Minimal lactazole scaffold for in vitro thiopeptide bioengineering

Alexander A. Vinogradov, Morito Shimomura, Yuki Goto (), Taro Ozaki, Shumpei Asamizu, Yoshinori Sugai, Hiroaki Suga () and Hiroyasu Onaka ()
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Alexander A. Vinogradov: The University of Tokyo
Morito Shimomura: The University of Tokyo
Yuki Goto: The University of Tokyo
Taro Ozaki: The University of Tokyo
Shumpei Asamizu: The University of Tokyo
Yoshinori Sugai: The University of Tokyo
Hiroaki Suga: The University of Tokyo
Hiroyasu Onaka: The University of Tokyo

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Lactazole A is a cryptic thiopeptide from Streptomyces lactacystinaeus, encoded by a compact 9.8 kb biosynthetic gene cluster. Here, we establish a platform for in vitro biosynthesis of lactazole A, referred to as the FIT-Laz system, via a combination of the flexible in vitro translation (FIT) system with recombinantly produced lactazole biosynthetic enzymes. Systematic dissection of lactazole biosynthesis reveals remarkable substrate tolerance of the biosynthetic enzymes and leads to the development of the minimal lactazole scaffold, a construct requiring only 6 post-translational modifications for macrocyclization. Efficient assembly of such minimal thiopeptides with FIT-Laz opens access to diverse lactazole analogs with 10 consecutive mutations, 14- to 62-membered macrocycles, and 18 amino acid-long tail regions, as well as to hybrid thiopeptides containing non-proteinogenic amino acids. This work suggests that the minimal lactazole scaffold is amenable to extensive bioengineering and opens possibilities to explore untapped chemical space of thiopeptides.

Date: 2020
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DOI: 10.1038/s41467-020-16145-4

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