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，是世界范围内的一个主要健康问题。利什曼原虫进化出了一个独特的磷酸聚糖(PG)-含糖缀合物家族，包括gpi锚定的原型脂磷酸聚糖（LPG）。利什曼原虫糖缀合物的丰度、位置和独特性暗示这些分子对寄生虫在其严酷的遗传生命周期中生存起着关键作用。不幸的是，PG单元和GPI结构域在相当多的不同糖缀合物中的广泛分布阻碍了对其个体功能和负责其生物合成的酶的全面评估。在一项单独资助的资助下，我们通过糖基化突变体的功能互补和跨物种操作分离相关基因，克服了这一困境。这些研究已经取得了足够的进展，使我们能够将这笔资助集中在参与糖缀合物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缀合物组装的分子途径提供了不可或缺的机会。通过充分表征选定基因编码的关键蛋白，我们期望有意义地推进我们对利什曼原虫如何组装这种复杂的、相互关联的糖缀合物的分类以及它们如何参与寄生虫生命周期的生化作用的理解。

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