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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疟疾病例。在无性繁殖期间，在红细胞的发育阶段，疟疾寄生虫从人血清中获得某些营养，保留了合成他人的能力。我们正在研究一种必需的酶辅因子，称为硫辛酸及其恶性疟原虫的代谢。我们的研究表明，红细胞期寄生虫是它们是脂肪酸的营养缺陷型，即使它们含有合成这种辅因子的代谢途径。蛋白顶质体细胞器依赖于硫辛酸合成，而寄生虫线粒体中的蛋白质依赖于清除，不能得到顶质体合成的硫辛酸。拟议的研究集中在两个方面本发明涉及硫辛酸清除方面，并采用生物化学、细胞生物学和遗传方法的组合。我们的第一个目标是确定脂肪酸依赖性蛋白质的必要作用，并确定所需的因素，支持这些活动的寄生虫。我们的第二个目标将探讨硫辛酸的机制摄取和附着到线粒体蛋白质，以了解如何，何时以及为什么这一过程是由氧化还原电位门控。这些研究将建立一个详细的联系之间的脂肪酸附着酶，它们的蛋白质底物。由于依赖于宿主营养素，这些蛋白质代表了宿主营养素的脆弱方面。寄生虫生物学，可以在几个层面上有针对性。