Cofactor metabolism and mitochondrial function in malaria parasites

每年数亿疟疾病例是由疟原虫引起的。在无性繁殖过程中 在红细胞的发育阶段，疟疾寄生虫从人类血清中获得某些营养物质，而 保持合成他人的能力。我们正在研究一种名为脂肪酸盐的重要酶辅助因子及其 恶性疟原虫体内的代谢。我们的研究表明，红细胞期寄生虫是 对脂类营养缺乏症，即使它们含有合成这种辅因子的代谢途径。中的蛋白质 质外体细胞器依赖于脂酸盐的合成，而寄生虫线粒体中的蛋白质依赖于 清除，不能获得在质外体中合成的脂酸盐。拟议的研究集中在两个方面 脂肪清除的方方面面，并使用生化、细胞生物学和遗传方法的组合。 我们的第一个目标是定义脂类依赖蛋白的基本作用，并确定所需的因素 支持寄生虫线粒体中的这些活动。我们的第二个目标是探索脂肪酸脂的作用机制。 摄取和附着到线粒体蛋白质，以便了解这一过程是如何、何时和为什么 受氧化还原电势控制。这些研究将在脂类附着酶和 它们的蛋白质底物。由于依赖于宿主的营养，这些蛋白质代表了 寄生虫生物学，可以在几个层面上作为目标。

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.