Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei

Juan P. Macedo, Rachel B. Currier, Corina Wirdnam, David Horn, Sam Alsford (Lead / Corresponding author), Doris Rentsch (Lead / Corresponding author)

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8 Citations (Scopus)
155 Downloads (Pure)

Abstract

Trypanosoma brucei, protozoan parasites that cause human African trypanosomiasis (HAT), depend on ornithine uptake and metabolism by ornithine decarboxylase (ODC) for survival. Indeed, ODC is the target of the WHO "essential medicine" eflornithine, which is antagonistic to another anti-HAT drug, suramin. Thus, ornithine uptake has important consequences in T. brucei, but the transporters have not been identified. We describe these amino acid transporters (AATs). In a heterologous expression system, TbAAT10-1 is selective for ornithine, whereas TbAAT2-4 transports both ornithine and histidine. These AATs are also necessary to maintain intracellular ornithine and polyamine levels in T. brucei, thereby decreasing sensitivity to eflornithine and increasing sensitivity to suramin. Consistent with competition for histidine, high extracellular concentrations of this amino acid phenocopied a TbAAT2-4 genetic defect. Our findings established TbAAT10-1 and TbAAT2-4 as the parasite ornithine transporters, one of which can be modulated by histidine, but both of which affect sensitivity to important anti-HAT drugs.-Macedo, J. P., Currier, R. B., Wirdnam, C., Horn, D., Alsford, S., Rentsch, D. Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei.

Original languageEnglish
Pages (from-to)4649-4660
Number of pages17
JournalFASEB Journal
Volume31
Issue number10
Early online date5 Jul 2017
DOIs
Publication statusPublished - Oct 2017

Keywords

  • African trypanosomiasis
  • Chemotherapy
  • Eflornithine
  • Suramin
  • Histidine

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