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  Evolution inspired engineering of megasynthetases

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.

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 Creators:
Bozhüyük, Kenan A. J.1, Author           
Präve, Leonard1, Author           
Kegler, Carsten1, Author           
Kaiser, Sebastian2, Author           
Shi, Yan-Ni3, Author
Kuttenlochner, Wolfgang3, Author
Schenk, Leonie1, Author           
Mohiuddin, T. M.3, Author
Groll, Michael3, Author
Hochberg, Georg K. A.2, 4, 5, Author                 
Bode, Helge B.1, 4, 5, 6, 7, Author                 
Affiliations:
1Natural Product Function and Engineering, Department of Natural Products in Organismic Interactions, Max Planck Institute for Terrestrial Microbiology, Max Planck Society, ou_3266308              
2Max Planck Research Group Evolutionary Biochemistry, Max Planck Institute for Terrestrial Microbiology, Max Planck Society, ou_3266300              
3external, ou_persistent22              
4Center for Synthetic Microbiology, Philipps-Universität Marburg, ou_persistent22              
5Department of Chemistry, Philipps-Universität Marburg, ou_persistent22              
6Molecular Biotechnology, Department of Biosciences, Goethe University Frankfurt, Frankfurt, Germany, External Organizations, ou_421891              
7Senckenberg Gesellschaft für Naturforschung, Frankfurt, ou_persistent22              

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 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.

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Language(s): eng - English
 Dates: 2022-12-08
 Publication Status: Issued
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: No review
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Title: bioRxiv : the preprint server for biology
  Abbreviation : bioRxiv
Source Genre: Journal
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Pages: - Volume / Issue: - Sequence Number: 2022.12.02.518901 Start / End Page: - Identifier: ZDB: 2766415-6
CoNE: https://pure.mpg.de/cone/journals/resource/2766415-6