Roles of Lipoate Pathways in Plasmodium Survival

硫辛酸途径在疟原虫存活中的作用

基本信息

批准号：
7350213
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
项目类别：
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/7350213
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 therapeutics prevent programs research study trafficking uptake

项目摘要

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.

疟疾寄生虫每年导致300-5亿感染和2-3万人死亡。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同时保留合成他人的能力。我们正在研究一种称为脂肪酸盐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，疟疾寄生虫含有代谢途径合成脂肪酸脂肪酸盐的脂肪酸生物合成中间体以及两个从人血清清除脂肪的机制。这些途径似乎存在于不同的寄生虫中的亚细胞隔室可能是独立的，对于寄生虫生存至关重要。这拟议的研究将采用生化，细胞生物学和遗传方法来研究这些方法未开发的途径，并在寄生虫存在中建立了合成和宿主衍生的脂肪的作用。特定目的1Will定义恶性疟原虫脂肪酸盐生物合成机械的活动和组织以及合成的脂肪酸在寄生虫存活中的作用。特定的目标2将定义外生的作用寄生虫生存中的脂肪，其在寄生虫中的分布以及P的活动和组织。恶性脂肪酸脂肪清除途径。这些研究可以确定细胞内的存在 Apicoplast Organelle和疟原虫线粒体之间的代谢物贩运途径。或者，这些研究可以表明，尽管脂肪酸生物合成途径的存在。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 - 尤其是因为抑制剂可能施加与已知的恶性脂肪酸脂肪酸生物合成的已知抑制剂协同作用。