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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月19日

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  • Lian Wu,
  • Jun-Bin He,
  • Wanqing Wei,
  • Hai-Xue Pan,
  • Xin Wang,
  • Sheng Yang,
  • Yong Liang,
  • Gong-Li Tang,
  • Jiahai Zhou

摘要

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.