Glycobiology of Leishmania

描述(由申请人提供)：利什曼原虫属寄生虫是利什曼病的病原体，利什曼病是世界范围内的主要健康问题。利什曼原虫已经进化出一个独特的含磷多糖(PG)的糖偶联物家族，包括GPI锚定的原型脂多糖(LPG)。利什曼原虫糖结合物的丰度、位置和独特性表明，这些分子在寄生虫艰难的双基因生命周期中对其生存起着至关重要的作用。不幸的是，PG单位和GPI结构域广泛分布在相当多不同的糖共轭化合物中，这阻碍了对它们各自功能和负责其生物合成的酶的全面评估。在一项单独资助的拨款中，我们通过糖基化突变体和跨物种操作的功能互补来分离相关基因，从而克服了这一困境。这些研究已经取得了足够的进展，使我们能够将这笔赠款集中在参与糖共轭生物合成和表达的编码蛋白的酶学上，这反过来又为仔细研究利什曼原虫糖共轭组装的分子途径提供了不可或缺的机会。通过对所选基因编码的关键蛋白进行充分的表征，我们希望有意义地促进我们对利什曼原虫如何组装这种复杂的、相互关联的糖结合物以及它们如何在生物化学上参与寄生虫的生命周期的理解。 这项相互竞争的续订申请的具体目标是： 1.研究高尔基体核苷酸-糖转运蛋白家族。 2.鉴定参与PG合成的多个甘露糖基磷酸转移酶(MPTS)。 3.确定伴侣蛋白与PG重复单元半乳糖化的关系。 4.研究控制液化石油气长度和侧链糖链修饰的蛋白质。

DESCRIPTION (provided by the applicant): Protozoan parasites of the genus Leishmania are the causative agents of leishmaniasis, a major health problem worldwide. Leishmania have evolved a unique family of phosphoglycan (PG)- containing glycoconjugates, including the GPI-anchored prototype lipophosphoglycan (LPG). The abundance, location, and uniqueness of the Leishmania glycoconjugates have implicated these molecules in critical roles for the parasite's survival in their harsh digenetic life cycle. Unfortunately, the wide distribution of PG units and GPI domains across a considerable number of diverse glycoconjugates has hindered a comprehensive assessment of their individual functions and the enzymes responsible for their biosynthesis. In a separately funded grant, we have surmounted this dilemma by isolating relevant genes via functional complementation of glycosylation mutants and cross-species manipulations. These studies have progressed sufficiently to enable us to focus this grant on the enzymology of the encoded proteins involved in glycoconjugate biosynthesis and expression, which in turn, represent indispensable opportunities toward scrutinizing the molecular pathways of glycoconjugate assembly in Leishmania. By fully characterizing key proteins encoded by selected genes, we expect to meaningfully advance our understanding of how Leishmania assemble such an assortment of complex, interrelated glycoconjugates and how they are biochemically involved in the parasite's life cycle. The specific aims of this competing renewal application are: 1. to investigate the family of Golgi nucleotide-sugar transporters. 2. to characterize the multiple mannosylphosphoryltransferases (MPTs) involved in PG synthesis. 3. to determinate the relationship of a chaperone with galactosylation of PG repeat units. 4. to examine the proteins involved in controlling LPG length and side chain sugar modifications