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.
Highlights
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 in newborns
G6PD is essential in preserving the integrity of erythrocytes because, lacking mitochondria, they have no other NADPH-generating enzymes to protect against oxidative stress[2]
In addition to the role of G6PD in preventing hemolysis, the anti-oxidant property of G6PD may relate to development of a variety of other pathologies, including kidney injury, heart failure, psychiatric disorder, diabetes, cholelithiasis, and cataract[44,45,46,47,48,49,50,51,52], suggesting that G6PD deficiency can be an underestimated risk factor for multiple human pathologies
Summary
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 in newborns. Impaired anti-oxidant defense in G6PD-deficient erythrocytes makes them vulnerable to early membrane damage and phagocytosis when infected with malaria[5]. G6PD-deficient individuals are at a high risk of severe hemolysis when given anti-malarial drugs, such as quinine, primaquine or chloroquine, through irreversible oxidative activity of their metabolites on erythrocytes[8,9]. Given the risk of hemolytic crisis and related sequelae from various triggers in affected subjects in both malaria endemic and nonendemic regions, we believe that developing a pharmacological agent that corrects G6PD deficiency may benefit affected individuals
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