title: Path Integral Simulation of the H/D Kinetic Isotope Effect in Monoamine Oxidase B Catalyzed Decomposition of Dopamine.
abstract: Brain monoamines regulate many centrally mediated body functions, and can cause adverse symptoms when they are out of balance. A starting point to address challenges raised by the increasing burden of brain diseases is to understand, at atomistic level, the catalytic mechanism of an essential amine metabolic enzyme-monoamine oxidase B (MAO B). Recently, we demonstrated that the rate-limiting step of MAO B catalyzed conversion of amines into imines represents the hydride anion transfer from the substrate α-CH2 group to the N5 atom of the flavin cofactor moiety. In this article we simulated for MAO B catalyzed dopamine decomposition the effects of nuclear tunneling by the calculation of the H/D kinetic isotope effect. We applied path integral quantization of the nuclear motion for the methylene group and the N5 atom of the flavin moiety in conjunction with the QM/MM treatment on the empirical valence bond (EVB) level for the rest of the enzyme. The calculated H/D kinetic isotope effect of 12.8 ± 0.3 is in a reasonable agreement with the available experimental data for closely related biogenic amines, which gives strong support for the proposed hydride mechanism. The results are discussed in the context of tunneling in enzyme centers and advent of deuterated drugs into clinical practice.
authors.affiliation: Laboratory for Biocomputing and Bioinformatics, National Institute of Chemistry , Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
authors.forename: Janez
authors.initials: J
authors.lastname: Mavri
authors.affiliation: University of Southern California , Department of Chemistry SGM 418, 3620 McClintock Avenue Los Angeles, California 90089-1062, United States.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Matute
authors.affiliation: University of Southern California , Department of Chemistry SGM 418, 3620 McClintock Avenue Los Angeles, California 90089-1062, United States.
authors.forename: Zhen T
authors.initials: ZT
authors.lastname: Chu
authors.affiliation: Computational Organic Chemistry and Biochemistry Group, Ruđer Bošković Institute , Bijenička 54, HR-10000 Zagreb, Croatia.
authors.forename: Robert
authors.initials: R
authors.lastname: Vianello
mesh_terms: D055162:Biocatalysis; D020134:Catalytic Domain; D003903:Deuterium; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D011789:Quantum Theory
chemical_list: D003903:Deuterium; D008995:Monoamine Oxidase; D004298:Dopamine