Abstract
Glycolysis controls cellular energy, redox balance, and biosynthesis. Antiglycolytic therapies are under investigation for treatment of obesity, cancer, aging, autoimmunity, and microbial diseases. Interrupting glycolysis is highly valued as a therapeutic strategy, because glycolytic disruption is generally tolerated in mammals. Unfortunately, anemia is a known dose-limiting side effect of these inhibitors and presents a major caveat to development of antiglycolytic therapies. We developed specific inhibitors of enolase – a critical enzyme in glycolysis – and validated their metabolic and cellular effects on human erythrocytes. Enolase inhibition increases erythrocyte susceptibility to oxidative damage and induces rapid and premature erythrocyte senescence, rather than direct hemolysis. We apply our model of red cell toxicity to address questions regarding erythrocyte glycolytic disruption in the context of Plasmodium falciparum malaria pathogenesis. Our study provides a framework for understanding red blood cell homeostasis under normal and disease states and clarifies the importance of erythrocyte reductive capacity in malaria parasite growth.
Highlights
Infection with Plasmodium spp. malaria parasites contributes to over 400,000 deaths annually
Continuous exposure to high concentrations of enolase inhibitors does not lead to erythrocyte lysis in static culture (Figure 4C). These results indicate that senescence and premature splenic clearance and destruction, rather than direct hemolysis, are the most likely mechanism for the decreased circulating half-life and anemia associated with interrupted glycolysis in erythrocytes in vivo
We find that the antimalarial potency of each compound was highly correlated (r2 = 0.94) to its capacity to disrupt erythrocyte redox balance (MetHb EC50) (Figure 4E)
Summary
Infection with Plasmodium spp. malaria parasites contributes to over 400,000 deaths annually. Chemotherapeutic resistance remains a central roadblock to malaria control, and novel antimalarials are urgently required. One approach to circumvent resistance is through targeting host, rather than parasitic, processes essential for parasite survival. As the pathogenic stage of Plasmodium spp. develops within erythrocytes, the red cell niche presents a unique set of potential host targets that are needed to maintain erythrocyte metabolic homeostasis. The promise of erythrocyte-targeted antimalarial therapies is underscored by the prevalence of hereditary erythrocyte metabolic disorders in humans. These include glucose-6-phosphate dehydrogenase deficiency (G6PDd, the most common inherited enzymopathy of humans), pyruvate kinase
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