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Evolution inspired engineering of megasynthetases

MPS-Authors
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Bozhüyük,  Kenan A. J.
Natural Product Function and Engineering, Department of Natural Products in Organismic Interactions, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

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Präve,  Leonard
Natural Product Function and Engineering, Department of Natural Products in Organismic Interactions, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

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Kegler,  Carsten
Natural Product Function and Engineering, Department of Natural Products in Organismic Interactions, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

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Kaiser,  Sebastian
Max Planck Research Group Evolutionary Biochemistry, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

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Schenk,  Leonie
Natural Product Function and Engineering, Department of Natural Products in Organismic Interactions, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

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Hochberg,  Georg K. A.       
Center for Synthetic Microbiology, Philipps-Universität Marburg;
Department of Chemistry, Philipps-Universität Marburg;
Max Planck Research Group Evolutionary Biochemistry, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

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Bode,  Helge B.       
Molecular Biotechnology, Department of Biosciences, Goethe University Frankfurt, Frankfurt, Germany, External Organizations;
Senckenberg Gesellschaft für Naturforschung, Frankfurt;
Center for Synthetic Microbiology, Philipps-Universität Marburg;
Department of Chemistry, Philipps-Universität Marburg;
Natural Product Function and Engineering, Department of Natural Products in Organismic Interactions, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

External Resource

https://doi.org/10.1101/2022.12.02.518901
(Preprint)

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Citation

Bozhüyük, K. A. J., Präve, L., Kegler, C., Kaiser, S., Shi, Y.-N., Kuttenlochner, W., et al. (2022). Evolution inspired engineering of megasynthetases. bioRxiv: the preprint server for biology, 2022.12.02.518901.


Cite as: https://hdl.handle.net/21.11116/0000-000D-0D52-9
Abstract
Many clinically used drugs are derived from or inspired by bacterial natural products that often are biosynthesised via non-ribosomal peptide synthetases (NRPS), giant megasynthases that activate and join individual amino acids in an assembly line fashion. Since NRPS are not limited to the incorporation of the 20 proteinogenic amino acids, their efficient manipulation would allow the biotechnological generation of complex peptides including linear, cyclic and further modified natural product analogues, e.g. to optimise natural product leads. Here we describe a detailed phylogenetic analysis of several bacterial NRPS that led to the identification of a new recombination breakpoint within the thiolation (T) domain that is important for natural NRPS evolution. From this, an evolution-inspired eXchange Unit between T domains (XUT) approach was developed which allows the assembly of NRPS fragments over a broad range of GC contents, protein similarities, and extender unit specificities, as demonstrated for the specific production of a proteasome inhibitor designed and assembled from five different NRPS fragments.Competing Interest StatementA patent describing the XUT approach was filed by the Goethe University Frankfurt. K.A.J.B. and H.B.B. are cofounder and shareholder of Myria Biosciences AG, of which K.A.J.B. is also CSO.