Small-Molecule Activators of Glucose-6-phosephate Dehydrogenase (G6PD) Bridging the Dimer Interface.

Small-Molecule Activators of Glucose-6-phosephate Dehydrogenase (G6PD) Bridging the Dimer Interface.
ChemMedChem. 2019 Jun 11;:
Authors: Raub A, Hwang S, Horikoshi N, Cunningham A, Rahighi S, Wakatsuki S, Mochly-Rosen D
Abstract
We have recently identified AG1, a small-molecule glucose-6-phosphate dehydrogenase (G6PD) activator that functions by promoting oligomerization of the enzyme to the catalytically competent forms. Biochemical experiments indicate 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 analogs 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 where control of oligomerization can enhance enzymatic activity and/or stability.
PMID: 31183991 [PubMed - as supplied by publisher]

Source: ChemMedChem - June 10, 2019 Category: Chemistry Authors: Raub A, Hwang S, Horikoshi N, Cunningham A, Rahighi S, Wakatsuki S, Mochly-Rosen D Tags: ChemMedChem Source Type: research