Roles of Lipoate Pathways in Plasmodium Survival

硫辛酸途径在疟原虫存活中的作用

• 批准号: 7094051
• 负责人: Sean Taylor PRIGGE
• 金额: $ 40.38万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7094051
• 关键词: Plasmodium falciparum; antioxidants; cofactor; fatty acid biosynthesis; fatty acid metabolism; fatty acid transport; host organism interaction; malaria; microorganism culture; nutrient bioavailability; short chain fatty acid

DESCRIPTION (provided by applicant): Malaria parasites are responsible for 300-500 million infections and 2-3 million deaths annually. During the asexual stages of development in red blood cells, parasites acquire certain nutrients from human serum while retaining the ability to synthesize others. We are studying an essential enzyme cofactor called lipoate and its metabolism in Plasmodium falciparum. Our recent studies indicate that malaria parasites contain a metabolic pathway to synthesize lipoate de novo from intermediates of fatty acid biosynthesis as well as two mechanisms for scavenging lipoate from human serum. These pathways appear to reside in different subcellular compartments in the parasite and may be independent and essential for parasite survival. The proposed studies will employ biochemical, cell biology and genetic approaches to investigate these unexplored pathways and establish the roles of synthesized and host-derived lipoate in parasite survival. Specific Aim 1 will define the activities and organization of the P. falciparum lipoate biosynthetic machinery and the role of synthesized lipoate in parasite survival. Specific Aim 2 will define the role of exogenous lipoate in parasite survival, its distribution in the parasite, and the activities and organization of the P. falciparum lipoate scavenging pathways. These studies could establish the existence of an intracellular metabolite trafficking pathway between the apicoplast organelle and the mitochondrion of malaria parasites. Alternatively, these studies could demonstrate that P. falciparum parasites are auxotrophic for lipoate despite the existence of a lipoate biosynthetic pathway. Proteins responsible for the metabolism of lipoate may ultimately prove to be attractive targets for therapeutic intervention - especially since inhibitors could act synergistically with known inhibitors of P. falciparum fatty acid biosynthesis.

描述（由申请人提供）：疟疾寄生虫每年造成300-5亿次感染和2-3万人死亡。在红细胞发育的无性阶段，寄生虫从人血清中获取某些营养，同时保持合成他人的能力。我们正在研究一种称为脂肪酸的必需酶辅助因子及其在恶性疟原虫中的代谢。我们最近的研究表明，疟疾寄生虫含有一种代谢途径，可以从脂肪酸生物合成中间体中合成脂肪酸盐，以及从人血清中清除脂肪酸的两种机制。这些途径似乎驻留在寄生虫的不同亚细胞隔室中，对于寄生虫存活可能是独立的，至关重要。拟议的研究将采用生化，细胞生物学和遗传学方法来研究这些未开发的途径，并确定合成和宿主衍生的脂肪酸在寄生虫存活中的作用。具体目标1将定义恶性疟原虫脂肪酸盐生物合成机械的活性和组织，以及合成的脂肪酸盐在寄生虫生存中的作用。具体目标2将定义外源脂肪酸在寄生虫生存中的作用，其在寄生虫中的分布以及恶性疟原虫脂肪酸脂肪酸疟原虫的清除途径的作用。这些研究可以确定apicopoplast细胞器和疟原虫线粒体之间的细胞内代谢物运输途径。另外，这些研究可以表明，尽管存在脂肪酸盐生物合成途径，但恶性疟原虫的寄生虫是可营养的。负责脂肪酸代谢的蛋白质最终可能被证明是治疗干预的有吸引力的靶标 - 尤其是因为抑制剂可以与已知的恶性疟原虫脂肪酸脂肪酸生物合成抑制剂协同作用。