Three distinct strategies lead to programmable aliphatic C−H oxidation in bicyclomycin biosynthesis
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 dioxyg...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58997-8 |
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| Summary: | 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. |
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| ISSN: | 2041-1723 |