A mechanistic insight for the biosynthesis of N,N-dimethyltryptamine: An ONIOM theoretical approach.
Biochemical and biophysical research communications October 20, 2023 Lucas Pinheiro Coutinho, Sérgio Ruschi Bergamachi Silva, Pedro de Lima-Neto et al. 3 citations
The biosynthetic pathway of the psychoactive compound N,N-dimethyltryptamine (DMT) involves two methylation steps of tryptamine, but the molecular details of the double methylation were previously unknown. Using computational modeling—molecular dynamics, density functional theory, and ONIOM QM:MM calculations—the authors show that the reaction follows an SN2 mechanism. The second methylation is the rate-limiting step, with an energy barrier 60 kJ·mol⁻¹ higher than the first, due to more repulsive non-covalent interactions in the second transition state. The findings provide geometric details about each reaction step and clarify the energetics of DMT biosynthesis.