Document Type
Article
Publication Date
10-2-2018
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.
Recommended Citation
Hwang S, Mruk K, Rahighi S, et al. Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator. Nat Commun. 2018;9:4045. doi: 10.1038/s41467-018-06447
Copyright
The authors
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Biological Phenomena, Cell Phenomena, and Immunity Commons, Chemical and Pharmacologic Phenomena Commons, Enzymes and Coenzymes Commons, Genetic Phenomena Commons, Genetic Processes Commons, Hemic and Lymphatic Diseases Commons, Medical Biochemistry Commons, Medicinal and Pharmaceutical Chemistry Commons, Other Pharmacy and Pharmaceutical Sciences Commons
Comments
This article was originally published in Nature Communications, volume 9, in 2018. DOI: 10.1038/s41467-018-06447