Dual role of G6PD as an antioxidant and pro-oxidant enzyme in redox biology
The housekeeping gene G6PD or its ortholog, can be found in prokaryotic and eukaryotic organisms [15,16] as well as in all cells of the human body encoding the rate-limiting enzyme in the hexose monophosphate shunt (HMS), also known as the pentose phosphate pathway (PPP). The main product of G6PD, NADPH, is required for reductive biosynthesis and the maintenance of redox homeostasis. NADPH is critical for the regeneration of glutathione (GSH), which serves a significant role in cellular antioxidant defense. NADPH also plays various roles in cytoregulation mediated by redox signaling, for instance, by reactive oxygen species (ROS) and reactive nitrogen species (RNS) produced from NADPH oxidase (NOX) and nitric oxide synthase (NOS), respectively [17].
G6PD status is extremely important in modulating the level of ROS. On the one hand, G6PD maintains redox homeostasis by keeping cytotoxic ROS at proper levels because high levels of ROS are cytotoxic. For example, 120-150 µM of hydrogen peroxide (H2O2) leads to temporary growth arrest, while repeated encounters of the treatment or an increase in concentration by 2-fold (250–450 µM) of H2O2 causes the cells to permanently undergo growth arrest or enter into a senescent state. At even higher concentrations (0.5–1 mM) of H2O2, cells undergo apoptosis. Cells exhibit necrosis when challenged with even higher concentrations (5-10 mM) of H2O2 [18]. On the other hand, different low levels of ROS can induce a wide spectrum of cellular responses such as with 3–15 µM of H2O2, which can stimulate mitogenic cell growth [19]. ROS at sub-micromolar ranges often serves as messengers for regulating cellular processes [20,21].