: 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

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI020941-19
Application #
6688116
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Rogers, Martin J
Project Start
1985-09-01
Project End
2008-02-29
Budget Start
2003-09-01
Budget End
2004-02-29
Support Year
19
Fiscal Year
2003
Total Cost
$189,615
Indirect Cost
Name
University of Kentucky
Department
Biochemistry
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Dobson, Deborah E; Kamhawi, Shaden; Lawyer, Phillip et al. (2010) Leishmania major survival in selective Phlebotomus papatasi sand fly vector requires a specific SCG-encoded lipophosphoglycan galactosylation pattern. PLoS Pathog 6:e1001185
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Soares, Rodrigo P P; Cardoso, Tatiana L; Barron, Tamara et al. (2005) Leishmania braziliensis: a novel mechanism in the lipophosphoglycan regulation during metacyclogenesis. Int J Parasitol 35:245-53
Soares, Rodrigo P P; Barron, Tamara; McCoy-Simandle, Kessler et al. (2004) Leishmania tropica: intraspecific polymorphisms in lipophosphoglycan correlate with transmission by different Phlebotomus species. Exp Parasitol 107:105-14

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