Evolution-inspired engineering of nonribosomal peptide synthetases

Kenan A.J. Bozhüyük, Leonard Präve, Carsten Kegler, Leonie Schenk, Sebastian Kaiser, Christian Schelhas, Yan Ni Shi, Wolfgang Kuttenlochner, Max Schreiber, Joshua Kandler, Mohammad Alanjary, T. M. Mohiuddin, Michael Groll, Georg K.A. Hochberg, Helge B. Bode

Research output: Contribution to journalArticlepeer-review

Abstract

Many clinically used drugs are derived from or inspired by bacterial natural products that often are produced through nonribosomal peptide synthetases (NRPSs), megasynthetases that activate and join individual amino acids in an assembly line fashion. In this work, we describe a detailed phylogenetic analysis of several bacterial NRPSs that led to the identification of yet undescribed recombination sites within the thiolation (T) domain that can be used for NRPS engineering. We then developed an evolution-inspired "eXchange Unit between T domains" (XUT) approach, 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.

Original languageEnglish
Pages (from-to)eadg4320
JournalScience
Volume383
Issue number6689
DOIs
StatePublished - 22 Mar 2024

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