A comparative computational investigation on the proton and hydridetransfer mechanisms of monoamine oxidase using model molecules

tMonoamine oxidase (MAO) enzymes regulate the level of neurotransmitters by catalyzing the oxidationof various amine neurotransmitters, such as serotonin, dopamine and norepinephrine. Therefore, theyare the important targets for drugs used in the treatment of depression, Parkinson, Alzeimer and otherneurodegenerative disorders. Elucidation of MAO-catalyzed amine oxidation will provide new insightsinto the design of more effective drugs. Various amine oxidation mechanisms have been proposed forMAO so far, such as single electron transfer mechanism, polar nucleophilic mechanism and hydridemechanism. Since amine oxidation reaction of MAO takes place between cofactor flavin and the aminesubstrate, we focus on the small model structures mimicking flavin and amine substrates so that threemodel structures were employed. Reactants, transition states and products of the polar nucleophilic(proton transfer), the water-assisted proton transfer and the hydride transfer mechanisms were fullyoptimized employing various semi-empirical, ab initio and new generation density functional theory(DFT) methods. Activation energy barriers related to these mechanisms revealed that hydride transfermechanism is more feasible.MARMARA ÜNİVERSİTESİ, BAPKO, Project No: FEN-C-DRP-181208-0279 and FEN-D-310510-019