Cutting the Gordian Knot of Iron, Oxygen Radicals, Erythropoiesis, and Red Cell Survival: Allosteric Regulation of Pyruvate Kinase Activity

Iron is an element critical to supporting a wide range of biological functions, chief among them being the support of oxygen transport and cellular respiration. However, iron reduction-oxidation reactions give rise to reactive oxygen species causing oxidative damage. Being both essential and potentially dangerous, iron metabolism from its absorption to utilization in erythropoiesis is tightly controlled. Erythrocyte health and oxygen delivery, reactive oxygen species generation and associated antioxidant activity are all interconnected through a network of feedback loops allowing for dynamic regulation in response to changing body requirements. When tangled by a pathology, this network becomes a real Gordian Knot. Resultant highly variable pathological homeostasis is reviewed with examples of pyruvate kinase (PK) deficiency, hereditary iron overload syndromes, chronic kidney disease, anemia of chronic inflammation, chronic Hepatitis C, beta-thalassemia and homozygous sickle cell disease, and blood transfusion therapy. Emerging understanding of the feedback links between different regulatory systems helps us to cut the metabolic Gordian Knot by tackling the underlying mechanisms of pathology, driving aberrant metabolism towards healthy homeostasis. One such opportunity lies in management of pathology-driven oxidative stress by modulation of the activity of the glycolytic cycle, specifically in the activation of its final energy producing step catalyzed by the pyruvate kinase enzyme. Allosteric regulation of its activity offers an attractive target in multiple therapeutic applications. Most of the evidence of clinical performance of pyruvate kinase activators comes from the work done with mitapivat (Agios Pharmaceuticals), a small-molecule allosteric PK activator that was granted an orphan drug designation by the Food and Drug Administration for PK deficiency, thalassemia, and sickle cell disease. It is currently approved for treatment of PK deficiency in adults and is under review for treatment of thalassemia. A number of other PK activity modulators are currently in development, with different PK isoforms targeted for a range of clinical applications. This potential is rooted in the ability of PK activators to re-activate the glycolytic pathway to generate energy for antioxidation systems, improve glucose utilization, and, in the case of the PK M2 isoform, shift the oligomeric balance away from the form associated with induced transcription of inflammatory cytokines. However, despite extensive research, application of PK activators in clinical practice remains limited. Available clinical evidence and emerging applications are discussed making a case for potential utility of PK activators in a wide spectrum of conditions associated with elevated reactive oxygen species production, increased oxidative stress and inflammation.