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: 7563261
• 负责人: Sean Taylor PRIGGE
• 金额: $ 39.05万
• 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/7563261
• 关键词: Abbreviations; Acyl Carrier Protein; Albumins; Antioxidants; Bacteria; Binding; Biochemical; Biological; Blood; Cell Respiration; Cells; Cellular biology; Cessation of life; Coenzyme A; Coenzymes; Communicable Diseases; Complex; Cytosol; Development; Digestion; Disease; Enzymes; Erythrocytes; Escherichia coli; Food; Genetic; Goals; Growth; Heme Iron; Hemoglobin; Housing; Human; Infection; Intestines; Iron; Ketoglutarate Dehydrogenase Complex; Life; Ligase; Lipids; Malaria; Mammalian Cell; Mammals; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular Genetics; Multienzyme Complexes; Nutrient; Organelles; Oxidoreductase; Parasites; Pathway interactions; Phosphate Buffer; Plasmodium; Plasmodium falciparum; Proteins; Pyruvate Dehydrogenase Complex; Reactive Oxygen Species; Research Personnel; Role; Saline; Serum; Serum Albumin; Staging; Stream; Therapeutic Intervention; Trichloroacetic Acid; asexual; base; cofactor; fatty acid biosynthesis; inhibitor/antagonist; lipoate; maltose-binding protein; novel therapeutic intervention; oxidative damage; prevent; programs; research study; trafficking; uptake

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.

疟疾寄生虫每年造成 300-5 亿人感染和 2-300 万人死亡。期间 在红细胞的无性发育阶段，寄生虫从人血清中获取某些营养物质 同时保留综合其他能力的能力。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 从脂肪酸生物合成的中间体立即合成硫辛酸的代谢途径以及两种 从人血清中清除硫辛酸的机制。这些途径似乎驻留在不同的地方 寄生虫中的亚细胞区室，可能是独立的并且对于寄生虫的生存至关重要。这 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 未探索的途径并确定合成的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器的活动和组织 以及合成硫辛酸在寄生虫存活中的作用。具体目标 2 将定义外源性的作用 硫辛酸对寄生虫生存的影响、其在寄生虫中的分布以及寄生虫的活动和组织。 恶性疟原虫硫辛酸清除途径。这些研究可以确定细胞内存在 疟原虫顶端体细胞器和线粒体之间的代谢物运输途径。 或者，这些研究可以证明恶性疟原虫寄生虫对于硫辛酸来说是营养缺陷型的，尽管 硫辛酸生物合成途径的存在。负责硫辛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目标——特别是因为抑制剂可以起作用 与已知的恶性疟原虫脂肪酸生物合成抑制剂具有协同作用。