Glycobiology of Leishmania

点击翻译按钮获取中文摘要

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