GLYCOCONJUGATES OF LEISHMANIA

利什曼病是人类的一个主要健康问题， 利什曼原虫属的原生寄生虫。 脂磷酸聚糖（LPG）是 前鞭毛体形式的表面上的重要大分子 这些寄生虫被认为是多功能的。 结构上，LPG 由四个结构域组成：（i）溶血-1-0-烷基磷脂酰肌醇 锚，（ii）磷酸糖核心，（iii）重复的聚合物 通过磷酸二酯桥连接在一起的糖单元，和（iv） 在末端非还原性末端的小的封端寡糖。 的 LPG的脂质锚和磷酸糖核心区是保守的， 各种利什曼原虫，而糖的变异性 重复磷酸化糖单元的组成和序列 和封盖结构。 虽然在这方面取得了重大进展， LPG的结构-功能关系，还有更多的东西有待了解 关于种间差异和种内发育 LPG结构的改进。 确定这些结构差异 沿着这种重要的糖缀合物的生物合成和周转 也将是我们研究的重点。 具体目标是 应用如下： L. LPG结构分析的继续。 具体而言是 来自L. donovani和分离的 L. braziliensis和L.将阐明亚马逊。 2. LPG生物合成的生化分析。 两个关键酶 （甘露糖磷酸转移酶和阿拉伯糖转移酶）参与LPG 生物合成将被纯化和表征。 3.液化石油气周转的特征。 寄生虫对液化石油气的周转 前鞭毛体感染巨噬细胞后LPG的命运将是 研究了 从这些研究中，我们希望有助于了解的作用 LPG在利什曼病的发病机制中起作用，并提供了一个 设计化疗方案的生化原理， 利用其独特的结构。

Leishmaniasis is a major health problem to humans and is caused by protozoan parasites of the genus Leishmania. Lipophosphoglycan (LPG) is an important macromolecule on the surface of the promastigote form of these parasites and is believed to be multifunctional. Structurally, LPG is composed of four domains: (i) a lyso-l-O-alkylphosphatidylinositol anchor, (ii) a phosphosaccharide core, (iii) a polymer of repeating saccharide units linked together by phosphodiester bridges, and (iv) a small, capping oligosaccharide at the terminal, non-reducing end. The lipid anchor and phosphosaccharide core regions of LPG are conserved among various Leishmania species, whereas there is variability of sugar composition and sequence in the repeating phosphorylated saccharide units and the capping structure. While significant progress has been made on structure-function relationships of LPG, much more remains to be learned concerning interspecies differences, and intraspecies developmental modifications of LPG structure. Determining these structural differences along with the biosynthesis and turnover of this important glycoconjugate will also be a focus of our research. The specific aims of this application are as follows: l. Continuation of structural analysis of LPGs. Specifically, the structure of LPG from Indian isolates of L. donovani and from isolates of L. braziliensis and L. amazonensis will be elucidated. 2. Biochemical analysis of LPG biosynthesis. Two key enzymes (mannosylphosphate transferase and arabinosyltransferase) involved in LPG biosynthesis will be purified and characterized. 3. Characterization of LPG turnover. The turnover of LPG by the parasite and the fate of LPG upon infection of macrophages by promastigotes will be investigated. From these studies, we hope to contribute to the understanding of the role LPG plays in the pathogenesis of leishmaniasis and to provide a biochemical rationale for the design of chemotherapeutic regimens that exploit its unique structure.