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

Autor: Coutinho LP; Departamento de Química Analítica e Físico-Química, Centro de Ciências, Universidade Federal do Ceará, 60021-970, Fortaleza, CE, Brazil., Silva SRB; Instituto do Cérebro, Universidade Federal do Rio Grande do Norte, 59078-900, Natal, RN, Brazil., de Lima-Neto P; Departamento de Química Analítica e Físico-Química, Centro de Ciências, Universidade Federal do Ceará, 60021-970, Fortaleza, CE, Brazil., Monteiro NKV; Departamento de Química Analítica e Físico-Química, Centro de Ciências, Universidade Federal do Ceará, 60021-970, Fortaleza, CE, Brazil. Electronic address: norbertokv@ufc.br.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2023 Oct 20; Vol. 678, pp. 148-157. Date of Electronic Publication: 2023 Aug 21.
DOI: 10.1016/j.bbrc.2023.08.043
Abstrakt: 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 S N 2 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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