skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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 C 2-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]
  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 Lab., 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:
Journal Article: Accepted Manuscript
Journal Name:
ChemMedChem(Print)
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.
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. doi:10.1002/cmdc.201900341.
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. doi:10.1002/cmdc.201900341. https://www.osti.gov/servlets/purl/1546795.
@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(Print)},
issn = {1860-7179},
number = 14,
volume = 14,
place = {United States},
year = {2019},
month = {6}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 1 work
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Estimating the size of the human interactome
journal, May 2008

  • Stumpf, M. P. H.; Thorne, T.; de Silva, E.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 19
  • DOI: 10.1073/pnas.0708078105

PPI inhibitor and stabilizer development in human diseases
journal, June 2017


The druggable genome
journal, September 2002

  • Hopkins, Andrew L.; Groom, Colin R.
  • Nature Reviews Drug Discovery, Vol. 1, Issue 9
  • DOI: 10.1038/nrd892

Peptides and peptidomimetics as regulators of protein–protein interactions
journal, June 2017

  • Cunningham, Anna D.; Qvit, Nir; Mochly-Rosen, Daria
  • Current Opinion in Structural Biology, Vol. 44
  • DOI: 10.1016/j.sbi.2016.12.009

Small-Molecule Stabilization of Protein-Protein Interactions: An Underestimated Concept in Drug Discovery?
journal, February 2012

  • Thiel, Philipp; Kaiser, Markus; Ottmann, Christian
  • Angewandte Chemie International Edition, Vol. 51, Issue 9
  • DOI: 10.1002/anie.201107616

Niedermolekulare Stabilisatoren von Protein-Protein-Wechselwirkungen: ein unterschätztes Konzept in der Wirkstoffentwicklung?
journal, February 2012

  • Thiel, Philipp; Kaiser, Markus; Ottmann, Christian
  • Angewandte Chemie, Vol. 124, Issue 9
  • DOI: 10.1002/ange.201107616

Stabilization of protein-protein interactions in drug discovery
journal, July 2017


Glucose-6-phosphate dehydrogenase deficiency
journal, January 2008


Glucose-6-Phosphate Dehydrogenase Deficiency and the Need for a Novel Treatment to Prevent Kernicterus
journal, June 2016

  • Cunningham, Anna D.; Hwang, Sunhee; Mochly-Rosen, Daria
  • Clinics in Perinatology, Vol. 43, Issue 2
  • DOI: 10.1016/j.clp.2016.01.010

Coupling between Protein Stability and Catalytic Activity Determines Pathogenicity of G6PD Variants
journal, March 2017


Activation of Aldehyde Dehydrogenase-2 Reduces Ischemic Damage to the Heart
journal, September 2008


Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant
journal, January 2010

  • Perez-Miller, Samantha; Younus, Hina; Vanam, Ram
  • Nature Structural & Molecular Biology, Vol. 17, Issue 2
  • DOI: 10.1038/nsmb.1737

Turning enzymes ON with small molecules
journal, February 2010

  • Zorn, Julie A.; Wells, James A.
  • Nature Chemical Biology, Vol. 6, Issue 3
  • DOI: 10.1038/nchembio.318

Discovery of Selective Small-Molecule Activators of a Bacterial Glycoside Hydrolase
journal, October 2014

  • Darby, John F.; Landström, Jens; Roth, Christian
  • Angewandte Chemie International Edition, Vol. 53, Issue 49
  • DOI: 10.1002/anie.201407081

Discovery of Selective Small-Molecule Activators of a Bacterial Glycoside Hydrolase
journal, October 2014

  • Darby, John F.; Landström, Jens; Roth, Christian
  • Angewandte Chemie, Vol. 126, Issue 49
  • DOI: 10.1002/ange.201407081

Structure and function of glucose-6-phosphate dehydrogenase-deficient variants in Chinese population
journal, April 2006


Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator
journal, October 2018


Allosteric FBPase inhibitors gain 105 times in potency when simultaneously binding two neighboring AMP sites
journal, August 2008

  • Hebeisen, Paul; Kuhn, Bernd; Kohler, Philipp
  • Bioorganic & Medicinal Chemistry Letters, Vol. 18, Issue 16
  • DOI: 10.1016/j.bmcl.2008.06.103

Human erythrocyte glucose 6-phosphate dehydrogenase. Physical properties
journal, April 1971

  • Bonsignore, A.; Cancedda, R.; Lorenzoni, I.
  • Biochemical and Biophysical Research Communications, Vol. 43, Issue 1
  • DOI: 10.1016/S0006-291X(71)80091-8

Apollo-NADP+: a spectrally tunable family of genetically encoded sensors for NADP+
journal, February 2016

  • Cameron, William D.; Bui, Cindy V.; Hutchinson, Ashley
  • Nature Methods, Vol. 13, Issue 4
  • DOI: 10.1038/nmeth.3764

2- and 4-Nitrobenzenesulfonamides: Exceptionally versatile means for preparation of secondary amines and protection of amines
journal, September 1995