Decoding and Reprogramming Fungal Iterative Nonribosomal Peptide Synthetases

Authors

Daya Yu, Utah State University
Fuchao Xu, Utah State University
Shuwei Zhang, Utah State University
Jixun Zhan, Utah State UniversityFollow

Document Type

Article

Journal/Book Title

Nature Communications

Publication Date

5-23-2017

Publisher

Nature Publishing Group

Volume

8

Abstract

Nonribosomal peptide synthetases (NRPSs) assemble a large group of structurally and functionally diverse natural products. While the iterative catalytic mechanism of bacterial NRPSs is known, it remains unclear how fungal NRPSs create products of desired length. Here we show that fungal iterative NRPSs adopt an alternate incorporation strategy. Beauvericin and bassianolide synthetases have the same C₁-A₁-T₁-C₂-A₂-MT-T_2a-T_2b-C₃ domain organization. During catalysis, C₃ and C₂ take turns to incorporate the two biosynthetic precursors into the growing depsipeptide chain that swings between T₁ and T_2a/T_2b with C₃ cyclizing the chain when it reaches the full length. We reconstruct the total biosynthesis of beauvericin in vitro by reacting C₂ and C₃ with two SNAC-linked precursors and present a domain swapping approach to reprogramming these enzymes for peptides with altered lengths. These findings highlight the difference between bacterial and fungal NRPS mechanisms and provide a framework for the enzymatic synthesis of non-natural nonribosomal peptides.

Recommended Citation

Yu, Daya; Xu, Fuchao; Zhang, Shuwei; and Zhan, Jixun, "Decoding and Reprogramming Fungal Iterative Nonribosomal Peptide Synthetases" (2017). Biological Engineering Faculty Publications. Paper 148.
https://digitalcommons.usu.edu/bioeng_facpub/148