Strukturelle Aufklärung der Bispezifität von A‐Domänen als Basis für die Aktivierung nicht‐natürlicher Aminosäuren

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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Nicht‐ribosomale Peptidsynthese – Prinzipien und Perspektiven

Süßmuth

Mainz

2017

Angewandte Chemie

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Nonribosomal Peptide Synthesis—Principles and Prospects

2017

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Nonribosomal peptide synthetases (NRPSs) are large multienzyme machineries that assemble numerous peptides with large structural and functional diversity. These peptides include more than 20 marketed drugs, such as antibacterials (penicillin, vancomycin), antitumor compounds (bleomycin), and immunosuppressants (cyclosporine). Over the past few decades biochemical and structural biology studies have gained mechanistic insights into the highly complex assembly line of nonribosomal peptides. This Review provides state-of-the-art knowledge on the underlying mechanisms of NRPSs and the variety of their products along with detailed analysis of the challenges for future reprogrammed biosynthesis. Such a reprogramming of NRPSs would immediately spur chances to generate analogues of existing drugs or new compound libraries of otherwise nearly inaccessible compound structures.

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Online Pyrophosphate Assay for Analyzing Adenylation Domains of Nonribosomal Peptide Synthetases

2016

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Nonribosomal peptide synthetases (NRPSs) produce many important and structurally complex natural products. Because of their architectures, reprogramming NRPSs has long been attempted to access new bioactive compounds. However, detailed characterization of NRPS catalysis and substrate selectivity by adenylation (A) domains is needed to support such efforts. We present a simple coupled NADH/pyrophosphate (PPi ) detection assay for analyzing A domain catalysis in vitro. PPi formation is coupled to the consumption of NADH by four enzymatic steps and is detected spectroscopically (λ=340 nm) for simple analysis. We demonstrate the effectiveness of this assay with several adenylation domains, including a stand-alone A domain (DltA, cell wall biosynthesis) and an embedded A domain (Tcp10, teicoplanin biosynthesis). Substrate acceptance of the Tcp10 A domain was explored for the first time, thus demonstrating the applicability of the assay for complex, multi-domain NRPSs.

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Strukturelle Aufklärung der Bispezifität von A‐Domänen als Basis für die Aktivierung nicht‐natürlicher Aminosäuren

Cited by 8 publications

References 21 publications

Nicht‐ribosomale Peptidsynthese – Prinzipien und Perspektiven

Nicht‐ribosomale Peptidsynthese – Prinzipien und Perspektiven

Nonribosomal Peptide Synthesis—Principles and Prospects

Online Pyrophosphate Assay for Analyzing Adenylation Domains of Nonribosomal Peptide Synthetases

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