Regio- and Stereoselective Halogenation by an Iron(II)- and 2‑Oxoglutarate-Dependent Halogenase in the Biosynthesis of Halogenated Nucleosides
Philip M. Palacios, Xiaoyun Li, Simahudeen Bathir Jaber Sathik Rifayee, Haoyu Tang, Tatyana Karabencheva-Christova, Christo Christov, Wei-chen Chang, Yisong Guo
TL;DR
This paper investigates how an iron-dependent enzyme selectively adds chlorine atoms to specific positions in nucleosides, revealing the mechanism behind its regio- and stereoselectivity.
Contribution
The study identifies two oxyferryl intermediates and their structural transformations that enable selective halogenation over hydroxylation in an Fe/2OG halogenase.
Findings
Two oxyferryl intermediates are formed sequentially during the AdeV reaction.
The stereochemistry of the C–Cl bond formation is suprafacial.
Structural conversion between offline and inline oxyferryl configurations is necessary for C–H activation and bond formation.
Abstract
Iron(II)- and 2-oxoglutarate-dependent (Fe/2OG) enzymes have garnered strong research interest in past decades due to their ability to catalyze regio- and stereoselective C–H functionalization via a single reactive intermediate, the oxyferryl species. In addition to the hydroxylation reaction that is commonly observed, other reaction outcomes have also been discovered in Fe/2OG enzymes. Among them, halogenation has attracted much research effort with the goal of revealing the molecular determinants to favor halogenation over hydroxylation; however, a full mechanistic picture is still missing. In this study, by investigating a recently identified Fe/2OG halogenase, AdeV, from the biosynthetic pathway of Adechlorin, we show, via biochemical, kinetics, and spectroscopic characterizations, that two oxyferryl intermediates are formed during the AdeV reaction in a sequential manner, which…
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Taxonomy
TopicsMetal-Catalyzed Oxygenation Mechanisms · Metalloenzymes and iron-sulfur proteins · Cyclopropane Reaction Mechanisms