Oxidative pentose phosphate pathway enzymes (oxPPP enzymes)

The oxidative pentose phosphate pathway (oxPPP) enzymes, primarily Glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD), catalyze the rate-limiting steps of the pentose phosphate pathway (Stanton, 2012, Free Radic Biol Med). These enzymes are essential for the production of nicotinamide adenine dinucleotide phosphate (NADPH), which provides the reducing power for fatty acid synthesis and the maintenance of reduced glutathione to protect cells against oxidative damage (Patra & Hay, 2014, Trends Biochem Sci). Additionally, the pathway generates ribose-5-phosphate, a critical precursor for nucleotide and nucleic acid biosynthesis (Jiang et al., 2014, Nat Rev Cancer). In many cancers, oxPPP enzymes are overexpressed to meet the high metabolic demands of rapid proliferation and to counteract increased reactive oxygen species (ROS) (Ge et al., 2020, Signal Transduct Target Ther). Consequently, inhibiting these enzymes, particularly G6PD and 6PGD, has emerged as a strategy to induce oxidative stress and metabolic exhaustion in tumor cells (Lin et al., 2015, Sci Rep). However, therapeutic intervention must account for the risk of hemolytic anemia, a well-known side effect associated with G6PD deficiency, as red blood cells rely exclusively on the oxPPP for antioxidant defense (Luzzatto et al., 2020, Blood).

Other names

Pentose phosphate pathway oxidative phase enzymesPPP oxidative branch enzymesGlucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase complexNADPH-generating enzymes of the pentose phosphate pathway

Inhibition of the rate-limiting enzymes Glucose-6-phosphate dehydrogenase (G6PD) or 6-phosphogluconate dehydrogenase (6PGD) to reduce the production of NADPH and ribose-5-phosphate, thereby inducing oxidative stress and impairing macromolecular synthesis in rapidly proliferating cells (Patra & Hay, 2014, Trends Biochem Sci).