Strukturaufklärung und Aktivität des aus einer riesigen nicht‐ ribosomalen Peptidsynthetase stammenden <scp>D</scp>‐/<scp>L</scp>‐Pentadecapeptids Kolossin A

Bode, Helge B.; Brachmann, Alexander O.; Jadhav, Kirtikumar B.; Seyfarth, Lydia; Dauth, Christina; Fuchs, Sebastian W.; Kaiser, Marcel; Waterfield, Nick; Sack, Holger; Heinemann, Stefan; Arndt, Hans‐Dieter

doi:10.1002/ange.201502835

Cited by 10 publications

(2 citation statements)

References 39 publications

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“…This further elongates the peptide chain and releases the PCP for another round of synthesis. NRPS systems can be as short as two modules or as long as 18 modules (Bode et al, 2015). Each module must function with its neighbors to successfully synthesize the nonribosomal peptide product.…”

Section: Introductionmentioning

confidence: 99%

X-Ray Crystallography and Electron Microscopy of Cross- and Multi-Module Nonribosomal Peptide Synthetase Proteins Reveal a Flexible Architecture

et al. 2017

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Nonribosomal peptide synthetases (NRPS) are macromolecular machines that produce peptides with diverse activities. Structural information exists for domains, didomains, and even modules, but little is known about higher-order organization. We performed a multi-technique study on constructs from the dimodular NRPS DhbF. We determined a crystal structure of a cross-module construct including the adenylation (A) and peptidyl carrier protein (PCP) domains from module 1 and the condensation domain from module 2, complexed with an adenosine-vinylsulfonamide inhibitor and an MbtH-like protein (MLP). The action of the inhibitor and the role of the MLP were investigated using adenylation reactions and isothermal titration calorimetry. In the structure, the PCP and A domains adopt a novel conformation, and noncovalent, cross-module interactions are limited. We calculated envelopes of dimodular DhbF using negative-stain electron microscopy. The data show large conformational variability between modules. Together, our results suggest that NRPSs lack a uniform, rigid supermodular architecture.

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Section: Introductionmentioning

confidence: 99%

X-Ray Crystallography and Electron Microscopy of Cross- and Multi-Module Nonribosomal Peptide Synthetase Proteins Reveal a Flexible Architecture

et al. 2017

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“…P. luminescens produces various toxins that kill insects and defeat other microbial competitors upon infection (ffrench-Constant et al, 2003;Joyce et al, 2006). Therefore, bacteria in this genus, as well as their relatives in the Xenorhabdus genus, are thought to be valuable sources of bioactive secondary metabolites for discovery of new therapeutics and agricultural agents (Antonello et al, 2018;Bode, 2009Bode, , 2011Bode et al, 2015b;Stock et al, 2017;Vizcaino et al, 2014). We previously cloned the same set of 10 BGCs and parallelly expressed them in diverse host strains using CRAGE.…”

Section: Introductionmentioning

confidence: 99%

CRAGE-CRISPR facilitates rapid activation of secondary metabolite biosynthetic gene clusters in bacteria

Robinson

et al. 2022

Cell Chemical Biology

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Nicht‐ribosomale Peptidsynthese – Prinzipien und Perspektiven

Süßmuth

Mainz

2017

Angewandte Chemie

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Nicht‐ribosomale Peptidsynthetasen (NRPSs) sind große Multienzymmaschinerien, die zahlreiche Peptide mit enormer struktureller und funktionaler Diversität erzeugen. Unter diesen Produkten befinden sich mehr als 20 auf dem Markt befindliche Wirkstoffe, darunter Antibiotika (Penicillin, Vancomycin), antitumorale Medikamente (Bleomycin) und Immunsuppressiva (Cyclosporin). In den vergangenen Jahrzehnten haben biochemische sowie strukturbiologische Studien mechanistische Einblicke in die hochkomplexen NRPSs gewährt. Dieser Aufsatz fasst den aktuellen Kenntnisstand über die zugrundeliegenden Mechanismen von NRPSs zusammen und gibt einen Überblick über die Vielfalt ihrer Produkte. Ebenso behandelt werden die Probleme und Herausforderungen, die mit der Umprogrammierung von NRPS‐Systemen einhergehen. Das Potenzial einer solchen Umprogrammierung liegt begründet in einer nachhaltigen Generierung von Wirkstoffanaloga und neuen Substanzbibliotheken, die anderenfalls kaum zugänglich sind.

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Strukturaufklärung und Aktivität des aus einer riesigen nicht‐ ribosomalen Peptidsynthetase stammenden D‐/L‐Pentadecapeptids Kolossin A

Cited by 10 publications

References 39 publications

X-Ray Crystallography and Electron Microscopy of Cross- and Multi-Module Nonribosomal Peptide Synthetase Proteins Reveal a Flexible Architecture

X-Ray Crystallography and Electron Microscopy of Cross- and Multi-Module Nonribosomal Peptide Synthetase Proteins Reveal a Flexible Architecture

CRAGE-CRISPR facilitates rapid activation of secondary metabolite biosynthetic gene clusters in bacteria

Nicht‐ribosomale Peptidsynthese – Prinzipien und Perspektiven

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