engleski

EVB simulation of the catalytic activity of monoamine oxidases: from chemical physics to neurodegeneration

Brain monoamines regulate many centrally mediated body functions, but can cause adverse symptoms when they are out of balance. This is why neurotransmitters, such as dopamine and serotonin, have been extensively implicated in the etiology and course of various psychiatric and neurodegenerative disorders. A starting point to address challenges raised by the increasing burden of brain diseases is to understand, at atomistic level, the catalytic mechanism of a common amine metabolic enzyme – monoamine oxidase (MAO) – that has been a subject of heated debates as to whether MAO initiates the conversion of amines into imines by abstracting a proton, a hydrogen atom, or a hydride anion from the substrate α–CH group. This chapter presents our recent results of multiscale simulations – from QM to combined QM/MM approaches within the Empirical Valence Bond framework – that convincingly demonstrate the prevailing feasibility of the hydride transfer mechanism, which we show to agree with all available experimental data, including substrate protonation state, free‐energy of activation, point‐mutation studies, and H/D kinetic isotope effects. Since MAO catalysis generates H2O2, which could easily lead to reactive oxygen species, at the end we offer strategies for the prevention and treatment of neurodegeneration including irreversible MAO inhibition.

neurodegeneration

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