PUBLICATION

Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator

Authors
Hwang, S., Mruk, K., Rahighi, S., Raub, A.G., Chen, C.H., Dorn, L.E., Horikoshi, N., Wakatsuki, S., Chen, J.K., Mochly-Rosen, D.
ID
ZDB-PUB-181004-3
Date
2018
Source
Nature communications   9: 4045 (Journal)
Registered Authors
Chen, James K., Mruk, Karen
Keywords
none
MeSH Terms
  • Zebrafish
  • Hemolysis/drug effects
  • Glucosephosphate Dehydrogenase/genetics
  • Glucosephosphate Dehydrogenase/metabolism*
  • Indoles/chemistry
  • Indoles/pharmacology
  • Indoles/therapeutic use*
  • Protein Stability
  • Glucosephosphate Dehydrogenase Deficiency/drug therapy*
  • Glucosephosphate Dehydrogenase Deficiency/genetics
  • Animals
  • Humans
  • Enzyme Activation
  • Mutation, Missense
  • Oxidative Stress/drug effects
  • Drug Evaluation, Preclinical
(all 16)
PubMed
30279493 Full text @ Nat. Commun.
Abstract
Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human genetic enzymopathies, is caused by over 160 different point mutations and contributes to the severity of many acute and chronic diseases associated with oxidative stress, including hemolytic anemia and bilirubin-induced neurological damage particularly in newborns. As no medications are available to treat G6PD deficiency, here we seek to identify a small molecule that corrects it. Crystallographic study and mutagenesis analysis identify the structural and functional defect of one common mutant (Canton, R459L). Using high-throughput screening, we subsequently identify AG1, a small molecule that increases the activity of the wild-type, the Canton mutant and several other common G6PD mutants. AG1 reduces oxidative stress in cells and zebrafish. Furthermore, AG1 decreases chloroquine- or diamide-induced oxidative stress in human erythrocytes. Our study suggests that a pharmacological agent, of which AG1 may be a lead, will likely alleviate the challenges associated with G6PD deficiency.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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Citation
Hwang, S., Mruk, K., Rahighi, S., Raub, A.G., Chen, C.H., Dorn, L.E., Horikoshi, N., Wakatsuki, S., Chen, J.K., Mochly-Rosen, D. (2018) Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator. Nature communications. 9:4045.