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

Abstract

Here, 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.

Authors:
ORCiD logo [1]; ORCiD logo [1];  [2];  [1];  [1]; ORCiD logo [3];  [1];  [1]; ORCiD logo [1]; ORCiD logo [1]
  1. Stanford Univ., Stanford, CA (United States)
  2. Stanford Univ., Stanford, CA (United States); Chapman Univ., Irvine, CA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States)
  3. Stanford Univ., Stanford, CA (United States); The Ohio State Univ., Columbus, OH (United States); Univ. of Wyoming School of Pharmacy, Laramie, WY (United States)
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1490641
Grant/Contract Number:  
AC02-76SF00515; HD084422
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Hwang, Sunhee, Mruk, Karen, Rahighi, Simin, Raub, Andrew G., Chen, Che -Hong, Dorn, Lisa E., Horikoshi, Naoki, Wakatsuki, Soichi, Chen, James K., and Mochly-Rosen, Daria. Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator. United States: N. p., 2018. Web. doi:10.1038/s41467-018-06447-z.
Hwang, Sunhee, Mruk, Karen, Rahighi, Simin, Raub, Andrew G., Chen, Che -Hong, Dorn, Lisa E., Horikoshi, Naoki, Wakatsuki, Soichi, Chen, James K., & Mochly-Rosen, Daria. Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator. United States. doi:10.1038/s41467-018-06447-z.
Hwang, Sunhee, Mruk, Karen, Rahighi, Simin, Raub, Andrew G., Chen, Che -Hong, Dorn, Lisa E., Horikoshi, Naoki, Wakatsuki, Soichi, Chen, James K., and Mochly-Rosen, Daria. Tue . "Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator". United States. doi:10.1038/s41467-018-06447-z. https://www.osti.gov/servlets/purl/1490641.
@article{osti_1490641,
title = {Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator},
author = {Hwang, Sunhee and Mruk, Karen and Rahighi, Simin and Raub, Andrew G. and Chen, Che -Hong and Dorn, Lisa E. and Horikoshi, Naoki and Wakatsuki, Soichi and Chen, James K. and Mochly-Rosen, Daria},
abstractNote = {Here, 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.},
doi = {10.1038/s41467-018-06447-z},
journal = {Nature Communications},
number = 1,
volume = 9,
place = {United States},
year = {2018},
month = {10}
}

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