Small‐Molecule Activators of Glucose‐6‐phosphate Dehydrogenase (G6PD) Bridging the Dimer Interface

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.