title: Two-State Reactivity of Histone Demethylases Containing Jumonji-C Active Sites: Different Mechanisms for Different Methylation Degrees.
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.
authors.affiliation: Department of Organic Chemistry I, Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Centro de Innovación en Química Avanzada (ORFEO-CINQA), Manuel Lardizabal Ibilbidea 3, 20018, San Sebastián/Donostia, Spain.
authors.forename: Nerea
authors.identifier: 0000-0002-6068-4155
authors.initials: N
authors.lastname: Alberro
authors.affiliation: Department of Organic Chemistry I, Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Centro de Innovación en Química Avanzada (ORFEO-CINQA), Manuel Lardizabal Ibilbidea 3, 20018, San Sebastián/Donostia, Spain.|Donostia International Physics Center (DIPC), Manuel Lardizabal Ibilbidea 4, 20018, San Sebastián/Donostia, Spain.|Ikerbasque, Basque Foundation for Science, María Díaz de Haro 3, 6 floor, 48013, Bilbao, Spain.
authors.forename: Miquel
authors.identifier: 0000-0003-2689-0278
authors.initials: M
authors.lastname: Torrent-Sucarrat
authors.affiliation: Donostia International Physics Center (DIPC), Manuel Lardizabal Ibilbidea 4, 20018, San Sebastián/Donostia, Spain.
authors.forename: Iosune
authors.identifier: 0000-0001-5533-3708
authors.initials: I
authors.lastname: Arrastia
authors.affiliation: Department of Organic Chemistry I, Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Centro de Innovación en Química Avanzada (ORFEO-CINQA), Manuel Lardizabal Ibilbidea 3, 20018, San Sebastián/Donostia, Spain.
authors.forename: Ana
authors.identifier: 0000-0002-0580-2542
authors.initials: A
authors.lastname: Arrieta
authors.affiliation: Department of Organic Chemistry I, Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Centro de Innovación en Química Avanzada (ORFEO-CINQA), Manuel Lardizabal Ibilbidea 3, 20018, San Sebastián/Donostia, Spain.|Donostia International Physics Center (DIPC), Manuel Lardizabal Ibilbidea 4, 20018, San Sebastián/Donostia, Spain.
authors.forename: Fernando P
authors.identifier: 0000-0002-4526-2122
authors.initials: FP
authors.lastname: Cossío
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D006657:Histones / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000737:chemistry / Q000378:metabolism*; D008745:Methylation; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D055672:Static Electricity; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D006657:Histones; D056484:Jumonji Domain-Containing Histone Demethylases
keywords: chemical biology; computational chemistry; epigenetics; histone demethylases; spin crossover