Three distinct strategies lead to programmable aliphatic C−H oxidation in bicyclomycin biosynthesis

Lian Wu, Jun-Bin He, Wanqing Wei, Hai-Xue Pan, Xin Wang, Sheng Yang (), Yong Liang (), Gong-Li Tang () and Jiahai Zhou ()
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Lian Wu: University of CAS
Jun-Bin He: University of CAS
Wanqing Wei: Jiangnan University
Hai-Xue Pan: University of CAS
Xin Wang: Henan University
Sheng Yang: University of CAS
Yong Liang: Henan University
Gong-Li Tang: University of CAS
Jiahai Zhou: Nanjing Normal University

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-58997-8

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