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

Abstract

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.

Authors:
 [1];  [1];  [2];  [1];  [3];  [3]; ORCiD logo [1]
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  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)
Publication Date:
Research Org.:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1546795
Grant/Contract Number:  
AC02-76SF00515; HD084422; UL1TR001085
Resource Type:
Accepted Manuscript
Journal Name:
ChemMedChem
Additional Journal Information:
Journal Volume: 14; Journal Issue: 14; Journal ID: ISSN 1860-7179
Publisher:
ChemPubSoc Europe
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; bivalent ligands; enzyme catalysis; glucose-6-phosphate dehydrogenase; protein–protein interactions; small-molecule activators

Citation Formats

Raub, Andrew G., Hwang, Sunhee, Horikoshi, Naoki, Cunningham, Anna D., Rahighi, Simin, Wakatsuki, Soichi, and Mochly‐Rosen, Daria. Small-Molecule Activators of Glucose-6-phosphate Dehydrogenase (G6PD) Bridging the Dimer Interface. United States: N. p., 2019. Web. doi:10.1002/cmdc.201900341.
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Raub, Andrew G., Hwang, Sunhee, Horikoshi, Naoki, Cunningham, Anna D., Rahighi, Simin, Wakatsuki, Soichi, & Mochly‐Rosen, Daria. Small-Molecule Activators of Glucose-6-phosphate Dehydrogenase (G6PD) Bridging the Dimer Interface. United States. https://doi.org/10.1002/cmdc.201900341
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Raub, Andrew G., Hwang, Sunhee, Horikoshi, Naoki, Cunningham, Anna D., Rahighi, Simin, Wakatsuki, Soichi, and Mochly‐Rosen, Daria. Thu . "Small-Molecule Activators of Glucose-6-phosphate Dehydrogenase (G6PD) Bridging the Dimer Interface". United States. https://doi.org/10.1002/cmdc.201900341. https://www.osti.gov/servlets/purl/1546795.
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@article{osti_1546795,
title = {Small-Molecule Activators of Glucose-6-phosphate Dehydrogenase (G6PD) Bridging the Dimer Interface},
author = {Raub, Andrew G. and Hwang, Sunhee and Horikoshi, Naoki and Cunningham, Anna D. and Rahighi, Simin and Wakatsuki, Soichi and Mochly‐Rosen, Daria},
abstractNote = {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.},
doi = {10.1002/cmdc.201900341},
journal = {ChemMedChem},
number = 14,
volume = 14,
place = {United States},
year = {Thu Jun 27 00:00:00 EDT 2019},
month = {Thu Jun 27 00:00:00 EDT 2019}
}
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Journal Article:
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Publisher's Version of Record
https://doi.org/10.1002/cmdc.201900341
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Cited by: 14 works
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Figures / Tables:

Figure 1 Figure 1: Residues expected to interact favorably with the pharmacophore of AG1 (PDB ID: 1QKI). A) The dimer interface of Canton G6PD located between the structural NADP+ (black, designated as NAP-800) with monomers shaded in dark and light grey. B) AG1 (teal) docked to the dimer interface using the Glide program inmore » the Schrödinger software suite.« less
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    Works referencing / citing this record:

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

    • Saddala, Madhu Sudhana; Lennikov, Anton; Huang, Hu
    • International Journal of Molecular Sciences, Vol. 21, Issue 4
    • DOI: 10.3390/ijms21041523

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

    • Saddala, Madhu Sudhana; Lennikov, Anton; Huang, Hu
    • International Journal of Molecular Sciences, Vol. 21, Issue 4
    • DOI: 10.3390/ijms21041523
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