ArticleChemistry (Weinheim an der Bergstrasse, Germany)2023
Catalysis by KDM6 Histone Demethylases - A Synergy between the Non-Heme Iron(II) Center, Second Coordination Sphere, and Long-Range Interactions.
Article in Chemistry (Weinheim an der Bergstrasse, Germany), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 24 citations in OpenAlex.
- Beyond Histone Demethylation: Mechanisms ofJACS Au · 2026Article
- Regio- and Stereoselective Halogenation by an Iron(II)- and 2-Oxoglutarate-Dependent Halogenase in the Biosynthesis of Halogenated Nucleosides.Journal of the American Chemical Society · 2025Article
- Mechanistic insights into the selective oxidation of D-arginine by the nonheme iron-dependent viomycin biosynthesis enzyme VioC.iScience · 2025Article
- Revealing the catalytic mechanism of the Fe(II)/2-oxoglutarate-dependent human epigenetic modifying enzyme ALKBH5.Cell reports. Physical science · 2025Article
- Uncovering the Origins of Selectivity in Non-Heme Iron Dioxygenase-Catalyzed Tropolone Biosynthesis.The journal of physical chemistry. B · 2025Article
- Three distinct strategies lead to programmable aliphatic C-H oxidation in bicyclomycin biosynthesis.Nature communications · 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
- Effects of Clinical Mutations in the Second Coordination Sphere and Remote Regions on the Catalytic Mechanism of Non-Heme Fe(II)/2-Oxoglutarate-Dependent Aspartyl Hydroxylase AspH.Chemphyschem : a European journal of chemical physics and physical chemistry · 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
- Unusual catalytic strategy by non-heme Fe(ii)/2-oxoglutarate-dependent aspartyl hydroxylase AspH.Chemical science · 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
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
KDM6A (UTX) and KDM6B (JMJD3) are human non-heme Fe(II) and 2-oxoglutarate (2OG) dependent JmjC oxygenases that catalyze the demethylation of trimethylated lysine 27 in the N-terminal tail of histone H3, a post-translational modification that regulates transcription. A Combined Quantum Mechanics/ Molecular Mechanics (QM/MM) and Molecular Dynamics (MD) study on the catalytic mechanism of KDM6A/B reveals that the transition state for the rate-limiting hydrogen atom transfer (HAT) reaction in KDM6A catalysis is stabilized by polar (Asn217) and aromatic (Trp369)/non-polar (Pro274) residues in contrast to KDM4, KDM6B and KDM7 demethylases where charged residues (Glu, Arg, Asp) are involved. KDM6A employs both σ- and π-electron transfer pathways for HAT, whereas KDM6B employs the σ-electron pathway. Differences in hydrogen bonding of the Fe-chelating Glu252(KDM6B) contribute to the lower energy barriers in KDM6B vs. KDM6A. The study reveals a dependence of the activation barrier of the rebound hydroxylation on the Fe-O-C angle in the transition state of KDM6A. Anti-correlation of the Zn-binding domain with the active site residues is a key factor distinguishing KDM6A/B from KDM7/4s. The results reveal the importance of communication between the Fe center, second coordination sphere, and long-range interactions in catalysis by KDMs and, by implication, other 2OG oxygenases.
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Registered trials
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