GLYCOCONJUGATES OF LEISHMANIA

点击翻译按钮获取中文摘要

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.