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Minimal lactazole scaffold for in vitro thiopeptide bioengineering

Author

Listed:
  • 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
    Hokkaido University)

  • Shumpei Asamizu

    (The University of Tokyo
    The University of Tokyo)

  • Yoshinori Sugai

    (The University of Tokyo)

  • Hiroaki Suga

    (The University of Tokyo)

  • Hiroyasu Onaka

    (The University of Tokyo
    The University of Tokyo)

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.

Suggested Citation

  • Alexander A. Vinogradov & Morito Shimomura & Yuki Goto & Taro Ozaki & Shumpei Asamizu & Yoshinori Sugai & Hiroaki Suga & Hiroyasu Onaka, 2020. "Minimal lactazole scaffold for in vitro thiopeptide bioengineering," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16145-4
    DOI: 10.1038/s41467-020-16145-4
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    Cited by:

    1. Wan-Qiu Liu & Xiangyang Ji & Fang Ba & Yufei Zhang & Huiling Xu & Shuhui Huang & Xiao Zheng & Yifan Liu & Shengjie Ling & Michael C. Jewett & Jian Li, 2024. "Cell-free biosynthesis and engineering of ribosomally synthesized lanthipeptides," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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