A mechanistic insight for the biosynthesis of N,N-dimethyltryptamine: An ONIOM theoretical approach.

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.

Study at a glance

Abstract

Psychoactive natural products are potent serotonergic agonists capable of modulating brain functions such as memory and cognition. These substances have shown therapeutic potential for treating various mental disorders. The fact that N,N-dimethyltryptamine (DMT) is produced endogenously in several plants and animals, including humans, makes it particularly attractive. As an amino acid-derived alkaloid, the DMT biosynthetic pathway is part of the L-tryptophan biochemical cascade and can be divided into the decarboxylation by an aromatic L-amino acid decarboxylase (AADC) for tryptamine formation and the subsequent double-methylation by the indolethylamine-N-methyltransferase (INMT) through the cofactor S-adenosyl-L-methionine (SAM), a methyl donor. Unlike the decarboxylation mechanism of L-tryptophan, the molecular details of the double methylation of tryptamine have not been elucidated. Therefore, we propose an in silico model using molecular dynamics (MD), non-covalent interaction index (NCI) and density functional theory (DFT) calculations with the ONIOM QM:MM B3LYP/6-31+G(d,p):MM/UFF level of theory. Based on the obtained energetic data, the potential energy surface (PES) indicates an SN2 mechanism profile, with the second methylation energy barrier being the rate-limiting step with δG‡=60kJ∙mol-1 larger than the previous methylation, following the NCI analysis showing more repulsive interactions for the second transition state. In addition, the hybridization information of each reaction step provides geometric details about the double-methylation.