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We have 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 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.


This is the accepted version of the following article:

Andrew Raub, Sunhee Hwang, Naoki Horikoshi, Anna Cunningham, Simin Rahighi, Soichi Wakatsuki, and Daria Mochly-Rosen. Small-Molecule Activators of Glucose-6-phosephate Dehydrogenase (G6PD) Bridging the Dimer Interface. ChemMedChem.

which has been published in final form at DOI: 10.1002/cmdc.201900341. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.



Available for download on Thursday, June 11, 2020