Reaction Mechanism of Monoamine Oxidase from QM/MM Calculations

The flavoenzyme monoamine oxidase
(MAO) is essential for the enzymatic
decomposition of neurotransmitters. While it is commonly accepted
that the rate limiting step of the reaction is the stereoselective
abstraction of a hydrogen from the substrate, the precise mechanism
is unknown. We modeled the reaction of human MAO-B with benzylamine
by means of QM/MM calculations based on density functional theory.
Oxidation of the unprotonated substrate was found to proceed with
rates in good agreement with experimental values, while the protonated
substrate does not react at room temperature. Our results support
a concerted asynchronous polar nucleophilic mechanism. The lone pair
of the amine-nitrogen interacts with a carbon atom of the flavin cofactor.
During the reaction, this lone pair, as well as a proton, are transferred
to the cofactor. Analysis of the electronic structure during the reaction
rules out a radical mechanism.