How are Biogenic Amines Metabolized by Monoamine Oxidases?

Abstract

Monoamine oxidases (MAOs) are flavoenzymes important in regulating amine neurotransmitter levels and are the central pharmacological targets in treating depression and Parkinson's disease. On the basis of quantum chemical calculations, we have proposed a new two‐step hydride mechanism for the MAO‐catalysed oxidative deamination of amines. In the rate‐limiting first step, through its N5 atom, the flavin abstracts a hydride anion from the substrate α‐carbon atom and forms a strong covalent adduct with the thus created cation. This is followed by flavin N1 deprotonation of the substrate amino group, facilitated with two active‐site water molecules, to produce fully reduced flavin, FADH2, and neutral imine. We have demonstrated that our mechanism is in agreement with available experimental data and provided evidence against both traditional polar nucleophilic and single‐electron radical pathways. These results provide valuable information for mechanistic studies on other flavoenzymes and for the design of new antidepressants and antiparkinsonian drugs.

Revealing Monoamine Oxidase B Catalytic Mechanisms by Means of the Quantum Chemical Cluster Approach

“…al. 7 ). Also, C4a of the flavin and the other water molecule (HOH2115) could stabilize the amine moiety of NBA.…”

“…In a later stage, a facilitated deprotonation of the adduct by two active-site water molecules would produce a fully reduced flavin, FADH 2 , and a neutral imine. 7 Experimentally, this two-step HT was shown to be energetically more feasible compared to other mechanistic pathways. 8 Despite the structural resemblance of both active sites, the electrostatic environment in MAO A and MAO B should not be identical, allowing for different degrees of charge transfer in the reactant complexes upon formation.…”

“…10 The PN and HT mechanisms have been widely discussed in order to shed light on the nature of the experimental rate-determining step. For instance, Orru et al 8 addressed the dilemma regarding the same or different mechanisms for both MAO isoforms; Abad et al 11 used computational chemistry to favour the PN mechanism; Vianello et al 7 were the first to show computationally the prevailing feasibility of the HT over all other mechanisms, suggesting that this two-step hydride transfer mechanism might operate in MAO-B. However, as stated by the authors considering the structural resemblances of both isoforms, i.e.…”

“…al. 7 have included full dimensionality of the enzyme by means of empirical valence bond simulations including thermal corrections. 13,24 …”

The Chemistry of Neurodegeneration: Kinetic Data and Their Implications

“…Interestingly, dopaminergic neurons contain more MAO A than MAO B while for serotonergic neurons the opposite is true [94,95]. Recently, we suggested and quantified a novel two-step hydride mechanism of the MAO catalytic reaction [96,97], which should aid in developing more specific and effective inhibitors as transitionstate analogues, acting as anti-depressants and antiparkinsonian drugs. The rate constant for MAO B catalysed dopamine decomposition is around 1 s −1 , which is faster than the metal-free dopamine auto-oxidation (0.43 s −1 ), yet slower than when auto-oxidation is assisted with heavy metal ions (6.75 s −1 ) [53, 98,99].…”