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

Raub, Andrew G.; Hwang, Sunhee; Horikoshi, Naoki; Cunningham, Anna D.; Rahighi, Simin; Wakatsuki, Soichi; Mochly‐Rosen, Daria

doi:10.1002/cmdc.201900341

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

Journal Article · 26 June 2019 · ChemMedChem

DOI: https://doi.org/10.1002/cmdc.201900341 · OSTI ID:1546795

Raub, Andrew G. ^[1]; Hwang, Sunhee ^[1]; Horikoshi, Naoki ^[2]; Cunningham, Anna D. ^[1]; Rahighi, Simin ^[3]; Wakatsuki, Soichi ^[3];

^[1]

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.

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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 Saddala, Madhu Sudhana; Lennikov, Anton; Huang, Hu International Journal of Molecular Sciences, Vol. 21, Issue 4 https://doi.org/10.3390/ijms21041523	journal	February 2020
Discovery of Small-Molecule Activators for Glucose-6-Phosphate Dehydrogenase (G6PD) Using Machine Learning Approaches Saddala, Madhu Sudhana; Lennikov, Anton; Huang, Hu International Journal of Molecular Sciences, Vol. 21, Issue 4 https://doi.org/10.3390/ijms21041523	journal	February 2020

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bivalent ligands
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glucose-6-phosphate dehydrogenase
protein–protein interactions
small-molecule activators

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

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