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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI020941-10
Application #
2061358
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1985-09-01
Project End
1998-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
10
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Biochemistry
Type
Schools of Medicine
DUNS #
832127323
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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Goswami, Mamta; Dobson, Deborah E; Beverley, Stephen M et al. (2006) Demonstration by heterologous expression that the Leishmania SCA1 gene encodes an arabinopyranosyltransferase. Glycobiology 16:230-6
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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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