Cofactor metabolism and mitochondrial function in malaria parasites

疟原虫的辅因子代谢和线粒体功能

基本信息

批准号：
10659968
负责人：
Manuel Llinas
金额：
$ 76.06万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-18 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659968
关键词：
Abbreviations Acetyl Coenzyme A Acyl Carrier Protein Adopted Amino Acids Biochemical Biology Blood Caprylates Cells Cellular biology Chemicals Coenzyme A Coenzymes Data Development Drug resistance Elements Environment Enzymes Erythrocytes Escherichia coli Eukaryotic Cell Genes Glycine Goals Hemagglutinin Human Iodoacetamide Ketoglutarate Dehydrogenase Complex Life Cycle Stages Ligase Ligation Link Malaria Metabolic Pathway Metabolism Mitochondria Mitochondrial Proteins Nuclear Nutrient Organelles Oxidation-Reduction Parasites Pathway interactions Plasmodium Plasmodium falciparum Process Production Protein Acetylation Proteins Pyrimidine Research Role Serum Source System Tricarboxylic Acids Work asexual auxotrophy cofactor forging genetic approach insight lipoamidase lipoate novel novel therapeutic intervention orotate pyruvate dehydrogenase transmission process uptake

项目摘要

Plasmodium parasites are responsible for hundreds of millions of 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 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 the essentail roles of lipoate-dependent proteins and identify the factors required to support these activities in the parasite mitochondrion. Our second aim will probe the mechanism of lipoate uptake and attachment to mitochondrial proteins in order to understand how, when and why this process is gated by redox potential. These studies will forge a detailed link between the lipoate attachment enzymes and their protein substrates. By virtue of relying on a host nutrient, these proteins represent a vulnerable aspect of parasite biology which could be targeted at several levels.

疟原虫寄生虫每年造成数亿个疟疾病例。在无性期间红细胞发育阶段，疟疾寄生虫从人血清中获取某些营养保留综合他人的能力。我们正在研究一种必需的酶辅因子，称为脂肪酸及其恶性疟原虫中的代谢。我们的研究表明，红细胞寄生虫是可营养性的脂酸盐，即使它们包含合成该辅助因子的代谢途径。蛋白质中的蛋白质 Apicoplast Organelle依赖脂肪酸盐合成，而寄生虫线粒体中的蛋白质依赖清除，无法获得apicoplast中合成的lipoate。拟议的研究集中于两个脂肪酸盐清除并采用生化，细胞生物学和遗传方法的组合。我们的第一个目的是定义脂肪酸依赖性蛋白的精致作用，并确定所需的因素在寄生虫线粒体中支持这些活动。我们的第二个目标将探测脂肪酸盐的机制吸收和依恋线粒体蛋白，以了解该过程如何，何时以及为什么通过氧化还原电势门控。这些研究将在脂肪酸酯附着酶和它们的蛋白质底物。由于依靠宿主营养素，这些蛋白质代表了脆弱的方面寄生虫生物学，可以针对多个层次。