Roles of Lipoate Pathways in Plasmodium Survival

疟疾寄生虫每年造成3亿至5亿人感染和200万至300万人死亡。在.期间 在红血球的无性发育阶段，寄生虫从人的血清中获取某些营养 同时保留合成他人的能力。我们正在研究一种叫做脂酸盐的重要酶辅因子。 及其在恶性疟原虫体内的代谢。我们最近的研究表明，疟疾寄生虫含有一种 由脂肪酸生物合成中间体和两种化合物合成脂肪酸脂的代谢途径 从人血清中清除脂类的机制。这些途径似乎驻留在不同的 寄生虫体内的亚细胞室，对寄生虫的生存可能是独立的和必不可少的。这个 拟议的研究将使用生化、细胞生物学和遗传学方法来研究这些 未探索的途径，并确定合成和宿主来源的脂酸盐在寄生虫生存中的作用。 具体目标1将确定恶性疟原虫脂肪酸盐生物合成机制的活动和组织 以及合成脂类在寄生虫生存中的作用。具体目标2将定义外源基因的作用 脂类在寄生虫生存中的作用，在寄生虫中的分布，以及P。 恶性疟原虫脂酸盐清除途径。这些研究可以证明细胞内存在一种 疟原虫质外体细胞器与线粒体之间的代谢产物运输途径。 或者，这些研究可以证明，尽管恶性疟原虫对脂类具有营养缺乏性，但 脂酸盐生物合成途径的存在。负责脂肪代谢的蛋白质可能 最终被证明是治疗干预的有吸引力的靶点--特别是因为抑制剂可以 与已知的恶性疟原虫脂肪酸生物合成抑制剂协同作用。

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 pathwayto synthesize lipoate de nowofrom 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 parasitesurvival. Specific Aim 1will define the activities and organization of the P. falciparum lipoate biosyntheticmachinery and the role of synthesized lipoate in parasite survival. Specific Aim 2 will define the role ofexogenous 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 couldact synergistically with known inhibitors of P. falciparum fatty acid biosynthesis.