Innovative medicine

Abstract

R eactive oxygen species (ROS) are an intricate part of normal cellular physiology. In excess, however, ROS can damage all three major classes of macromolecules and compromise cell viability. We briefl y discuss the physiology of ROS but focus on the mechanisms cells use to preserve redox homeostasis upon oxidative stress, with particular emphasis on glycolysis. ROS inhibits multiple glycolytic enzymes, including glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase M2, and phosphofructokinase-1. Consistently, glycolytic inhibition promotes fl ux into the oxidative arm of the pentose phosphate pathway to generate NADPH. NADPH is critically important, as it provides the reducing power that fuels the protein-based antioxidant systems and recycles oxidized glutathione. The unique ability of pyruvate kinase M2 inhibition to promote serine synthesis in the context of oxidative stress is also discussed.