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.

糖酵解控制细胞能量、氧化还原平衡和生物合成。抗糖酵解疗法正在研究用于治疗肥胖、癌症、衰老、自身免疫和微生物疾病。中断糖酵解作为一种治疗策略受到高度重视，因为哺乳动物通常可以耐受糖酵解中断。不幸的是，贫血是这些抑制剂已知的剂量限制性副作用，并且对开发抗糖酵解疗法提出了主要警告。我们开发了烯醇化酶（糖酵解中的一种关键酶）的特异性抑制剂，并验证了它们对人类红细胞的代谢和细胞作用。烯醇化酶抑制增加红细胞对氧化损伤的敏感性并诱导红细胞快速和过早衰老，而不是直接溶血。恶性疟原虫疟疾发病机制。我们的研究为了解正常和疾病状态下的红细胞稳态提供了一个框架，并阐明了红细胞还原能力在疟原虫生长中的重要性。