Density Functional Theory Study on the Demethylation Reaction between Methylamine, Dimethylamine, Trimethylamine, and Tamoxifen Catalyzed by a Fe(IV)-Oxo Porphyrin Complex.

In this work, we studied computationally the N-demethylation reaction of methylamine, dimethylamine, and trimethylamine as archetypal examples of primary, secondary, and tertiary amines catalyzed by high-field low-spin Fe-containing enzymes such as cytochromes P450. Using DFT calculations, we found that the expected C-H hydroxylation process was achieved for trimethylamine. When dimethylamine and methylamine were studied, two different reaction mechanisms (C-H hydroxylation and a double hydrogen atom transfer) were computed to be energetically accessible and both are equally preferred. Both processes led to the formation of formaldehyde and the N-demethylated substrate. Finally, as an illustrative example, the relative contribution of the three primary oxidation routes of tamoxifen was rationalized through energetic barriers obtained from density functional calculations and docking experiments involving CYP3A4 and CYP2D6 isoforms. We found that the N-demethylation process was the intrinsically favored one, whereas other oxidation reactions required most likely preorganization imposed by the residues close to the active sites.

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 (H2 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.