Human African trypanosomiasis (HAT) is caused by the parasitic protozoan, Trypanosoma brucei. Fifty million people are at risk for the disease, which is fatal if not treated. There is a great need to translate recent advances in the understanding of the basic biology of the parasite into new drugs.
Polyamine biosynthesis in T. brucei
Polyamines are small organic cations that are required for cell growth and in the kinetoplastid parasites and the metabolic pathway is novel in the parasites. The polyamine spermidine is used to form a novel conjugate with glutathione (trypanothione) and the mechanism of polyamine regulation differs from other eukaryotic cells. The pathway has proven to be a rich source for the identification of anti-trypanosomal compounds and the biosynthetic enzyme ornithine decarboxylase (ODC) is the target of eflornithine, the only clinically used compound with a known mechanism of action.
Our lab goals are to understand the function of polyamines in the parasite, to learn how the parasite regulates the pathway and to identify additional targets to be exploited for the development of new drugs. We systematically explored the structure and function of key enzymes in the pathway including ODC, S-adenosylmethionine decarboxylase (AdoMetDC), and more recently, deoxyhypusine synthase (DHS), which conjugates spermidine to the essential translation factor eIF5A to form the hypusine modification that is required for its activity.
We use genetic approaches and metabolite profiling to identify essential enzymes and to learn how the pathway is regulated. Key recent findings include our discovery that both AdoMetDC and DHS are allosterically activated by formation of multimers with inactive paralogs – which we termed prozymes – and that this mechanism of enzyme activation is specific to parasitic protozoa. We are currently focused on understanding this regulation at a molecular level.
We also have a collaborative project with Scynexis, Inc, to identify and develop inhibitors of AdoMetDC to treat HAT.