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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：
8435938
负责人：
Sean Taylor PRIGGE
金额：
$ 39.97万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8435938
关键词：
Abbreviations Acyl Carrier Protein Adopted Amino Acids Bacteria Binding Biochemical Biology Blood Carbon Cells Cellular biology Chemicals Citric Acid Cycle Coenzyme A Coenzymes Complex Development Dihydrofolate Reductase Drug resistance Elements Environment Enzymes Erythrocytes Escherichia coli Future Gene Expression Regulation Genes Genetic Glutathione Glycine Goals Green Fluorescent Proteins Housing Human Kinetics Label Ligase Link Malaria Mammals Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Mitochondrial Proteins Multienzyme Complexes Multivitamin Mus Nutrient Organelles Organism Orthologous Gene Oxidoreductase Parasites Pathway interactions Plasmodium Plasmodium falciparum Play Proteins Research Role Serum Staging Substrate Specificity Tricarboxylic Acids Work asexual auxotrophy cofactor forging in vitro Assay ketoglutarate dehydrogenase killings lipoamidase lipoate maltose-binding protein novel therapeutic intervention protein complex protein metabolism protein structure pyruvate dehydrogenase research study uptake

项目摘要

DESCRIPTION (provided by applicant): Plasmodium parasites are responsible for over half a billion malaria cases annually. During the asexual stages of development in red blood cells, malaria 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 demonstrate that erythrocytic stage parasites are auxotrophic for lipoate, even though they contain a metabolic pathway to synthesize this cofactor. Proteins in the apicoplast organelle rely on lipoate synthesis while proteins in the parasite mitochondrion rely on scavenging and cannot obtain lipoate synthesized in the apicoplast. The proposed studies are focused on two aspects of lipoate scavenging and employ a combination of biochemical, cell biology and genetic approaches. Our first aim is to define how lipoate is taken up from the external environment and attached to specific proteins in the parasite mitochondrion. These experiments will identify rate limiting steps in the uptake of lipoate and they will forge a detailed link between the lipoate attachment enzymes and their protein substrates. Our second aim is to identify the lipoate-dependent mitochondrial proteins that are essential for parasite survival and determine the roles of these proteins in parasite biology. In other organisms, these proteins form large multi-enzyme complexes which can have a variety of metabolic and non-metabolic roles. Our experiments will dissect the domain structure of these proteins, determine their activities, and identify their binding partners in protein complexes. Genetic approaches will define the roles of lipoate metabolism proteins in the survival of blood stage parasites. By virtue of relying on a host nutrient, these proteins represent a vulnerable aspect of parasite biology which could be targeted at several levels.

描述（由申请人提供）：疟原虫寄生虫每年造成超过 5 亿例疟疾病例。在红细胞发育的无性阶段，疟原虫从人血清中获取某些营养物质，同时保留合成其他营养物质的能力。我们正在研究一种称为硫辛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，红细胞阶段寄生虫对于硫辛酸来说是营养缺陷型的，尽管它们含有合成这种辅因子的代谢途径。顶质体细胞器中的蛋白质依赖于硫辛酸合成，而寄生虫线粒体中的蛋白质依赖于清除，无法获得顶质体中合成的硫辛酸。拟议的研究重点关注硫辛酸清除的两个方面，并采用生化、细胞生物学和遗传学方法的组合。我们的首要目标是确定硫辛酸如何从外部环境中吸收并附着在寄生虫线粒体中的特定蛋白质上。这些实验将确定硫辛酸摄取的限速步骤，并将在硫辛酸附着酶与其蛋白质底物之间建立详细的联系。我们的第二个目标是鉴定对寄生虫生存至关重要的脂酸依赖性线粒体蛋白，并确定这些蛋白质在寄生虫生物学中的作用。在其他生物体中，这些蛋白质形成大型多酶复合物，具有多种代谢和非代谢作用。我们的实验将剖析这些蛋白质的结构域，确定它们的活性，并识别它们在蛋白质复合物中的结合伙伴。遗传方法将确定硫辛酸代谢蛋白在血液阶段寄生虫存活中的作用。由于依赖于宿主营养素，这些蛋白质代表了寄生虫生物学的一个脆弱方面，可以在多个层面上进行攻击。