Small-Molecule Activators of Glucose-6-phosphate Dehydrogenase (G6PD) Bridging the Dimer Interface
- Stanford Univ. School of Medicine, CA (United States). Dept. of Chemical and Systems Biology
- Univ. of Tsukuba (Japan). Life Science Center for Survival Dynamics; Stanford Univ. School of Medicine, CA (United States). Dept. of Structural Biology; SLAC National Accelerator Lab., Menlo Park, CA (United States)
- Stanford Univ. School of Medicine, CA (United States). Dept. of Structural Biology; SLAC National Accelerator Lab., Menlo Park, CA (United States)
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.
- Research Organization:
- SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
- Sponsoring Organization:
- USDOE; National Institutes of Health (NIH)
- Grant/Contract Number:
- AC02-76SF00515; HD084422; UL1TR001085
- OSTI ID:
- 1546795
- Journal Information:
- ChemMedChem, Vol. 14, Issue 14; ISSN 1860-7179
- Publisher:
- ChemPubSoc EuropeCopyright Statement
- Country of Publication:
- United States
- Language:
- English
Web of Science
Discovery of Small-Molecule Activators for Glucose-6-Phosphate Dehydrogenase (G6PD) Using Machine Learning Approaches
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journal | February 2020 |
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