G6PD Role in Red Blood Cells

Diminished G6PD activity impairs the ability of the cell to form the NADPH that is essential for the maintenance of the G-SH pool. This results in a decrease in the detoxification of free radicals and peroxides formed within the cell (Fig. 1).

G-SH also helps maintain the reduced states of sulfhydryl groups in proteins, including hemoglobin. Oxidation of those sulfhydryl groups leads to the formation of denatured proteins that form insoluble masses (called Heinz bodies) that attach to RBC membranes (Fig. 2). Additional oxidation of membrane proteins causes RBC to be rigid (less deformable), and they are removed from the circulation by macrophages in the spleen and liver. Although G6PD deficiency occurs in all cells of the affected individual, it is most severe in RBC, where the pentose phosphate pathway provides the only means of generating NADPH.
Additionally, the RBC has no nucleus or ribosomes and cannot renew its supply of the enzyme. Thus, RBC are particularly vulnerable to enzyme variants with diminished stability. [Note: Other tissues have an alternative source of NADPH (NADP+-dependent malate dehydrogenase [malic enzyme];) that can keep G-SH reduced.]

Figure 1:  Pathways of glucose 6-phosphate metabolism in the erythrocyte. NADP(H) = nicotinamide adenine dinucleotide phosphate; G-SH = reduced glutathione; G-S-S-G = oxidized glutathione; H2O2 = hydrogen peroxide; PPP = pentose phosphate pathway.

Figure 2:  Heinz bodies in the erythrocytes of a patient with glucose 6-phosphate dehydrogenase deficiency.