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.

中文翻译：

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靶向宿主糖酵解作为抗疟疾发展的策略。

糖酵解控制细胞能量，氧化还原平衡和生物合成。目前正在研究抗糖酵解疗法，以治疗肥胖症，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具有很高的价值，因为通常在哺乳动物中可以耐受糖酵解。不幸的是，贫血是这些抑制剂的已知剂量限制副作用，并且对抗糖酵解疗法的发展提出了重大警告。我们开发了烯醇酶（糖酵解中的关键酶）的特异性抑制剂，并验证了它们对人红细胞的代谢和细胞作用。烯醇酶的抑制作用增加了红细胞对氧化损伤的敏感性，并引起了快速和过早的红细胞衰老，而不是直接溶血。我们应用我们的红细胞毒性模型来解决关于恶性疟原虫疟疾发病机制中红细胞糖酵解破坏的问题。我们的研究为理解正常和疾病状态下的红细胞稳态提供了框架，并阐明了红细胞还原能力在疟原虫生长中的重要性。