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<p>Cytochrome P450s (CYPs) constitute a superfamily of thiolate-ligated heme metalloenzymes principally responsible for the hydroxylation of unactivated C–H bonds. The proximal cysteine is an obligatory and universally conserved residue for the CYP enzyme class. Herein, we challenge this paradigm by systematically identifying noncanonical CYPs (ncCYPs) that do not harbor a proximal cysteine ligand. Our bioinformatic search revealed 20 distinct ncCYP families encoded in diverse microbial genomes with alternative residues at this position. We characterize a native serine-ligated CYP with a high-spin ferric resting state that catalyzes azide reduction and nitrene insertion reactions. Its crystal structure clearly shows a typical CYP fold and a serine alkoxide as a proximal heme ligand. In addition, we report the discovery and characterization of the first native selenocysteine-ligated CYP in nature. Our findings expand the CYP metalloenzyme family and provide opportunities for future enzymatic and biocatalytic discoveries.</p><p></p>

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Discovery of noncanonical cytochrome P450 enzymes in nature

  • 期刊论文

  • 发表日期：

    2026年6月22日

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  • Andy K. L. Nguy,
  • Kendra A. Ireland,
  • Chase M. Kayrouz,
  • Juan Carlos Cáceres,
  • Jonathan Z. Huang,
  • Vanessa Y. Ying,
  • Joanna A. Quaye,
  • Brandon L. Greene,
  • Katherine M. Davis,
  • Mohammad R. Seyedsayamdost

摘要

Cytochrome P450s (CYPs) constitute a superfamily of thiolate-ligated heme metalloenzymes principally responsible for the hydroxylation of unactivated C–H bonds. The proximal cysteine is an obligatory and universally conserved residue for the CYP enzyme class. Herein, we challenge this paradigm by systematically identifying noncanonical CYPs (ncCYPs) that do not harbor a proximal cysteine ligand. Our bioinformatic search revealed 20 distinct ncCYP families encoded in diverse microbial genomes with alternative residues at this position. We characterize a native serine-ligated CYP with a high-spin ferric resting state that catalyzes azide reduction and nitrene insertion reactions. Its crystal structure clearly shows a typical CYP fold and a serine alkoxide as a proximal heme ligand. In addition, we report the discovery and characterization of the first native selenocysteine-ligated CYP in nature. Our findings expand the CYP metalloenzyme family and provide opportunities for future enzymatic and biocatalytic discoveries.