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<p>The activation of inert C(<i>sp</i><sup>3</sup>)–H bonds by nonheme Fe enzymes provides a powerful biocatalytic platform for the chemical synthesis of molecules with increased <i>sp</i><sup>3</sup> complexity. In this context, Fe<sup>II</sup>/α-ketoglutarate-dependent radical halogenases are uniquely capable of carrying out transfer of a diverse array of bound anions following C–H activation. Here, we provide experimental evidence that bifurcation of radical rebound after H-atom abstraction can be driven both by the ability of a dynamic metal coordination sphere to reorganize and by a second-sphere hydrogen-bonding network where only two residues are sufficient. In addition, we present crystallographic data supporting the existence of an early peroxyhemiketal intermediate in the O<sub>2</sub> activation pathway of Fe<sup>II</sup>/α-ketoglutarate-dependent enzymes. These data provide a paradigm for understanding the evolution of catalytic plasticity in these enzymes and yields insight into the design principles by which to expand their reaction scope.</p><p></p>

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Dynamic metal coordination controls chemoselectivity in a radical halogenase

  • 期刊论文

  • 发表日期：

    2025年11月21日

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  • Elijah N. Kissman,
  • Ioannis Kipouros,
  • Jeffrey W. Slater,
  • Elizabeth A. Stone,
  • Avery Y. Yang,
  • Augustin Braun,
  • Alder R. Ensberg,
  • Andrew M. Whitten,
  • Kuntal Chatterjee,
  • Isabel Bogacz,
  • Junko Yano,
  • J. Martin Bollinger Jr.,
  • Michelle C. Y. Chang

摘要

The activation of inert C(sp3)–H bonds by nonheme Fe enzymes provides a powerful biocatalytic platform for the chemical synthesis of molecules with increased sp3 complexity. In this context, FeII/α-ketoglutarate-dependent radical halogenases are uniquely capable of carrying out transfer of a diverse array of bound anions following C–H activation. Here, we provide experimental evidence that bifurcation of radical rebound after H-atom abstraction can be driven both by the ability of a dynamic metal coordination sphere to reorganize and by a second-sphere hydrogen-bonding network where only two residues are sufficient. In addition, we present crystallographic data supporting the existence of an early peroxyhemiketal intermediate in the O2 activation pathway of FeII/α-ketoglutarate-dependent enzymes. These data provide a paradigm for understanding the evolution of catalytic plasticity in these enzymes and yields insight into the design principles by which to expand their reaction scope.