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PreprintCC BY-NC-NDChemRxiv

Stage-Defined Prenyltransferase Integration for Hybrid RiPP Biosynthesis

  • Sota Uchida1,2,3
  • Taro Shiraishi1,2
  • Marin Yokomine1,2
  • Julien Alessandro König4
  • Zhong Hui Lim4
  • Dora Racunica4
  • Anna L. Vagstad4
  • Hiroaki Suga1,3
  • Jörn Piel4
  • Yuki Goto1,2,3,5
5 affiliations
  1. 1Department of Chemistry, Graduate School of Science
  2. 2Kyoto University
  3. 3University of Tokyo
  4. 4Institute of Microbiology, Eidgenössische Technische Hochschule (ETH) Zürich, Vladimir-Prelog-Weg 4, Zurich, Switzerland, 8093
  5. 5Toyota Riken Rising Fellow
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Abstract

Combining biosynthetic enzymes from distinct ribosomally synthesized and post-translationally modified peptide (RiPP) families offers a route to hybrid RiPPs but poses challenges in coordinating noncognate enzymatic transformations. Here, leveraging the temporal control enabled by in vitro biosynthesis, we first explored stage-defined integration of a cyanobactin prenyltransferase (PTase) into thiopeptide biosynthesis, a highly coordinated multienzyme pathway involving interdependent transformations of a single precursor peptide. Whereas early- and intermediate-stage prenylation interfered with thiopeptide maturation, late-stage prenylation of fully matured thiopeptides proceeded efficiently, enabling the production of diverse prenylated thiopeptides. We then extended this late-stage strategy to structurally distinct RiPPs, nonribosomal peptides, and artificial cyclic peptides using multiple cyanobactin PTases. Stage-controlled integration of non-cognate tailoring enzymes thus provides access to hybrid peptidic natural products.

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Cite

BibTeXRIS
BibTeX
@misc{uchida2026stagedefined,
  title = {{Stage-Defined Prenyltransferase Integration for Hybrid RiPP Biosynthesis}},
  author = {Sota Uchida and Taro Shiraishi and Marin Yokomine and Julien Alessandro König and Zhong Hui Lim and Dora Racunica and Anna L. Vagstad and Hiroaki Suga and Jörn Piel and Yuki Goto},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.15009020/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009020/v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - Stage-Defined Prenyltransferase Integration for Hybrid RiPP Biosynthesis
AU  - Sota Uchida
AU  - Taro Shiraishi
AU  - Marin Yokomine
AU  - Julien Alessandro König
AU  - Zhong Hui Lim
AU  - Dora Racunica
AU  - Anna L. Vagstad
AU  - Hiroaki Suga
AU  - Jörn Piel
AU  - Yuki Goto
PY  - 2026
DA  - 2026/09/17
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15009020/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009020/v1
AB  - Combining biosynthetic enzymes from distinct ribosomally synthesized and post-translationally modified peptide (RiPP) families offers a route to hybrid RiPPs but poses challenges in coordinating noncognate enzymatic transformations. Here, leveraging the temporal control enabled by in vitro biosynthesis, we first explored stage-defined integration of a cyanobactin prenyltransferase (PTase) into thiopeptide biosynthesis, a highly coordinated multienzyme pathway involving interdependent transformations of a single precursor peptide. Whereas early- and intermediate-stage prenylation interfered with thiopeptide maturation, late-stage prenylation of fully matured thiopeptides proceeded efficiently, enabling the production of diverse prenylated thiopeptides. We then extended this late-stage strategy to structurally distinct RiPPs, nonribosomal peptides, and artificial cyclic peptides using multiple cyanobactin PTases. Stage-controlled integration of non-cognate tailoring enzymes thus provides access to hybrid peptidic natural products.
ER  -