1. 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.
- Author
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Chaturvedi, Shobhit Sanjeev, Thomas, Midhun, Rifayee, Simahudeen, White, Walter, Wildey, Jon, Warner, Cait, Schofield, Christopher, Hu, Jian, Hausinger, Robert, Karabencheva-Christova, Tatayana, and Christov, Christo
- Subjects
QM/MM metadynamics ,dioxygen diffusion ,ethylene-forming enzymes ,histone demethylation ,molecular dynamics ,Oxygenases ,Histone Demethylases ,Ketoglutaric Acids ,Oxygen ,Ferric Compounds ,Ferrous Compounds ,Ethylenes - Abstract
This 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.
- Published
- 2023