ArticleChemistry (Weinheim an der Bergstrasse, Germany)2021
What Is the Catalytic Mechanism of Enzymatic Histone N-Methyl Arginine Demethylation and Can It Be Influenced by an External Electric Field?
Article in Chemistry (Weinheim an der Bergstrasse, Germany), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 29 citations in OpenAlex.
- Beyond Histone Demethylation: Mechanisms ofJACS Au · 2026Article
- Elucidating the Oxygen-Activation Mechanism in Nonheme MnInorganic chemistry · 2026Article
- How Fe(II)/2-Oxoglutarate Oxygenase Chooses Chlorination over Hydroxylation: Electric Field-Driven Ligand Exchange Governs C-Cl Formation.Journal of the American Chemical Society · 2026Article
- Oriented Electric Fields─Universal Catalysts.Accounts of chemical research · 2025Article
- Origins of Catalysis in Non-Heme Fe(II)/2-Oxoglutarate-Dependent Histone Lysine Demethylase KDM4A with Differently Methylated Histone H3 Peptides.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Article
- JmjC catalysed histone H2a N-methyl arginine demethylation and C4-arginine hydroxylation reveals importance of sequence-reactivity relationships.Communications biology · 2024Article
- The Unique Role of the Second Coordination Sphere to Unlock and Control Catalysis in Nonheme Fe(II)/2-Oxoglutarate Histone Demethylase KDM2A.Inorganic chemistry · 2024Article
- Catalytic Mechanism of Collagen Hydrolysis by Zinc(II)-Dependent Matrix Metalloproteinase-1.The journal of physical chemistry. B · 2023Article
- From random to rational: improving enzyme design through electric fields, second coordination sphere interactions, and conformational dynamics.Chemical science · 2023Review
- Revealing the Catalytic Strategy of FTO.Chem catalysis · 2023Article
- Catalysis by KDM6 Histone Demethylases - A Synergy between the Non-Heme Iron(II) Center, Second Coordination Sphere, and Long-Range Interactions.Chemistry (Weinheim an der Bergstrasse, Germany) · 2023Article
- The catalytic domains of all human KDM5 JmjC demethylases catalyse N-methyl arginine demethylation.FEBS letters · 2023Article
- YfeX - A New Platform for Carbene Transferase Development with High Intrinsic Reactivity.Chemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
- Article
- How Human TET2 Enzyme Catalyzes the Oxidation of Unnatural Cytosine Modifications in Double-Stranded DNA.ACS catalysis · 2022Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 3 countries.
Funding
Abstract
Arginine methylation is an important mechanism of epigenetic regulation. Some Fe(II) and 2-oxoglutarate dependent Jumonji-C (JmjC) Nϵ-methyl lysine histone demethylases also have N-methyl arginine demethylase activity. We report combined molecular dynamic (MD) and Quantum Mechanical/Molecular Mechanical (QM/MM) studies on the mechanism of N-methyl arginine demethylation by human KDM4E and compare the results with those reported for N-methyl lysine demethylation by KDM4A. At the KDM4E active site, Glu191, Asn291, and Ser197 form a conserved scaffold that restricts substrate dynamics; substrate binding is also mediated by an out of active site hydrogen-bond between the substrate Ser1 and Tyr178. The calculations imply that in either C-H or N-H potential bond cleaving pathways for hydrogen atom transfer (HAT) during N-methyl arginine demethylation, electron transfer occurs via a σ-channel; the transition state for the N-H pathway is ∼10 kcal/mol higher than for the C-H pathway due to the higher bond dissociation energy of the N-H bond. The results of applying external electric fields (EEFs) reveal EEFs with positive field strengths parallel to the Fe=O bond have a significant barrier-lowering effect on the C-H pathway, by contrast, such EEFs inhibit the N-H activation rate. The overall results imply that KDM4 catalyzed N-methyl arginine demethylation and N-methyl lysine demethylation occur via similar C-H abstraction and rebound mechanisms leading to methyl group hydroxylation, though there are differences in the interactions leading to productive binding of intermediates.
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