Date of Award

5-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Genetics

Advisor

James Morris

Committee Member

Kimberly Paul

Committee Member

Kerry Smith

Committee Member

William Marcotte Jr.

Abstract

Protozoan parasites find a glucose rich environment when inhabiting the human host. As a consequence of this glucose rich environment, many parasites have evolved streamlined metabolisms that repress more complex pathways (such as the TCA cycle) in favor of high glycolytic activity, making glycolytic enzymes potential drug targets. The parasites also need to produce glycoprotein coats to shield themselves from the immune system, nucleotides for rapid proliferation, and reducing equivalents for redox homeostasis. The first enzyme of the glycolytic pathway, hexokinase (HK), is critical to the biosynthesis of all of these molecules, representing a here-to-fore underappreciated drug target. Herein I present evidence that HK is a promising target in the parasites Trypanosoma brucei, Leishmania major, and Plasmodium falciparum, and identify novel inhibitors of these HKs, which may have potential for drug development. T. brucei and Leishmania are neglected tropical diseases in dire need of new treatments, while P. falciparum is the world’s deadliest parasite, notorious for rapidly evolving drug resistance. In addition to my work on drug development, I have also investigated the unique biology of the T. brucei HK and its alternative cellular localization. This alternative cellular localization is driven by a unique peptide sequence found only in kinetoplastid parasites. Together, these findings demonstrate the fascinating novelty of parasite glucose metabolism, and its great potential as a drug target.

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