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: 8795158
• 负责人: Maria Belen Cassera
• 金额: $ 39.48万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8795158
• 关键词: Address; Affect; Anabolism; Antimalarials; Bacteria; Biological Process; Biology; Carotenoids; Chemicals; Contracts; Data; Development; Disease; Dolichol; Drug Targeting; Drug resistance; Enzymes; Eukaryota; Future; Goals; Health; Human; Knock-out; Knowledge; Label; Longitudinal Studies; Malaria; Mass Spectrum Analysis; Metabolic; Metabolic Pathway; Metabolism; Naphthoquinones; Parasites; Pathway interactions; Pharmaceutical Preparations; Plasmodium falciparum; Population; Prokaryotic Cells; Proteomics; Purine-Nucleoside Phosphorylase; Reporting; Resolution; Risk; Role; Route; Source; Staging; Therapeutic Intervention; Time; Tracer; Ubiquinone; Vitamin K 2; asexual; drug development; fosmidomycin; futalosine; inhibitor/antagonist; inorganic phosphate; insight; isopentenyl pyrophosphate; isoprenoid; liquid chromatography mass spectrometry; novel; research study; 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）：世界上有40％以上的人口有癌症和抗药性的风险是一个恒定的问题；因此，需要鉴定和表征以不同作用方式开发抗疟药的新靶标。此外，疟疾的传播阶段针对配子细胞的新药的活性被认为是消除疟疾的努力的优先事项。这 类异型生物合成途径是疟疾特异性靶标的有希望的来源，因为：a）它通过疟原虫寄生虫存在的疟原虫磷酸甲酯途径发生，人类在人类中不存在； b）类异戊二烯下游产品与人类宿主中的产品不同； c）类异戊二烯涉及多种重要的生物学功能。我们对类吸生物合成的大多数知识都来自在无性关注阶段进行的研究。但是，这是未知的：a）如果异丙因生物合成发生在配子型生成期间 c）类吸收在配子细胞生成中的作用是什么。我们假设异急动物生物合成存在于配子细胞阶段，对于配子细胞生成至关重要。此外，我们已经确定了甲喹酮生物合成的新途径，这是一种类异on-产物。因此，该应用的总体目标是研究疟疾配子细胞阶段中的类异型生物合成，并表征疟疾寄生虫中的甲喹酮生物合成。为了解决这些目标，我们将主要使用13C代谢标记与最先进的质谱分析结合使用。在这些研究的基础上，该提案的长期目标是确定新颖的目标并验证配子细胞中的已知靶标，以使未来的药物开发以治愈疟疾并停止其传播。