Roles of Lipoate Pathways in Plasmodium Survival

描述（由申请人提供）：疟疾寄生虫每年造成3 - 5亿人感染和2-3百万人死亡。在红细胞发育的无性阶段，寄生虫从人类血清中获得某些营养素，同时保留合成其他营养素的能力。我们正在研究一种称为硫辛酸的必需酶辅因子及其在恶性疟原虫中的代谢。我们最近的研究表明，疟疾寄生虫含有一个代谢途径，从脂肪酸生物合成的中间体，以及两个机制，从人血清中清除硫辛酸从头合成。这些途径似乎存在于寄生虫的不同亚细胞区室中，并且可能是寄生虫生存所必需的独立途径。拟议的研究将采用生物化学，细胞生物学和遗传学方法来研究这些未探索的途径，并建立合成和宿主衍生的硫辛酸在寄生虫生存中的作用。具体目标1将定义恶性疟原虫硫辛酸生物合成机制的活动和组织以及合成的硫辛酸在寄生虫存活中的作用。具体目标2将定义外源性硫辛酸在寄生虫存活中的作用、其在寄生虫中的分布以及恶性疟原虫硫辛酸清除途径的活性和组织。这些研究可以建立一个细胞内代谢物运输途径之间的顶质体细胞器和疟原虫的寄生虫。或者，这些研究可以证明，恶性疟原虫是营养缺陷型的硫辛酸，尽管存在的硫辛酸生物合成途径。负责脂肪酸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标-特别是因为抑制剂可以与恶性疟原虫脂肪酸生物合成的已知抑制剂协同作用。

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.