Download MendeleyThree distinct strategies lead to programmable aliphatic C-H oxidation in bicyclomycin biosynthesis.
Wu, L., He, J.B., Wei, W., Pan, H.X., Wang, X., Yang, S., Liang, Y., Tang, G.L., Zhou, J.(2025) Nat Commun 16: 4651-4651
- PubMed: 40389404
- DOI: https://doi.org/10.1038/s41467-025-58997-8
- Primary Citation of Related Structures:
8XHP, 8XHQ, 8XHT, 8XHX, 8XHY - PubMed 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.
Organizational Affiliation:
Key Laboratory of Synthetic Biology, Chinese Academy of Sciences (CAS) Center for Excellence in Molecular Plant Sciences, University of CAS, Shanghai, 200032, China.
