Two-State Reactivity of Histone Demethylases Containing Jumonji-C Active Sites: Different Mechanisms for Different Methylation Degrees.

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 (H ₂ O)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.
(© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)