How Monoamine Oxidase A Decomposes Serotonin: An Empirical Valence Bond Simulation of the Reactive Step

Abstract

The enzyme-catalyzed degradation of the biogenic amine serotonin is an essential regulatory mechanism of its level in the human organism. In particular, monoamine oxidase A (MAO A) is an important flavoenzyme involved in the metabolism of monoamine neurotransmitters. Despite extensive research efforts, neither the catalytic nor the inhibition mechanisms of MAO enzymes are currently fully understood. In this article, we present the quantum mechanics/molecular mechanics simulation of the rate-limiting step for the serotonin decomposition, which consists of hydride transfer from the serotonin methylene group to the N5 atom of the flavin moiety. Free-energy profiles of the reaction were computed by the empirical valence bond method. Apart from the enzymatic environment, the reference reaction in the gas phase was also simulated, facilitating the estimation of the catalytic effect of the enzyme. The calculated barrier for the enzyme-catalyzed reaction of 14.82 ± 0.81 kcal mol –1 is in good agreement with the experimental value of 16.0 kcal mol –1 , which provides strong evidence for the validity of the proposed hydride-transfer mechanism. Together with additional experimental and computational work, the results presented herein contribute to a deeper understanding of the catalytic mechanism of MAO A and flavoenzymes in general, and in the long run, they should pave the way toward applications in neuropsychiatry.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…A recent example is the study of MAO-A and MAO-B inhibition by naturally occurring flavonoids that originate from medicinal plants [994]. Quantum mechanics/molecular mechanics simulations have also been used to elucidate the mechanism of enzymatic reaction catalyzed by MAO-A (e.g., [995]) and MOA-B (e.g., [996,997]); for a review of this topic, see ref. [998].…”

Questions in the Chemical Enzymology of MAO

“…Hydride transfer was established for D-amino acid oxidase after high-resolution structures with bound substrates were solved giving insight into the probable transition state [29]. On the other hand, X-ray structures of MAO are available only with inhibitors bound (see, for example, [30]), but since computational modeling based on these structures became practical, evidence for a hydride transfer reaction in both MAO A and MAO B has been mounting [31][32][33][34]. In a QM/MM simulation of the rate-limiting step for the serotonin oxidation via hydride transfer to the N5 of the FAD in MAO A, the calculated barrier was 14.8 ± 0.8 kcal mol −1 , in good agreement with the experimental value of 16.0 kcal mol −1 .…”

Monoamine Oxidase Inhibitors: A Review of Their Anti-Inflammatory Therapeutic Potential and Mechanisms of Action

“…FAD is reduced to its hydroquinone (FADH 2 ) while the amine is reduced to the corresponding imine. This catalytic process has not been fully resolved, however, using semiempirical quantum mechanics/molecular mechanics (QM/ MM) simulations, it was shown that hydride transfer from the substrate onto the flavin moiety was rate limiting (Repic et al, 2014;Prah et al, 2020). Once dissociated from the enzyme, the imine is spontaneously hydrolyzed with generation of aldehyde [RCHO] and ammonium [NH 4 + ].…”