African trypanosomes are parasitic protozoa which are responsible for major diseases in humans and animals. They inhabit their host's bloodstream, and evade immune defenses by antigenic variation. Antigenic variation is mediated by Variant Surface Glycoprotein (VSG), which forms a surface coat covering the entire cell. During antigenic variation the parasite synthesizes a new VSG, with a different amino acid sequence, and exchanges its old coat for a new one. It has the genetic potential to synthesize hundreds of different VSG molecules and therefore can maintain a chronic infection. The research concerns biochemical mechanisms associated with antigen variation, and many studies concern the phosphatidylinositol-containing glycolipid which is linked to the VSG and which anchors it to the plasma membrane. We will investigate the trypanosome phospholipase C, known as VSG lipase, which cleaves the glycolipid and releases VSG from the cell (possibly during antigenic variation). This enzyme is already purified to homogeneity and it is highly specific for VSG-related structures. Further studies should define its intracellular localization and may also reveal any regulatory mechanisms. Other studies are planned on the biosythesis of the glycolipid. A pre-formed glycolipid precursor has already been isolated. The next objectives will be to map the pathway by which this precursor is synthesized and to determine the mechanism by which it is covalently linked to the VSG polypeptide. Finally, studies are aimed at characterizing other processing events which occur during VSG biosynthesis. These include N-linked glycosylation and processing of the glycolipid after it is linked to the VSG. These studies may clarify biochemical mechanisms in trypanosomes which may be useful in chemotherapy against these parasites.
| Clayton, April M; Guler, Jennifer L; Povelones, Megan L et al. (2011) Depletion of mitochondrial acyl carrier protein in bloodstream-form Trypanosoma brucei causes a kinetoplast segregation defect. Eukaryot Cell 10:286-92 |
| Hu, Rong; Mukhina, Galina L; Lee, Soo Hee et al. (2009) Silencing of genes required for glycosylphosphatidylinositol anchor biosynthesis in Burkitt lymphoma. Exp Hematol 37:423-434.e2 |
| Guler, Jennifer L; Kriegova, Eva; Smith, Terry K et al. (2008) Mitochondrial fatty acid synthesis is required for normal mitochondrial morphology and function in Trypanosoma brucei. Mol Microbiol 67:1125-42 |
| Autio, Kaija J; Guler, Jennifer L; Kastaniotis, Alexander J et al. (2008) The 3-hydroxyacyl-ACP dehydratase of mitochondrial fatty acid synthesis in Trypanosoma brucei. FEBS Lett 582:729-33 |
| Stephens, Jennifer L; Lee, Soo Hee; Paul, Kimberly S et al. (2007) Mitochondrial fatty acid synthesis in Trypanosoma brucei. J Biol Chem 282:4427-36 |
| Lee, Soo Hee; Stephens, Jennifer L; Paul, Kimberly S et al. (2006) Fatty acid synthesis by elongases in trypanosomes. Cell 126:691-9 |
| Englund, P T; Agbo, E E C; Lindsay, M E et al. (2005) RNAi libraries and kinetoplast DNA. Biochem Soc Trans 33:1409-12 |
| Jiang, David W; Werbovetz, Karl A; Varadhachary, Atul et al. (2004) Purification and identification of a fatty acyl-CoA synthetase from Trypanosoma brucei. Mol Biochem Parasitol 135:149-52 |
| Paul, Kimberly S; Bacchi, Cyrus J; Englund, Paul T (2004) Multiple triclosan targets in Trypanosoma brucei. Eukaryot Cell 3:855-61 |
| Leal, Simone; Acosta-Serrano, Alvaro; Morris, James et al. (2004) Transposon mutagenesis of Trypanosoma brucei identifies glycosylation mutants resistant to concanavalin A. J Biol Chem 279:28979-88 |
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