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.