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

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

Journal Article · Thu Jun 27 00:00:00 EDT 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.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE

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

References (25)

Niedermolekulare Stabilisatoren von Protein-Protein-Wechselwirkungen: ein unterschätztes Konzept in der Wirkstoffentwicklung? Thiel, Philipp; Kaiser, Markus; Ottmann, Christian Angewandte Chemie, Vol. 124, Issue 9 https://doi.org/10.1002/ange.201107616	journal	February 2012
Discovery of Selective Small-Molecule Activators of a Bacterial Glycoside Hydrolase Darby, John F.; Landström, Jens; Roth, Christian Angewandte Chemie, Vol. 126, Issue 49 https://doi.org/10.1002/ange.201407081	journal	October 2014
Small-Molecule Stabilization of Protein-Protein Interactions: An Underestimated Concept in Drug Discovery? Thiel, Philipp; Kaiser, Markus; Ottmann, Christian Angewandte Chemie International Edition, Vol. 51, Issue 9 https://doi.org/10.1002/anie.201107616	journal	February 2012
Discovery of Selective Small-Molecule Activators of a Bacterial Glycoside Hydrolase Darby, John F.; Landström, Jens; Roth, Christian Angewandte Chemie International Edition, Vol. 53, Issue 49 https://doi.org/10.1002/anie.201407081	journal	October 2014
Structure and function of glucose-6-phosphate dehydrogenase-deficient variants in Chinese population Jiang, Weiying; Yu, Guolong; Liu, Peng Human Genetics, Vol. 119, Issue 5 https://doi.org/10.1007/s00439-005-0126-5	journal	April 2006
2- and 4-Nitrobenzenesulfonamides: Exceptionally versatile means for preparation of secondary amines and protection of amines Fukuyama, Tohru; Jow, Chung-Kuang; Cheung, Mui Tetrahedron Letters, Vol. 36, Issue 36 https://doi.org/10.1016/0040-4039(95)01316-A	journal	September 1995
Human erythrocyte glucose 6-phosphate dehydrogenase. Physical properties Bonsignore, A.; Cancedda, R.; Lorenzoni, I. Biochemical and Biophysical Research Communications, Vol. 43, Issue 1 https://doi.org/10.1016/S0006-291X(71)80091-8	journal	April 1971
Glucose-6-phosphate dehydrogenase deficiency Cappellini, Md; Fiorelli, G. The Lancet, Vol. 371, Issue 9606 https://doi.org/10.1016/S0140-6736(08)60073-2	journal	January 2008
Human glucose-6-phosphate dehydrogenase: the crystal structure reveals a structural NADP + molecule and provides insights into enzyme deficiency Au, Shannon WN; Gover, Sheila; Lam, Veronica MS Structure, Vol. 8, Issue 3 https://doi.org/10.1016/S0969-2126(00)00104-0	journal	March 2000
Allosteric FBPase inhibitors gain 105 times in potency when simultaneously binding two neighboring AMP sites Hebeisen, Paul; Kuhn, Bernd; Kohler, Philipp Bioorganic & Medicinal Chemistry Letters, Vol. 18, Issue 16 https://doi.org/10.1016/j.bmcl.2008.06.103	journal	August 2008
Coupling between Protein Stability and Catalytic Activity Determines Pathogenicity of G6PD Variants Cunningham, Anna D.; Colavin, Alexandre; Huang, Kerwyn Casey Cell Reports, Vol. 18, Issue 11 https://doi.org/10.1016/j.celrep.2017.02.048	journal	March 2017
Glucose-6-Phosphate Dehydrogenase Deficiency and the Need for a Novel Treatment to Prevent Kernicterus Cunningham, Anna D.; Hwang, Sunhee; Mochly-Rosen, Daria Clinics in Perinatology, Vol. 43, Issue 2 https://doi.org/10.1016/j.clp.2016.01.010	journal	June 2016
PPI inhibitor and stabilizer development in human diseases Bosch, Jürgen Drug Discovery Today: Technologies, Vol. 24 https://doi.org/10.1016/j.ddtec.2017.10.004	journal	June 2017
Peptides and peptidomimetics as regulators of protein–protein interactions Cunningham, Anna D.; Qvit, Nir; Mochly-Rosen, Daria Current Opinion in Structural Biology, Vol. 44 https://doi.org/10.1016/j.sbi.2016.12.009	journal	June 2017
Glucose-6-Phosphate Dehydrogenase Deficiency Bienzle, U. Clinics in Haematology, Vol. 10, Issue 3 https://doi.org/10.1016/s0308-2261(21)00299-x	journal	October 1981
Turning enzymes ON with small molecules Zorn, Julie A.; Wells, James A. Nature Chemical Biology, Vol. 6, Issue 3 https://doi.org/10.1038/nchembio.318	journal	February 2010
Apollo-NADP+: a spectrally tunable family of genetically encoded sensors for NADP+ Cameron, William D.; Bui, Cindy V.; Hutchinson, Ashley Nature Methods, Vol. 13, Issue 4 https://doi.org/10.1038/nmeth.3764	journal	February 2016
The druggable genome Hopkins, Andrew L.; Groom, Colin R. Nature Reviews Drug Discovery, Vol. 1, Issue 9 https://doi.org/10.1038/nrd892	journal	September 2002
Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant Perez-Miller, Samantha; Younus, Hina; Vanam, Ram Nature Structural & Molecular Biology, Vol. 17, Issue 2 https://doi.org/10.1038/nsmb.1737	journal	January 2010
Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator Hwang, Sunhee; Mruk, Karen; Rahighi, Simin Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-06447-z	journal	October 2018
Estimating the size of the human interactome Stumpf, M. P. H.; Thorne, T.; de Silva, E. Proceedings of the National Academy of Sciences, Vol. 105, Issue 19 https://doi.org/10.1073/pnas.0708078105	journal	May 2008
Stabilization of protein-protein interactions in drug discovery Andrei, Sebastian A.; Sijbesma, Eline; Hann, Michael Expert Opinion on Drug Discovery, Vol. 12, Issue 9 https://doi.org/10.1080/17460441.2017.1346608	journal	July 2017
Activation of Aldehyde Dehydrogenase-2 Reduces Ischemic Damage to the Heart Chen, Che-Hong; Budas, Grant R.; Churchill, Eric N. Science, Vol. 321, Issue 5895 https://doi.org/10.1126/science.1158554	journal	September 2008
Glucose-6-phosphate dehydrogenase deficiency. Mehta, A. B. Postgraduate Medical Journal, Vol. 70, Issue 830 https://doi.org/10.1136/pgmj.70.830.871	journal	December 1994
Glucose-6-phosphate dehydrogenase deficiency. Kaplan, M.; Hammerman, C. Postgraduate Medical Journal, Vol. 71, Issue 842 https://doi.org/10.1136/pgmj.71.842.765-b	journal	December 1995

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
bivalent ligands
enzyme catalysis
glucose-6-phosphate dehydrogenase
protein–protein interactions
small-molecule activators

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

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References (25)

Cited By (1)

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