Project

Discipline

Trypanosoma brucei; Phospholipid synthesis; Cardiolipin; Phosphatidylethanolamine; Phosphatidylserine; Eukaryotic elongation factor 1A; Protein modification; Trypanosomes; membranes; phospholipids; biosynthesis; mitochondrium; eEF1A; Lipids; Metabolism

Lead
Lay summary
African trypanosomes are protozoan parasites causing human African sleeping sickness and a related disease, Nagana, in cattle. These diseases have a major impact on human and animal health by severely affecting social and economic development among the poorest, mostly rural, populations in sub-Saharan Africa. During their complex life cycles, Trypanosoma brucei parasites alternate between the mammalian bloodstream and the insect host, the tsetse fly. Interestingly, research on trypanosomes has led to the discovery of several important biological phenomena, such as RNA editing, trans-splicing, GPI-anchoring and antigenic variation, which were subsequently found to occur in other eukaryotic organisms as well.A major focus of our research is to study the biosynthesis and metabolism of phospholipids, the major building blocks of most biological membranes, in T. brucei parasites. This area of research that has received little attention in the past, but is currently investigated as potential drug target to fight sleeping sickness, and other neglected tropical diseases. We have recently shown that the structure of the major energy-producing organelle, the mitochondrion, in T. brucei is severely affected by changes in the cellular phospholipid composition. We now focus on establishing in T. brucei parasites the biosynthetic pathways required for the production of several phospholipid classes that have been shown to be important for the functional integrity of mitochondria in eukaryotes.Another research focus of our laboratory, using T. brucei as a eukaryotic model organism, is on a rare protein modification, i.e. ethanolamine phosphoglycerol (EPG) bound to eukaryotic elongation factor 1A (eEF1A). Such modifications often regulate the biological function of a protein, its distribution within a cell, and interactions with partner molecules. We are currently studying the protein sequence requirement for EPG attachment to eEF1A, its pathway of synthesis, and functional significance. The results from these studies will delineate a novel pathway for protein modification and, hopefully, shed light on its importance for eEF1A function.

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Last update: 21.02.2013

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African trypanosomes are protozoan parasites causing human African sleeping sickness and a related disease, nagana, in animals. Despite the devastating impact of the diseases on human and animal health in rural sub-Saharan Africa, research on trypanosomes has received little recognition among the scientific community for decades. However, the discovery of several important biological phenomena in trypanosomes, such as RNA editing, trans-splicing, glycosylphosphatidylinositol-anchoring and antigenic variation, which were subsequently found to occur in other eukaryotic organisms as well, has changed the attitude towards trypanosomes and they have become a valuable model organism to study basic questions in biology.Because African trypanosomes are human and animal pathogens, research on trypanosomes has often focused on identifying cellular and metabolic events that may have the potential to become drug targets to inhibit parasite proliferation. We decided to focus our research on two aspects in trypanosome biology that have received little attention in the past, the modification of eukaryotic elongation factor 1A (eEF1A) by ethanolamine phosphoglycerol (EPG) and the metabolism of phospholipids in Trypanosoma brucei. Although EPG modification of eEF1A has been discovered more than two decades ago, the pathway for EPG synthesis and attachment to protein, and its functional significance, have remained elusive. We plan to address these questions by introducing eEF1A constructs, containing amino acid point mutations or deletions, into T. brucei procyclic forms to study functional complementation of these mutant proteins and their interactions with other cellular components. In addition, since we recently demonstrated a direct link between EPG modification and phospholipid metabolism, by showing that the ethanolamine moiety of EPG derives from the phospholipid, phosphatidylethanolamine, we plan to identify and characterize selected metabolic pathways involved in phospholipid synthesis in T. brucei. Based on our previously published observation that the parasite mitochondrium is particularly sensitive to changes in lipid composition, we will focus on characterizing the reactions involved in the biosynthesis of cardiolipin, a characteristic and functionally important phospholipid in mitochondria. Our preliminary observation that one reaction in the synthesis of cardiolipin in T. brucei may involve the action of a bacterial-type, rather than eukaryotic-type, enzyme offers the possibility that this pathway may represent a potential drug target against trypanosomes. In addition, since alterations in membrane lipid composition, induced by experimentally interfering with biosynthetic pathways, are expected to cause pleiotropic or lethal effects in T. brucei, our studies will contribute to a better understanding of the general roles of phospholipids in eukaryotes.Together, our studies have the potential to reveal unique, i.e. parasite-specific, pathways for phospholipid synthesis and turnover in T. brucei and, in addition, shed light on the biosynthesis and function of the EPG modification of eEF1A in a eukaryotic model organism.