (non-ribosomal peptide synthase); GAN16C9B8O (Glutathione)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE
[do] DOI:10.1186/s12858-017-0090-4


  2 / 3210 MEDLINE  
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[PMID]:27775185
[Au] Autor:Oakley CE; Ahuja M; Sun WW; Entwistle R; Akashi T; Yaegashi J; Guo CJ; Cerqueira GC; Russo Wortman J; Wang CC; Chiang YM; Oakley BR
[Ad] Endereço:Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, Kansas, 66045, USA.
[Ti] Título:Discovery of McrA, a master regulator of Aspergillus secondary metabolism.
[So] Source:Mol Microbiol;103(2):347-365, 2017 Jan.
[Is] ISSN:1365-2958
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Fungal secondary metabolites (SMs) are extremely important in medicine and agriculture, but regulation of their biosynthesis is incompletely understood. We have developed a genetic screen in Aspergillus nidulans for negative regulators of fungal SM gene clusters and we have used this screen to isolate mutations that upregulate transcription of the non-ribosomal peptide synthetase gene required for nidulanin A biosynthesis. Several of these mutations are allelic and we have identified the mutant gene by genome sequencing. The gene, which we designate mcrA, is conserved but uncharacterized, and it encodes a putative transcription factor. Metabolite profiles of mcrA deletant, mcrA overexpressing, and parental strains reveal that mcrA regulates at least ten SM gene clusters. Deletion of mcrA stimulates SM production even in strains carrying a deletion of the SM regulator laeA, and deletion of mcrA homologs in Aspergillus terreus and Penicillum canescens alters the secondary metabolite profile of these organisms. Deleting mcrA in a genetic dereplication strain has allowed us to discover two novel compounds as well as an antibiotic not known to be produced by A. nidulans. Deletion of mcrA upregulates transcription of hundreds of genes including many that are involved in secondary metabolism, while downregulating a smaller number of genes.
[Mh] Termos MeSH primário: Aspergillus nidulans/genética
Aspergillus nidulans/metabolismo
Peptídeo Sintases/genética
Peptídeo Sintases/metabolismo
[Mh] Termos MeSH secundário: Proteínas Fúngicas/genética
Proteínas Fúngicas/metabolismo
Regulação Fúngica da Expressão Gênica
Genes Fúngicos
Família Multigênica
Mutação
Metabolismo Secundário
Deleção de Sequência
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
Ativação Transcricional
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fungal Proteins); 0 (Transcription Factors); EC 6.3.2.- (Peptide Synthases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE
[do] DOI:10.1111/mmi.13562


  3 / 3210 MEDLINE  
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[PMID]:28455448
[Au] Autor:Goodrich AC; Meyers DJ; Frueh DP
[Ad] Endereço:From the Department of Biophysics and Biophysical Chemistry and.
[Ti] Título:Molecular impact of covalent modifications on nonribosomal peptide synthetase carrier protein communication.
[So] Source:J Biol Chem;292(24):10002-10013, 2017 06 16.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nonribosomal peptide synthesis involves the interplay between covalent protein modifications, conformational fluctuations, catalysis, and transient protein-protein interactions. Delineating the mechanisms involved in orchestrating these various processes will deepen our understanding of domain-domain communication in nonribosomal peptide synthetases (NRPSs) and lay the groundwork for the rational reengineering of NRPSs by swapping domains handling different substrates to generate novel natural products. Although many structural and biochemical studies of NRPSs exist, few studies have focused on the energetics and dynamics governing the interactions in these systems. Here, we present detailed binding studies of an adenylation domain and its partner carrier protein in apo-, holo-, and substrate-loaded forms. Results from fluorescence anisotropy, isothermal titration calorimetry, and NMR titrations indicated that covalent modifications to a carrier protein modulate domain communication, suggesting that chemical modifications to carrier proteins during NRPS synthesis may impart directionality to sequential NRPS domain interactions. Comparison of the structure and dynamics of an apo-aryl carrier protein with those of its modified forms revealed structural fluctuations induced by post-translational modifications and mediated by modulations of protein dynamics. The results provide a comprehensive molecular description of a carrier protein throughout its life cycle and demonstrate how a network of dynamic residues can propagate the molecular impact of chemical modifications throughout a protein and influence its affinity toward partner domains.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Proteínas de Transporte/metabolismo
Coenzima A Ligases/metabolismo
Modelos Moleculares
Peptídeo Sintases/metabolismo
Modificação Traducional de Proteínas
Processamento de Proteína Pós-Traducional
Yersinia pestis/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Apoenzimas/química
Apoenzimas/genética
Apoenzimas/metabolismo
Apoproteínas/química
Apoproteínas/genética
Apoproteínas/metabolismo
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Calorimetria
Isótopos de Carbono
Proteínas de Transporte/química
Proteínas de Transporte/genética
Coenzima A Ligases/química
Coenzima A Ligases/genética
Polarização de Fluorescência
Holoenzimas/química
Holoenzimas/genética
Holoenzimas/metabolismo
Cinética
Mutação
Isótopos de Nitrogênio
Ressonância Magnética Nuclear Biomolecular
Peptídeo Sintases/química
Peptídeo Sintases/genética
Conformação Proteica
Domínios e Motivos de Interação entre Proteínas
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Titulometria
Yersinia pestis/enzimologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Apoenzymes); 0 (Apoproteins); 0 (Bacterial Proteins); 0 (Carbon Isotopes); 0 (Carrier Proteins); 0 (Holoenzymes); 0 (Nitrogen Isotopes); 0 (Recombinant Proteins); EC 6.2.1.- (Coenzyme A Ligases); EC 6.2.1.- (YbtE protein, Yersinia pestis); EC 6.3.2.- (Peptide Synthases); EC 6.3.2.- (non-ribosomal peptide synthase)
[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:170430
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.766220


  4 / 3210 MEDLINE  
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[PMID]:28920687
[Au] Autor:Jaremko MJ; Lee DJ; Patel A; Winslow V; Opella SJ; McCammon JA; Burkart MD
[Ad] Endereço:Department of Chemistry and Biochemistry, University of California, San Diego , 9500 Gilman Drive, La Jolla, California 92093-0358, United States.
[Ti] Título:Manipulating Protein-Protein Interactions in Nonribosomal Peptide Synthetase Type II Peptidyl Carrier Proteins.
[So] Source:Biochemistry;56(40):5269-5273, 2017 Oct 10.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In an effort to elucidate and engineer interactions in type II nonribosomal peptide synthetases, we analyzed biomolecular recognition between the essential peptidyl carrier proteins and adenylation domains using nuclear magnetic resonance (NMR) spectroscopy, molecular dynamics, and mutational studies. Three peptidyl carrier proteins, PigG, PltL, and RedO, in addition to their cognate adenylation domains, PigI, PltF, and RedM, were investigated for their cross-species activity. Of the three peptidyl carrier proteins, only PigG showed substantial cross-pathway activity. Characterization of the novel NMR solution structure of holo-PigG and molecular dynamics simulations of holo-PltL and holo-PigG revealed differences in structures and dynamics of these carrier proteins. NMR titration experiments revealed perturbations of the chemical shifts of the loop 1 residues of these peptidyl carrier proteins upon their interaction with the adenylation domain. These experiments revealed a key region for the protein-protein interaction. Mutational studies supported the role of loop 1 in molecular recognition, as mutations to this region of the peptidyl carrier proteins significantly modulated their activities.
[Mh] Termos MeSH primário: Peptídeo Sintases/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Simulação de Dinâmica Molecular
Peptídeo Sintases/química
Ligação Proteica
Conformação Proteica em alfa-Hélice
Domínios Proteicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 6.3.2.- (Peptide Synthases); EC 6.3.2.- (non-ribosomal peptide synthase)
[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.7b00884


  5 / 3210 MEDLINE  
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[PMID]:28890318
[Au] Autor:von Tesmar A; Hoffmann M; Pippel J; Fayad AA; Dausend-Werner S; Bauer A; Blankenfeldt W; Müller R
[Ad] Endereço:Department of Microbial Natural Products (MINS), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI) and Institute for Pharmaceutical Biotechnology, Saarland University, 66123 Saarbrücken, Germany; German Center for Infection Research (DZIF
[Ti] Título:Total Biosynthesis of the Pyrrolo[4,2]benzodiazepine Scaffold Tomaymycin on an In Vitro Reconstituted NRPS System.
[So] Source:Cell Chem Biol;24(10):1216-1227.e8, 2017 Oct 19.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In vitro reconstitution and biochemical analysis of natural product biosynthetic pathways remains a challenging endeavor, especially if megaenzymes of the nonribosomal peptide synthetase (NRPS) type are involved. In theory, all biosynthetic steps may be deciphered using mass spectrometry (MS)-based analyses of both the carrier protein-coupled intermediates and the free intermediates. We here report the "total biosynthesis" of the pyrrolo[4,2]benzodiazepine scaffold tomaymycin using an in vitro reconstituted NRPS system. Proteoforms were analyzed by liquid chromatography (LC)-MS to decipher every step of the biosynthesis on its respective megasynthetase with up to 170 kDa in size. To the best of our knowledge, this is the first report of a comprehensive analysis of virtually all chemical steps involved in the biosynthesis of nonribosomally synthesized natural products. The study includes experiments to determine substrate specificities of the corresponding A-domains in competition assays by analyzing the adenylation step as well as the transfer to the respective carrier protein domain.
[Mh] Termos MeSH primário: Benzodiazepinas/química
Peptídeo Sintases/metabolismo
Pirróis/química
[Mh] Termos MeSH secundário: Benzodiazepinonas/química
Benzodiazepinonas/metabolismo
Modelos Moleculares
Peptídeo Sintases/química
Domínios Proteicos
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzodiazepinones); 0 (Pyrroles); 0 (pyrrolo(2,1-c)(1,4)benzodiazepine); 12794-10-4 (Benzodiazepines); 35050-55-6 (tomaymycin); EC 6.3.2.- (Peptide Synthases); EC 6.3.2.- (non-ribosomal peptide synthase)
[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:170912
[St] Status:MEDLINE


  6 / 3210 MEDLINE  
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[PMID]:28880538
[Au] Autor:Schomer RA; Thomas MG
[Ad] Endereço:Department of Bacteriology, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
[Ti] Título:Characterization of the Functional Variance in MbtH-like Protein Interactions with a Nonribosomal Peptide Synthetase.
[So] Source:Biochemistry;56(40):5380-5390, 2017 Oct 10.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Many nonribosomal peptide synthetases (NRPSs) require MbtH-like proteins (MLPs) for solubility or for activation of amino acid substrate by the adenylation domain. MLPs are capable of functional crosstalk with noncognate NRPSs at varying levels. Using enterobactin biosynthesis in Escherichia coli as a model MLP-dependent NRPS system, we use in vivo and in vitro techniques to characterize how seven noncognate MLPs influence the function of the enterobactin NRPS EntF when the cognate MLP, YbdZ, is absent. Using a series of in vitro assays to analyze EntF solubility, adenylation, aminoacylation, and in vitro enterobactin production, we show that interactions between MLPs and NRPSs are multifaceted and more complex than previously appreciated. We separate MLP influence on solubility and function in a manner that shows altered solubility is not indicative of a functional MLP/NRPS pair. Although much of the functional variation among these noncognates can be explained by differences in EntF affinity for an MLP or the extent an MLP alters EntF l-Ser affinity, we demonstrate that MLPs can have a broader impact beyond solubility and adenylation. First, we show that a noncognate MLP can affect formation of l-Ser-S-EntF. Second, under in vitro conditions saturating for substrate and MLP, enterobactin production remains compromised in the absence of an appropriate MLP partner. These data suggest that we expand our investigations into how the MLPs influence NRPS enzymology. A more detailed understanding of these influences will be essential for downstream engineering of hybrid NRPS systems.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Peptídeo Sintases/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Proteínas de Bactérias/química
Ligação Proteica
Solubilidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); EC 6.3.2.- (Peptide Synthases); EC 6.3.2.- (non-ribosomal peptide synthase)
[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:170908
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00517


  7 / 3210 MEDLINE  
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[PMID]:28805802
[Au] Autor:Zha L; Jiang Y; Henke MT; Wilson MR; Wang JX; Kelleher NL; Balskus EP
[Ad] Endereço:Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.
[Ti] Título:Colibactin assembly line enzymes use S-adenosylmethionine to build a cyclopropane ring.
[So] Source:Nat Chem Biol;13(10):1063-1065, 2017 Oct.
[Is] ISSN:1552-4469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Despite containing an α-amino acid, the versatile cofactor S-adenosylmethionine (SAM) is not a known building block for nonribosomal peptide synthetase (NRPS) assembly lines. Here we report an unusual NRPS module from colibactin biosynthesis that uses SAM for amide bond formation and subsequent cyclopropanation. Our findings showcase a new use for SAM and reveal a novel biosynthetic route to a functional group that likely mediates colibactin's genotoxicity.
[Mh] Termos MeSH primário: Ciclopropanos/química
Ciclopropanos/metabolismo
Peptídeo Sintases/metabolismo
Peptídeos/metabolismo
Policetídeos/metabolismo
S-Adenosilmetionina/metabolismo
[Mh] Termos MeSH secundário: Escherichia coli/metabolismo
Peptídeo Sintases/química
Peptídeos/química
Policetídeos/química
S-Adenosilmetionina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclopropanes); 0 (Peptides); 0 (Polyketides); 0 (colibactin); 7LP2MPO46S (S-Adenosylmethionine); 99TB643425 (cyclopropane); EC 6.3.2.- (Peptide Synthases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171028
[Lr] Data última revisão:
171028
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE
[do] DOI:10.1038/nchembio.2448


  8 / 3210 MEDLINE  
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[PMID]:28784817
[Au] Autor:Petersen LM; LaCourse K; Schöner TA; Bode H; Tisa LS
[Ad] Endereço:Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire, Durham, New Hampshire, USA.
[Ti] Título:Inactivation of the Major Hemolysin Gene Influences Expression of the Nonribosomal Peptide Synthetase Gene in the Insect Pathogen Serratia sp. Strain SCBI.
[So] Source:J Bacteriol;199(21), 2017 Nov 01.
[Is] ISSN:1098-5530
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hemolysins are important virulence factors for many bacterial pathogens, including The role of the major hemolysin gene in the insect pathogen sp. strain SCBI was investigated using both forward and reverse-genetics approaches. Introduction of the major hemolysin gene into resulted in a gain of both virulence and hemolytic activity. Inactivation of this hemolysin in sp. SCBI resulted in a loss of hemolysis but did not attenuate insecticidal activity. Unexpectedly, inactivation of the hemolysin gene in sp. SCBI resulted in significantly increased motility and increased antimicrobial activity. Reverse transcription-quantitative PCR (qRT-PCR) analysis of mutants with a disrupted hemolysin gene showed a dramatic increase in mRNA levels of a nonribosomal peptide synthetase gene, , which produces the surfactant serrawettin W2. Mutation of the gene in sp. SCBI resulted in highly varied antibiotic activity, motility, virulence, and hemolysis phenotypes that were dependent on the site of disruption within this 17.75-kb gene. When introduced into , increases rates of motility and confers antimicrobial activity. While it is unclear how inactivation of the major hemolysin gene influences the expression of , these results suggest that plays an important role in motility and antimicrobial activity in sp. SCBI. The opportunistic Gram-negative bacteria of the genus are widespread in the environment and can cause human illness. A comparative genomics analysis between and a new species from South Africa, termed sp. strain SCBI, shows that these two organisms are closely related but differ in pathogenesis. kills nematodes, while sp. SCBI is not harmful and forms a beneficial association with them. This distinction presented the opportunity to investigate potential differences in regulation of common virulence mechanisms between these two species. With the emergence of antibiotic-resistant microorganisms, there is a widespread need to understand the regulation of pathogenesis. The significance of this study is the presentation of evidence for cross-pathway regulation of virulence factors and how the elimination of one mechanism may be compensated for by the upregulation of others.
[Mh] Termos MeSH primário: Regulação Bacteriana da Expressão Gênica
Inativação Gênica
Proteínas Hemolisinas/genética
Proteínas Hemolisinas/metabolismo
Peptídeo Sintases/biossíntese
Serratia/genética
Serratia/metabolismo
[Mh] Termos MeSH secundário: Animais
Anti-Infecciosos/metabolismo
Clonagem Molecular
Escherichia coli/genética
Escherichia coli/crescimento & desenvolvimento
Escherichia coli/metabolismo
Expressão Gênica
Perfilação da Expressão Gênica
Insetos/microbiologia
Insetos/fisiologia
Locomoção
Peptídeo Sintases/genética
RNA Mensageiro/análise
Reação em Cadeia da Polimerase em Tempo Real
Serratia/enzimologia
Serratia/patogenicidade
Análise de Sobrevida
Virulência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Infective Agents); 0 (Hemolysin Proteins); 0 (RNA, Messenger); EC 6.3.2.- (Peptide Synthases); EC 6.3.2.- (non-ribosomal peptide synthase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE


  9 / 3210 MEDLINE  
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[PMID]:28759017
[Au] Autor:Alfermann J; Sun X; Mayerthaler F; Morrell TE; Dehling E; Volkmann G; Komatsuzaki T; Yang H; Mootz HD
[Ad] Endereço:Institute of Biochemistry, Department of Chemistry and Pharmacy, University of Muenster, Münster, Germany.
[Ti] Título:FRET monitoring of a nonribosomal peptide synthetase.
[So] Source:Nat Chem Biol;13(9):1009-1015, 2017 Sep.
[Is] ISSN:1552-4469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nonribosomal peptide synthetases (NRPSs) are multidomain enzyme templates for the synthesis of bioactive peptides. Large-scale conformational changes during peptide assembly are obvious from crystal structures, yet their dynamics and coupling to catalysis are poorly understood. We have designed an NRPS FRET sensor to monitor, in solution and in real time, the adoption of the productive transfer conformation between phenylalanine-binding adenylation (A) and peptidyl-carrier-protein domains of gramicidin synthetase I from Aneurinibacillus migulanus. The presence of ligands, substrates or intermediates induced a distinct fluorescence resonance energy transfer (FRET) readout, which was pinpointed to the population of specific conformations or, in two cases, mixtures of conformations. A pyrophosphate switch and lysine charge sensors control the domain alternation of the A domain. The phenylalanine-thioester and phenylalanine-AMP products constitute a mechanism of product inhibition and release that is involved in ordered assembly-line peptide biosynthesis. Our results represent insights from solution measurements into the conformational dynamics of the catalytic cycle of NRPSs.
[Mh] Termos MeSH primário: Técnicas Biossensoriais/métodos
Transferência Ressonante de Energia de Fluorescência
Modelos Biológicos
Peptídeo Sintases/química
[Mh] Termos MeSH secundário: Ligantes
Ligação Proteica
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); EC 6.3.2.- (Peptide Synthases); EC 6.3.2.- (non-ribosomal peptide synthase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170908
[Lr] Data última revisão:
170908
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE
[do] DOI:10.1038/nchembio.2435


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[PMID]:28722191
[Au] Autor:Konno S; Ishikawa F; Suzuki T; Dohmae N; Kakeya H; Tanabe G
[Ad] Endereço:Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo, Kyoto, 606-8501, Japan.
[Ti] Título:A Chemoproteomics Approach to Investigate Phosphopantetheine Transferase Activity at the Cellular Level.
[So] Source:Chembiochem;18(18):1855-1862, 2017 Sep 19.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Phosphopantetheinylation is an essential post-translational protein modification to primary and secondary metabolic pathways that ensures bacterial cell viability and virulence, and it is used in the production of many pharmaceuticals. Traditional methods have not provided a comprehensive understanding of these modifications. By using chemical proteomic probes for adenylation and thiolation domains in nonribosomal peptide synthetases (NRPSs), chemoproteomics has been applied to survey and validate the cellular activity of 4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-N-(4-methoxypyridin-2-yl)piperazine-1-carbothioamide (ML267), which is a potent and selective small-molecule 4'-phosphopantetheinyl transferase (PPTase) inhibitor that attenuates secondary metabolism and viability of bacterial cells. ML267 inhibited Sfp-type PPTase and antagonized phosphopantetheinylation in cells, which resulted in a decrease in phosphopantetheinylated NRPSs and the attenuation of Sfp-PPTase-dependent metabolite production. These results indicate that this chemoproteomics platform should enable a precise interpretation of the cellular activities of Sfp-type PPTase inhibitors.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Proteômica
Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo
[Mh] Termos MeSH secundário: Antibacterianos/química
Antibacterianos/metabolismo
Antibacterianos/farmacologia
Bacillus subtilis/efeitos dos fármacos
Bacillus subtilis/enzimologia
Proteínas de Bactérias/antagonistas & inibidores
Lipopeptídeos/metabolismo
Peptídeo Sintases/análise
Peptídeo Sintases/metabolismo
Peptídeos Cíclicos/metabolismo
Ligação Proteica
Processamento de Proteína Pós-Traducional
Piridinas/química
Piridinas/metabolismo
Piridinas/farmacologia
Tioureia/análogos & derivados
Tioureia/química
Tioureia/metabolismo
Tioureia/farmacologia
Transferases (Outros Grupos de Fosfato Substituídos)/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(4-methoxypyridin-2-yl)piperazine-1-carbothioamide); 0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (Lipopeptides); 0 (Peptides, Cyclic); 0 (Pyridines); 0 (phosphopantetheinyl transferase); 24730-31-2 (surfactin peptide); EC 2.7.8.- (Transferases (Other Substituted Phosphate Groups)); EC 6.3.2.- (Peptide Synthases); EC 6.3.2.- (non-ribosomal peptide synthase); GYV9AM2QAG (Thiourea)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170720
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201700301



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