Paris, Jared C.Hei Cheung, YukZhang, TaoChang, Wei-ChenLiu, PinghuaGuo, Yisong2025-04-172025-04-172024-11-18J.C. Paris, Y. Hei Cheung, T. Zhang, W.-C. Chang, P. Liu, Y. Guo. 2024. "New Frontiers in Nonheme Enzymatic Oxyferryl Species." ChemBioChem, Volume 25, Issue 22, pp.e202400307-. https://doi.org/10.1002/cbic.2024003071439-42271439-7633https://hdl.handle.net/2144/50106Non-heme mononuclear iron dependent (NHM-Fe) enzymes exhibit exceedingly diverse catalytic reactivities. Despite their catalytic versatilities, the mononuclear iron centers in these enzymes show a relatively simple architecture, in which an iron atom is ligated with 2-4 amino acid residues, including histidine, aspartic or glutamic acid. In the past two decades, a common high-valent reactive iron intermediate, the S=2 oxyferryl (Fe(IV)-oxo or Fe(IV)=O) species, has been repeatedly discovered in NHM-Fe enzymes containing a 2-His-Fe or 2-His-1-carboxylate-Fe center. However, for 3-His/4-His-Fe enzymes, no common reactive intermediate has been identified. Recently, we have spectroscopically characterized the first S=1 Fe(IV) intermediate in a 3-His-Fe containing enzyme, OvoA, which catalyzes a novel oxidative carbon-sulfur bond formation. In this review, we summarize the broad reactivities demonstrated by S=2 Fe(IV)-oxo intermediates, the discovery of the first S=1 Fe(IV) intermediate in OvoA and the mechanistic implication of such a discovery, and the intrinsic reactivity differences of the S=2 and the S=1 Fe(IV)-oxo species. Finally, we postulate the possible reasons to utilize an S=1 Fe(IV) species in OvoA and their implications to other 3-His/4-His-Fe enzymes.p. e202400307-Print-Electronicen© 2024 The Author(s). ChemBioChem published by Wiley-VCH GmbH. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International.http://creativecommons.org/licenses/by-nc/4.0/C−H activationFerryl intermediatesNonheme iron enzymesOxidative C−S bond formationSpin stateC-H activationOrganic chemistryBiochemistry and cell biologyMedicinal and biomolecular chemistryIronOxidation-reductionNonheme iron proteinsArticle10.1002/cbic.2024003070000-0001-9932-5208 (Paris, Jared C)0000-0002-2341-9846 (Chang, Wei-Chen)0000-0002-9768-559X (Liu, Pinghua)0000-0002-4132-3565 (Guo, Yisong)964760