Abstract
Monoamine oxidase A (MAO A) is a well-known enzyme responsible for the oxidative deamination of several important monoaminergic neurotransmitters. The rate-limiting step of amine decomposition is hydride anion transfer from the substrate α–CH2 group to the N5 atom of the flavin cofactor moiety. In this work, we focus on MAO A-catalyzed benzylamine decomposition in order to elucidate nuclear quantum effects through the calculation of the hydrogen/deuterium (H/D) kinetic isotope effect. The rate-limiting step of the reaction was simulated using a multiscale approach at the empirical valence bond (EVB) level. We applied path integral quantization using the quantum classical path method (QCP) for the substrate benzylamine as well as the MAO cofactor flavin adenine dinucleotide. The calculated H/D kinetic isotope effect of 6.5 ± 1.4 is in reasonable agreement with the available experimental values.
Highlights
Understanding the mechanisms underlying neurodegenerative and neuropsychiatric diseases, such as depression, Alzheimer’s disease, obsessive disorders, and Parkinson’s disease, is of prime importance for the development of novel drugs [1,2]
The reaction they catalyze is the oxidative deamination of biogenic and dietary monoamines such as dopamine, serotonin, histamine, noradrenaline, and phenylethylamine
monoamine oxidases A and B (MAOs) exist in two isoforms: Monoamine oxidase A (MAO A), which mainly decomposes serotonin and dopamine, and MAO B, which predominantly metabolizes benzylamine and phenylethylamine [6,7]
Summary
Understanding the mechanisms underlying neurodegenerative and neuropsychiatric diseases, such as depression, Alzheimer’s disease, obsessive disorders, and Parkinson’s disease, is of prime importance for the development of novel drugs [1,2]. MAOs are flavoenzymes found on the outer mitochondrial membrane of cells The reaction they catalyze is the oxidative deamination of biogenic and dietary monoamines such as dopamine, serotonin, histamine, noradrenaline, and phenylethylamine. Molecular simulation on the multiscale (QM/MM) level is a powerful tool that provides information about the transition state and the activation free energy As such, it allows for treatment of enzyme reactions and reactions in solution [14,15,16,17,18,19]. We applied multiscale QM/MM simulations using the empirical valence bond (EVB) method developed by Warshel [14,20,21], in order to obtain insight into MAO A-catalyzed decomposition of benzylamine. The EVB methodology, in conjunction with the quantum classical path (QCP) method, was applied in order to calculate the free energy barriers for both the hydrogen and the deuterium isotopomer, and a critical comparison with the experimental values was made
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