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Title: Small-Molecule Activators of Glucose-6-phosphate Dehydrogenase (G6PD) Bridging the Dimer Interface

Journal Article · · ChemMedChem
 [1];  [1];  [2];  [1];  [3];  [3]; ORCiD logo [1]
  1. Stanford Univ. School of Medicine, CA (United States). Dept. of Chemical and Systems Biology
  2. 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)
  3. 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
OSTI ID:
1546795
Journal Information:
ChemMedChem, Journal Name: ChemMedChem Journal Issue: 14 Vol. 14; ISSN 1860-7179
Publisher:
ChemPubSoc EuropeCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (2)

Discovery of Small-Molecule Activators for Glucose-6-Phosphate Dehydrogenase (G6PD) Using Machine Learning Approaches journal February 2020
Discovery of Small-Molecule Activators for Glucose-6-Phosphate Dehydrogenase (G6PD) Using Machine Learning Approaches journal February 2020