Small-Molecule Activators of Glucose-6-phosphate Dehydrogenase (G6PD) Bridging the Dimer Interface.
ChemMedChem
; 14(14): 1321-1324, 2019 07 17.
Article
em En
| MEDLINE
| ID: mdl-31183991
ABSTRACT
We recently identified AG1, a small-molecule activator that functions by promoting oligomerization of glucose-6-phosphate dehydrogenase (G6PD) to the catalytically competent forms. Biochemical experiments indicate that the activation of G6PD by the original hit molecule (AG1) is noncovalent and that one C2 -symmetric region of the G6PD homodimer is important for ligand function. Consequently, the disulfide in AG1 is not required for activation of G6PD, and a number of analogues were prepared without this reactive moiety. Our study supports a mechanism of action whereby AG1 bridges the dimer interface at the structural nicotinamide adenine dinucleotide phosphate (NADP+ ) binding sites of two interacting G6PD monomers. Small molecules that promote G6PD oligomerization have the potential to provide a first-in-class treatment for G6PD deficiency. This general strategy could be applied to other enzyme deficiencies in which control of oligomerization can enhance enzymatic activity and/or stability.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ativadores de Enzimas
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Glucosefosfato Desidrogenase
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Indóis
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article