Research on Trypanosoma brucei, the causative agent of African sleeping sickness, has revealed novel biological mechanisms which one day may provide drug targets and lead to improved treatments for this disease. For example, the variant surface glycoprotein, a molecule that allows evasion of the host immune system, was found to contain exclusively myristate (a 14-carbon fatty acid) in its GPI anchor. This discovery eventually led to an understanding of the trypanosome's unusual lipid metabolism. Instead of salvaging myristate from the blood (where its concentration appears inadequate) or like other organisms, making it de novo using a soluble, cytosolic fatty acid synthase, trypanosomes employ a unique set of membrane-bound, microsomal elongases to make fatty acids. My thesis reports a second trypanosomal fatty acid synthase residing in the mitochondrion. This synthase makes specialized products such as octanoate (an 8-carbon fatty acid), which is a precursor for lipoic acid, and palmitate (a 16-carbon fatty acid) for use within the organelle (Chapter 1 and a manuscript published in JBC). Mitochondrial fatty acid synthesis is not only essential for trypanosome growth but in addition, knockdown of this pathway disrupts respiration, mitochondrial membrane potential and morphology, and division of its mitochondrial genome. Based on these observations and those from other organisms, we speculate that mitochondrially-synthesized palmitate contributes to the synthesis or repair of mitochondrial phospholipids. In support of this hypothesis, the levels of cardiolipin (a mitochondrial phospholipid required for assembly of respiratory complexes) and, to a lesser extent, other phospholipids were decreased following knockdown of this pathway (Chapter 2). Finally, several inhibitors have been found to target fatty acid synthesis. One such class, the pantothenamides, mimic pantothenate and are incorporated into two fatty acid carrier molecules, coenzyme A and acyl carrier protein, using a series of enzymes including pantothenate kinase (PanK). In addition to identifying a unique trypanosome homolog of PanK, we found that pantothenamides inhibit mitochondrial fatty acid synthesis and effectively kill trypanosomes (Chapter 3). Taken together, these studies have shown that mitochondrial fatty acid synthesis contributes to several essential aspects of trypanosome metabolism, making it a prime candidate for drug development.
|Advisor:||Englund, Paul T.|
|School:||The Johns Hopkins University|
|School Location:||United States -- Maryland|
|Source:||DAI-B 68/04, Dissertation Abstracts International|
|Subjects:||Molecular biology, Biochemistry, Parasitology|
|Keywords:||Fatty acid synthesis, Mitochondria, Trypanosomes|
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