Characterization of isoprenoid biosynthesis in human malaria gametocytes

描述（由申请人提供）：超过40%的世界人口面临感染疟疾的风险，耐药性是一个持续存在的问题;因此，迫切需要鉴定和表征具有不同作用模式的抗疟药物开发的新靶标。此外，针对配子体（疟疾的传播阶段）的新药活性被认为是消灭疟疾努力的优先事项。的 类异戊二烯生物合成途径是疟疾特异性靶的有希望的来源，因为：a）它通过存在于顶质体中的疟疾寄生虫中的甲基异戊二酸磷酸途径发生，而在人类中不存在; B）类异戊二烯下游产物不同于人类宿主中的那些;和c）类异戊二烯涉及多种重要的生物功能。我们关于类异戊二烯生物合成的知识大多来自于仅在无性红细胞内阶段进行的研究。然而，它是未知的：a）如果类异戊二烯生物合成发生在配子体发生期间，B）如果类异戊二烯库与无性阶段中存在的相似 以及c）类异戊二烯在配子细胞发生中的作用。我们推测类异戊二烯生物合成存在于配子体阶段，并且对于配子体发生是必不可少的。此外，我们已经确定了一个新的途径甲基萘醌的生物合成，类异戊二烯产品。因此，本申请的首要目标是研究疟疾配子母细胞阶段中的类异戊二烯生物合成并表征疟疾寄生虫中的甲萘醌生物合成。为了实现这些目标，我们将主要使用13 C-代谢标记结合最先进的质谱分析。在这些研究的基础上，该提案的长期目标是确定新的靶点，并验证配子细胞中的已知靶点，用于未来的药物开发，以治愈疟疾并阻止其传播。

DESCRIPTION (provided by applicant): More than 40% of the world's population is at risk of contracting malaria and drug resistance is a constant problem; thus, identification and characterization of new targets for development of antimalarial drugs with different modes of action is critically needed. Moreover, the activity of new drugs against gametocytes, the transmission stage of malaria, is recognized as a priority in the efforts to eradicate malaria. The isoprenoid biosynthetic pathway is a promising source of malaria-specific targets because: a) it occurs through the methylerythritol phosphate pathway in malaria parasites present in the apicoplast and is absent in humans; b) isoprenoid downstream products differ from those in the human host; and c) isoprenoids are involved in a wide variety of vital biological functions. Most of our knowledge about isoprenoid biosynthesis comes from studies performed in the asexual intraerythrocytic stages only. However, it is unknown: a) if isoprenoid biosynthesis occurs during gametocytogenesis, b) if the isoprenoid repertoire is similar to that present in the asexual stages and c) what the role of the isoprenoids are during gametocytogenesis. We hypothesize that isoprenoid biosynthesis is present in gametocyte stages and is essential for gametocytogenesis. In addition, we have identified a novel pathway for menaquinone biosynthesis, an isoprenoid product. Thus, the overarching goal of this application is to study isoprenoid biosynthesis in the malaria gametocyte stages and to characterize the menaquinone biosynthesis in the malaria parasites. To address these aims we will mainly use 13C-metabolic labeling in combination with state-of-the-art mass spectrometry analysis. Building on these studies, the long- term goal of this proposal is to identify novel targets and to validate known targets in gametocytes for future drug development to cure malaria and stop its transmission.