Three distinct strategies lead to programmable aliphatic C−H oxidation in bicyclomycin biosynthesis
The C-H bond functionalization has been widely used in chemical synthesis over the past decade. However, regio- and stereoselectivity still remain a significant challenge, especially for inert aliphatic C-H bonds. Here we report the mechanism of three Fe(II)/α-ketoglutarate-dependent dioxygenases in bicyclomycin synthesis, which depicts the natural tactic to sequentially hydroxylate specific C-H bonds of similar substrates (cyclodipeptides). Molecular basis by crystallographic studies, computational simulations, and site-directed mutagenesis reveals the exquisite arrangement of three enzymes using mutually orthogonal strategies to realize three different regio-selectivities. Moreover, this programmable selective hydroxylation can be extended to other cyclodipeptides. This evidence not only provides a naturally occurring showcase corresponding to the widely used methods in chemical catalysis but also expands the toolbox of biocatalysts to address the regioselective functionalization of C-H bonds.
Authors
- Gong‐Li Tang (ORCID: https://orcid.org/0000-0003-3149-4683)
- Lian Wu (ORCID: https://orcid.org/0000-0003-3110-7380)
- Hai‐Xue Pan (ORCID: https://orcid.org/0000-0002-7263-522X)
- Yong Liang (ORCID: https://orcid.org/0000-0001-5026-6710)
- Wanqing Wei (ORCID: https://orcid.org/0000-0001-8768-5273)
- Jun‐Bin He (ORCID: https://orcid.org/0000-0002-8267-9904)
- Sheng Yang (ORCID: https://orcid.org/0000-0003-3742-9989)
- Jiahai Zhou
- Xin Wang (ORCID: https://orcid.org/0009-0004-2370-0779)
Institutions
- Jiangnan University (CN)
- Nanjing Normal University (CN)
- Henan University (CN)
- Westlake University (CN)
- Shanghai Institute of Organic Chemistry (CN)
- Institute for Advanced Study (DE)
- Center for Excellence in Molecular Plant Sciences (CN)
- Nanjing University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-19
- DOI
- https://doi.org/10.1038/s41467-025-58997-8
- Citations
- 1
- Primary Topic
- Microbial Natural Products and Biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 1.39
Funders
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- Government of Jiangsu Province
- Natural Science Foundation of Jiangsu Province
- Nanjing University
- National Key Research and Development Program of China