Dioxygen Binding Is Controlled by the Protein Environment in Non‐heme FeII and 2‐Oxoglutarate Oxygenases: A Study on Histone Demethylase PHF8 and an Ethylene‐Forming Enzyme

Abstract

AbstractThis study investigates dioxygen binding and 2‐oxoglutarate (2OG) coordination by two model non‐heme FeII/2OG enzymes: a class 7 histone demethylase (PHF8) that catalyzes the hydroxylation of its H3K9me2 histone substrate leading to demethylation reactivity and the ethylene‐forming enzyme (EFE), which catalyzes two competing reactions of ethylene generation and substrate l‐Arg hydroxylation. Although both enzymes initially bind 2OG by using an off‐line 2OG coordination mode, in PHF8, the substrate oxidation requires a transition to an in‐line mode, whereas EFE is catalytically productive for ethylene production from 2OG in the off‐line mode. We used classical molecular dynamics (MD), quantum mechanics/molecular mechanics (QM/MM) MD and QM/MM metadynamics (QM/MM‐MetD) simulations to reveal that it is the dioxygen binding process and, ultimately, the protein environment that control the formation of the in‐line FeIII‐OO⋅− intermediate in PHF8 and the off‐line FeIII‐OO⋅− intermediate in EFE.