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.

Trial registration: ClinicalTrials.gov NCT02937363 NCT02124083 NCT03056495 NCT03894826 NCT03167437.

Keywords: G6PD deficiency; N-acetyl-cysteine; enzyme activators; therapeutic strategy; transcriptional regulators.

Conflict of interest statement

Declaration of interests None are declared.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1.

A potential mechanism for ascorbate induced AHA in G6PDdef. a) Ascorbate concentration increases in the plasma as a result of IV or oral administration. b) In the presence of oxidative stress, ascorbate is oxidized to DHA in the plasma. c) Subsequently, DHA and ascorbate are imported into erythrocytes, with DHA having a higher preference for import. d) Once inside, DHA is reduced by GSH, depleting the already small GSH pool in G6PDdef. e) The ascorbate, imported from the plasma or generated via DHA reduction, can interact with oxidized iron to generate radicals. f) Both GSH depletion and iron-generated radicals likely contribute to cell damage and a hemolytic phenotype in G6PDdef.

Figure 2.

Metabolic rewiring in G6PDdef erythrocytes and NAC as a potential therapeutic route. G6PDdef erythrocytes have reduced (red) and elevated (teal) metabolites, favoring GSH production, however LC is limiting. a) NAC concentration increases in the plasma as a result of IV or oral administration. b) NAC undergoes redox exchange reactions in the plasma to generate LC. c) LC and NAC are imported into erythrocytes, where (d) NAC is deacylated to produce LC. (e) LC is used for GSH biosynthesis, (f) which may restore the GSH pool. NAC treatment combined with a GCL activator may maximize GSH biosynthesis and overcome GSH imbalance in G6PDdef erythrocytes. Abbreviations: 1,3 BPG, 1,3-bisphosphoglycerate; 2PG, 2-phosphoglycerate; 3PG, 3-phosphoglycerate; 6PG, 6-phosphogluconate; 6PGD, 6-phosphogluconate dehydrogenase; 6PGL, 6-phosphogluconolactone; E4P, erythrose 4-phosphate; F6P, fructose 6-phosphate; GGC, gamma-glutamylcysteine; G6P, glucose 6-phosphate; G3P, glyceraldehyde 3-phosphate; PEP, phosphoenolpyruvate; R5P, ribose 5-phosphate; Ru5P, ribulose 5-phosphate; S7P, sedoheptulose 7-phosphate; X5P, xylulose 5-phosphate.

Figure 3.

The process and consequence of HDACi-mediated transcriptional activation of the G6PD gene in erythroid cells. a) HDACi exposes the G6PD core promoter; b) SP1, HAT, HDAC, and DNA polymerase localize to the core promoter to induce G6PD transcription in erythroid precursor cells and c,d) subsequently increase protein levels in new erythrocytes. However, HDAC5 and HDAC2 have been found to disrupt erythropoiesis and therefore, inhibition of these two HDACs may have adverse side effects. Other transcriptional modulators, such as a Nrf2/Keap1 protein-protein-interaction inhibitor, may also increase G6PD transcriptional output. e) G6PD variant biochemical properties will likely influence the efficacy of a transcriptional activator, with protein stability being a major determinant of residual protein levels in aging erythrocytes.

Figure 4.

Summary of some of the chronic diseases associated with G6PDdef and strategies to treat G6PD related disorders. Treatment strategies include increasing GSH biosynthesis by activating GCL and co-supplementing with LC/NAC; activating NADPH compensatory enzymes ME1, IDH1; upregulating G6PD protein levels via HDAC inhibitors (HDACi) or Nrf2; small molecule chaperones increasing catalytic activity and stability of G6PD; antioxidants; and gene therapy (this strategy is likely for most severe Class I variants).