Characterization of isoprenoid biosynthesis in human malaria gametocytes

人疟疾配子细胞中类异戊二烯生物合成的表征

• 批准号: 9206475
• 负责人: Maria Belen Cassera
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-05 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206475
• 关键词: Address; Anabolism; Antimalarials; Bacteria; Biological; Biological Process; Biology; Carotenoids; Chemicals; Contracts; Data; Development; Disease; Dolichol; Drug Targeting; Drug resistance; Enzymes; Eukaryota; Future; Goals; Human; Knock-out; Knowledge; Label; Malaria; Mass Spectrum Analysis; Metabolic; Metabolic Pathway; Metabolism; Morphology; Naphthoquinones; Parasites; Pathway interactions; Pharmaceutical Preparations; Plasmodium falciparum; Population; Prokaryotic Cells; Proteomics; Purine-Nucleoside Phosphorylase; Reporting; Resolution; Risk; Role; Route; Source; Therapeutic Intervention; Time; Tracer; Ubiquinone; Vitamin K 2; asexual; drug development; experimental study; fosmidomycin; futalosine; inhibitor/antagonist; inorganic phosphate; insight; isopentenyl pyrophosphate; isoprenoid; liquid chromatography mass spectrometry; new therapeutic target; novel; novel therapeutics; public health relevance; transmission process

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.

描述（由申请人提供）：世界上超过 40% 的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，迫切需要确定和表征新靶点，以开发具有不同作用方式的抗疟药物。此外，针对配子体（疟疾传播阶段）的新药活性被认为是根除疟疾工作的优先事项。这 类异戊二烯生物合成途径是疟疾特异性靶点的一个有前途的来源，因为：a）它通过疟疾寄生虫中的甲基赤藓糖醇磷酸途径发生，存在于顶质体中，而在人类中不存在； b) 类异戊二烯下游产物与人类宿主中的下游产物不同； c) 类异戊二烯参与多种重要的生物功能。我们关于类异戊二烯生物合成的大部分知识仅来自于无性红细胞内阶段进行的研究。然而，目前尚不清楚：a）类异戊二烯生物合成是否发生在配子细胞发生过程中，b）类异戊二烯库是否与无性阶段中存在的相似 c) 类异戊二烯在配子细胞发生过程中的作用是什么。我们假设类异戊二烯生物合成存在于配子细胞阶段并且对于配子细胞发生至关重要。此外，我们还发现了一种新的甲基萘醌生物合成途径（一种类异戊二烯产物）。因此，本申请的总体目标是研究疟疾配子细胞阶段的类异戊二烯生物合成，并表征疟疾寄生虫中的甲基萘醌生物合成。为了实现这些目标，我们将主要使用 13C 代谢标记与最先进的质谱分析相结合。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体中的已知靶点，以便将来开发治疗疟疾并阻止其传播的药物。