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

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  • Andrew G. Raub
    Department of Chemical and Systems Biology Stanford University School of Medicine Stanford CA 94305 USA
  • Sunhee Hwang
    Department of Chemical and Systems Biology Stanford University School of Medicine Stanford CA 94305 USA
  • Naoki Horikoshi
    Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance University of Tsukuba Ibaraki 305-8575 Japan
  • Anna D. Cunningham
    Department of Chemical and Systems Biology Stanford University School of Medicine Stanford CA 94305 USA
  • Simin Rahighi
    Department of Structural Biology Stanford University School of Medicine Stanford CA 94305 USA
  • Soichi Wakatsuki
    Department of Structural Biology Stanford University School of Medicine Stanford CA 94305 USA
  • Daria Mochly‐Rosen
    Department of Chemical and Systems Biology Stanford University School of Medicine Stanford CA 94305 USA

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Description

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>C</jats:italic><jats:sub>2</jats:sub>‐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<jats:sup>+</jats:sup>) 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.</jats:p>

Journal

  • ChemMedChem

    ChemMedChem 14 (14), 1321-1324, 2019-06-27

    Wiley

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