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Publication Abstract from PubMed

Cytochrome P450s (CYPs) are a superfamily of thiolate-ligated heme metalloenzymes principally responsible for the hydroxylation of unactivated C-H bonds. The lower-axial cysteine is an obligatory and universally conserved residue for the CYP enzyme class. Herein, we challenge this paradigm by systematically identifying non-canonical CYPs (ncCYPs) that do not harbor a cysteine ligand. Our bioinformatic search reveals 20 distinct ncCYP families with diverse ligands encoded in microbial genomes. We characterize a native serine-ligated CYP with a high-spin ferric resting state. Its crystal structure clearly shows a typical CYP fold and a serine alkoxide as a lower axial heme ligand. In addition, we report the discovery and characterization of the first native selenocysteine-ligated CYP in nature. Our findings radically expand the CYP metalloenzyme family.

Non-Canonical Cytochrome P450 Enzymes in Nature.,Nguy AKL, Ireland KA, Kayrouz CM, Caceres JC, Greene BL, Davis KM, Seyedsayamdost MR bioRxiv [Preprint]. 2024 Dec 23:2024.12.22.630014. doi: , 10.1101/2024.12.22.630014. PMID:39763895^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.