Document Type

Article

Publication Date

6-11-2019

Abstract

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.

Comments

This is the accepted version of the following article:

Raub A, Hwang S, Horikoshi N, et al. Small-molecule activators of glucose-6-phosephate Dehydrogenase (G6PD) bridging the dimer interface. ChemMedChem. 2019;14(14):1321-1324.

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

Copyright

Wiley

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