Computational Analysis of the Nicotine Oxidoreductase Mechanism by the ONIOM Method

Nicotine oxidoreductase
(NicA2) is a monoamine oxidase (MAO)-based
flavoenzyme that catalyzes the oxidation of S-nicotine into N-methylmyosmine. Due to its nanomolar binding affinity
toward nicotine, it is seen as an ideal candidate for the treatment
of nicotine addiction. Based on the crystal structure of the substrate-bound
enzyme, hydrophobic interactions mainly govern the binding of the
substrate in the active site through Trp108, Trp364, Trp427, and Leu217
residues. In addition, Tyr308 forms H-bonding with the pyridyl nitrogen
of the substrate. Experimental and computational studies support the
hydride transfer mechanism for MAO-based enzymes. In this mechanism,
a hydride ion transfers from the substrate to the flavin cofactor.
In this study, computational models involving the ONIOM method were
formulated to study the hydride transfer mechanism based on the crystal
structure of the enzyme–substrate complex. The geometry and
energetics of the hydride transfer mechanism were analyzed, and the
roles of active site residues were highlighted.