Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) maintains redox balance in a variety of cell types and is essential for erythrocyte resistance to oxidative stress. G6PD deficiency, caused by mutations in the G6PD gene, is present in ~400 million people worldwide, and can cause acute hemolytic anemia. Currently, there are no therapeutics for G6PD deficiency. We discuss the role of G6PD in hemolytic and nonhemolytic disorders, treatment strategies attempted over the years, and potential reasons for their failure. We also discuss potential pharmacological pathways, including glutathione (GSH) metabolism, compensatory NADPH production routes, transcriptional upregulation of the G6PD gene, highlighting potential drug targets. The needs and opportunities described here may motivate the development of a therapeutic for hematological and other chronic diseases associated with G6PD deficiency. G6PD deficiency as a hematological disorderGlucose-6-phosphate dehydrogenase (G6PD; see Glossary) regulates glycolytic flux through the pentose phosphate pathway (PPP) and plays a central role in redox homeostasis; it produces NADPH, an essential cofactor for glutathione (GSH) regeneration. G6PD is a major source of NADPH and loss of G6PD function is detrimental in erythrocytes; it causes G6PD deficiency (G6PD def ), a potentially hemolytic disorder [1]. HighlightsGlucose-6-phosphate dehydrogenase (G6PD) deficiency is better known as a hematological disorder. However, G6PD may play a role in other chronic disorders such as diabetes, cardiovascular disease, viral infectivity and complications, and neurodegeneration.

Neurons undergo pathogenic metabolic reprogramming in models of familial ALS

“…The opposing pro- and anti-oxidant activities of G6PDH may be linked to its dynamic subcellular localization [ 30 ]. Because G6PDH deficiency can cause a number of different conditions such as hemolytic anemia or jaundice [ 104 , 105 ] it seems unlikely G6PDH is druggable. While the metabolic effects of G6PDH in the setting of fALS mutant proteins is clearly not straightforward, we believe that deconstructing the role of G6PDH and pathological rewired metabolism in general will reveal novel targets for therapeutic intervention.…”

A Novel Sesquiterpene Lactone Xanthatin-13-(pyrrolidine-2-carboxylic acid) Isolated from Burdock Leaf Up-Regulates Cells’ Oxidative Stress Defense Pathway

“…It is recognized today that two regulations take part in the modulation of the G6PD activity in response to an oxidative stress. Two mechanisms are proposed: firstly a transcriptional regulation increasing the G6PD level and secondly part a post-traductional regulation allowing to convert inactive to active G6PD [31,47].…”

The Possible Role of Glucose-6-Phosphate Dehydrogenase in the SARS-CoV-2 Infection

“…Class II variants are not associated with chronic no spherocytic hemolytic anemia. Patients present acute hemolysis due to infection and food exposure (fava bean), chemicals (naphthalene mothballs), and certain drugs (antibiotics and antimalarial drugs) [47]. In these subjects, there is extensive intravascular hemolysis resulting in tubular necrosis and acute kidney failure.…”

“…They have the G6PD A − variant. African American males (12.2%) and females (4.1%), along with Asian males (4.3%), have the highest rates of G6PD deficiency and individuals with class III variants, and these individuals have intermittent hemolysis caused by oxidant exposure and infection [47]. Subjects with class IV variants have more than 60% of normal G6PD activity in their erythrocytes and show moderate pathological manifestations.…”