Computational Study Into the Oxidative Ring-Closure Mechanism During the Biosynthesis of Deoxypodophyllotoxin.
Chemistry
; 30(22): e202400019, 2024 Apr 16.
Article
em En
| MEDLINE
| ID: mdl-38323740
ABSTRACT
The nonheme iron dioxygenase deoxypodophyllotoxin synthase performs an oxidative ring-closure reaction as part of natural product synthesis in plants. How the enzyme enables the oxidative ring-closure reaction of (-)-yatein and avoids substrate hydroxylation remains unknown. To gain insight into the reaction mechanism and understand the details of the pathways leading to products and by-products we performed a comprehensive computational study. The work shows that substrate is bound tightly into the substrate binding pocket with the C7'-H bond closest to the iron(IV)-oxo species. The reaction proceeds through a radical mechanism starting with hydrogen atom abstraction from the C7'-H position followed by ring-closure and a final hydrogen transfer to form iron(II)-water and deoxypodophyllotoxin. Alternative mechanisms including substrate hydroxylation and an electron transfer pathway were explored but found to be higher in energy. The mechanism is guided by electrostatic perturbations of charged residues in the second-coordination sphere that prevent alternative pathways.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Podofilotoxina
/
Medicamentos de Ervas Chinesas
/
Hidrogênio
/
Ferro
Idioma:
En
Revista:
Chemistry
Ano de publicação:
2024
Tipo de documento:
Article