Probing Exchange Units for Combining Iterative and Linear Fungal Nonribosomal Peptide Synthetases.

A considerable number of complex peptides are synthesized by nonribosomal peptide synthetases (NRPSs). Due to their multimodular architecture and widely understood basic biosynthetic reactions, these synthetases represent a promising target for compound diversification by active reprogramming. Nevertheless, the limited knowledge about mechanistic details such as C domain specificity hampers rational synthetase engineering. Here, we present a systematic investigation of three fungal NRPS exchange units (C-A-Mt-T, CCTD-A-Mt-T, and A-Mt-T) focusing on the influence of C domains at heterologous domain junctions. By functionally integrating units from linear cyclosporine synthetase into iterative cyclodepsipeptide synthetases in vivo, we demonstrate that fungal NRPSs of different assembly types can be combined using different swapping sites, while respecting the C domain integrity and specificity. Based on 24 hybrid synthetases, we suggest exchange rules for efficient fungal NRPS engineering. The findings are of importance for rational synthetase design and provide a new set of options for combinatorial reprogramming.

• Publication year

  2019

• Venue

  Cell Chemical Biology

• Publication date

  2019-11-21

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1016/j.chembiol.2019.08.005PMID 31471217
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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