BIOSYNTHESIS--TRYPANOSOME VARIANT SURFACE GLYCOPROTEIN

生物合成--锥虫变体表面糖蛋白

• 批准号: 3131332
• 负责人: PAUL T ENGLUND
• 金额: $ 18.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-05-01 至 1992-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3131332
• 关键词: Trypanosoma; carbohydrate biosynthesis; chromatography; complementary DNA; enzyme structure; enzyme substrate; ethanolamines; glycolipids; high performance liquid chromatography; laboratory mouse; laboratory rabbit; laboratory rat; lipid biosynthesis; membrane lipids; molecular cloning; oligosaccharides; phosphatidylinositols; phospholipase C; protein biosynthesis; surface antigens

African trypanosomes are parasitic protozoa which are responsible for major diseases in humans and animals. They inhabit their host's bloodstream, and evade immune defenses by antigenic variation. Antigenic variation is mediated by Variant Surface Glycoprotein (VSG), which forms a surface coat covering the entire cell. During antigenic variation the parasite synthesizes a new VSG, with a different amino acid sequence, and exchanges its old coat for a new one. It has the genetic potential to synthesize hundreds of different VSG molecules and therefore can maintain a chronic infection. The research concerns biochemical mechanisms associated with antigen variation, and many studies concern the phosphatidylinositol-containing glycolipid which is linked to the VSG and which anchors it to the plasma membrane. We will investigate the trypanosome phospholipase C, known as VSG lipase, which cleaves the glycolipid and releases VSG from the cell (possibly during antigenic variation). This enzyme is already purified to homogeneity and it is highly specific for VSG-related structures. Further studies should define its intracellular localization and may also reveal any regulatory mechanisms. Other studies are planned on the biosythesis of the glycolipid. A pre-formed glycolipid precursor has already been isolated. The next objectives will be to map the pathway by which this precursor is synthesized and to determine the mechanism by which it is covalently linked to the VSG polypeptide. Finally, studies are aimed at characterizing other processing events which occur during VSG biosynthesis. These include N-linked glycosylation and processing of the glycolipid after it is linked to the VSG. These studies may clarify biochemical mechanisms in trypanosomes which may be useful in chemotherapy against these parasites.

非洲锥虫是寄生原生动物，负责主要 人类和动物的疾病。 他们居住在宿主的血液中， 通过抗原变异来逃避免疫防御。 抗原变异是 由变体表面糖蛋白（VSG）介导的，该糖蛋白（VSG）形成表面涂层 覆盖整个牢房。 在抗原变异期间 合成具有不同氨基酸序列的新VSG，并交换 它的新外套。 它具有合成的遗传潜力 数百种不同的VSG分子，因此可以维持慢性 感染。 该研究涉及与抗原相关的生化机制 变异和许多研究涉及含磷酰肌醇的含量 与VSG链接并将其固定到等离子体的糖胶质 膜。 我们将研究锥虫磷脂酶C，称为 VSG脂肪酶，裂解糖脂并从细胞中释放VSG （可能在抗原变异期间）。 该酶已经纯化为 同质性且对与VSG相关的结构高度特异。 更远 研究应定义其细胞内定位，也可能揭示 任何监管机制。 计划了其他研究 糖脂。 预先形成的糖脂前体已经是 孤立。 下一个目标将是映射此途径 综合前体并确定它的机制 共价链接与VSG多肽。 最后，研究的目的是 表征VSG期间发生的其他处理事件 生物合成。 这些包括N连接的糖基化和处理 糖脂链接到VSG后。 这些研究可能会阐明锥虫中的生化机制 在对这些寄生虫的化学疗法中有用。