Central Laboratory, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan.
Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan.
PLoS Pathog. 2024 Aug 22;20(8):e1012435. doi: 10.1371/journal.ppat.1012435. eCollection 2024 Aug.
Entamoeba histolytica is a protozoan parasite belonging to the phylum Amoebozoa that causes amebiasis, a global public health problem. E. histolytica alternates its form between a proliferative trophozoite and a dormant cyst. Trophozoite proliferation is closely associated with amebiasis symptoms and pathogenesis whereas cysts transmit the disease. Drugs are available for clinical use; however, they have issues of adverse effects and dual targeting of disease symptoms and transmission remains to be improved. Development of new drugs is therefore urgently needed. An untargeted lipidomics analysis recently revealed structural uniqueness of the Entamoeba lipidome at different stages of the parasite's life cycle involving very long (26-30 carbons) and/or medium (8-12 carbons) acyl chains linked to glycerophospholipids and sphingolipids. Here, we investigated the physiology of this unique acyl chain diversity in Entamoeba, a non-photosynthetic protist. We characterized E. histolytica fatty acid elongases (EhFAEs), which are typically components of the fatty acid elongation cycle of photosynthetic protists and plants. An approach combining genetics and lipidomics revealed that EhFAEs are involved in the production of medium and very long acyl chains in E. histolytica. This approach also showed that the K3 group herbicides, flufenacet, cafenstrole, and fenoxasulfone, inhibited the production of very long acyl chains, thereby impairing Entamoeba trophozoite proliferation and cyst formation. Importantly, none of these three compounds showed toxicity to a human cell line; therefore, EhFAEs are reasonable targets for developing new anti-amebiasis drugs and these compounds are promising leads for such drugs. Interestingly, in the Amoebazoan lineage, gain and loss of the genes encoding two different types of fatty acid elongase have occurred during evolution, which may be relevant to parasite adaptation. Acyl chain diversity in lipids is therefore a unique and indispensable feature for parasitic adaptation of Entamoeba.
溶组织内阿米巴是一种属于肉足鞭毛门的原生动物寄生虫，可引起阿米巴病，这是一个全球性的公共卫生问题。溶组织内阿米巴在增殖的滋养体和休眠的包囊之间交替形态。滋养体的增殖与阿米巴病的症状和发病机制密切相关，而包囊则传播疾病。目前已有用于临床的药物，但存在不良反应问题，且疾病症状和传播的双重靶向仍有待改善。因此，迫切需要开发新的药物。最近的一项非靶向脂质组学分析揭示了寄生虫生命周期不同阶段的内阿米巴脂质组的结构独特性，涉及非常长（26-30 个碳原子）和/或中（8-12 个碳原子）酰链与甘油磷脂和鞘脂的连接。在这里，我们研究了这种独特的酰链多样性在非光合原生动物溶组织内阿米巴中的生理学。我们鉴定了溶组织内阿米巴脂肪酸延长酶（EhFAEs），这些酶通常是光合原生生物和植物脂肪酸延长循环的组成部分。一种结合遗传学和脂质组学的方法表明，EhFAEs 参与了溶组织内阿米巴中中链和长链酰基的产生。该方法还表明，K3 组除草剂氟草烟、杀草丹和 Fenoxasulfone 抑制了长链酰基的产生，从而损害了内阿米巴滋养体的增殖和包囊的形成。重要的是，这三种化合物对人细胞系均没有毒性；因此，EhFAEs 是开发新型抗阿米巴病药物的合理靶点，这些化合物是此类药物的有希望的先导化合物。有趣的是，在肉足鞭毛门的谱系中，两种不同类型的脂肪酸延长酶的基因在进化过程中发生了获得和丢失，这可能与寄生虫的适应性有关。因此，脂质中的酰链多样性是内阿米巴寄生虫适应性的一个独特和不可或缺的特征。
