Cofactor metabolism and mitochondrial function in malaria parasites

疟原虫的辅因子代谢和线粒体功能

• 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
• 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

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.

疟原虫每年造成数亿例疟疾病例。在无性恋期间