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- Title
Two-State Reactivity of Histone Demethylases Containing Jumonji-C Active Sites: Different Mechanisms for Different Methylation Degrees.
- Authors
Alberro, Nerea; Torrent‐Sucarrat, Miquel; Arrastia, Iosune; Arrieta, Ana; Cossío, Fernando P.
- Abstract
The N-demethylation reactions of N, N, N-trimethylpropan-1-ammonium and N, N-dimethyl- and N-methylpropan-1-aminium cations in the presence of [(AcO)2(imidazole)2(H2O)Fe=O] complex have been studied by density functional theory. These transformations are suitable models for the N -demethylation of tri-, di-, and monomethylated lysine residues of histones in the presence of Jumonji-C containing histone demethylases. It has been found that the N -demethylation reaction is stepwise and occurs on triplet and quintet potential energy hypersurfaces. Both spin states are nearly degenerated and the quantum jump from one state to another has a transition probability close to one. The preferred intrinsic mechanism depends upon the methylation degree. For trimethylated residues the mechanism consists of a proton abstraction from a methyl group followed by a formation of a hydroxymethylaminium intermediate. This mechanism also occurs when dimethylated residues are able to orientate one methyl group towards the Fe=O group of the catalytic site. In contrast, when a N−H group of the substrate is close enough to the Fe=O group, the intrinsically preferred N -demethylation reaction leads to the formation of an iminium intermediate that can be hydrolyzed to form the corresponding N -demethylated product.
- Subjects
HISTONE demethylases; METHYLATION; DEMETHYLATION; DENSITY functional theory; AMMONIUM; HYPERSURFACES; ATOMIC transitions
- Publication
Chemistry - A European Journal, 2017, Vol 23, Issue 1, p137
- ISSN
0947-6539
- Publication type
Article
- DOI
10.1002/chem.201604219