Quantum chemical (QMMM) investigation of the mechanism of enzymatic reaction of tryptamine and N,N-dimethyltryptamine with monoamine oxidase A.
The endogenous psychedelic (mind-altering) N,N-dimethyltryptamine (DMT) molecule has an important role in tissue protection, regeneration, and immunity via sigma-1 receptor activation as its natural ligand. The immunologic properties of DMT suggest this biogenic compound should be investigated thoroughly in other aspects as well. In our in silico project, we examined the metabolism of DMT and its primary analogue, the tryptamine (T), by the monoamine oxidase (MAO) flavoenzyme. MAO has two isoforms, MAO-A and MAO-B. MAOs perform the oxidation of various monoamines by their flavin adenine dinucleotide (FAD) cofactor. Two-layer QMMM calculations at the ONIOM(M06-2X6-31G(d,p)UFFQEq) level were performed including the whole enzyme to explore the potential energy surface (PES) of the reactions. Our findings reinforced that a hybrid mechanism, a mixture of pure H