Discovery of noncanonical cytochrome P450 enzymes in nature.

Authors

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

Published in

Nature chemical biology. Jun 22, 2026. Epub Jun 22, 2026.

Abstract

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.

PMID:
42332020
Bibliographic data and abstract were imported from PubMed on 23 Jun 2026.

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