Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei

Pereira de Macêdo, Juan; Currier, Rachel B.; Wirdnam, Corina; Horn, David; Alsford, Sam; Rentsch, Doris (2017). Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei. FASEB journal, 31(10), pp. 4649-4660. Federation of American Societies for Experimental Biology 10.1096/fj.201700311R

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Department of Biology > Institute of Plant Sciences (IPS) > Molecular Plant Physiology
08 Faculty of Science > Department of Biology > Institute of Plant Sciences (IPS)

UniBE Contributor:

Pereira de Macêdo, Juan; Wirdnam, Corina and Rentsch, Doris

Subjects:

500 Science > 580 Plants (Botany)

ISSN:

0892-6638

Publisher:

Federation of American Societies for Experimental Biology

Language:

English

Submitter:

Peter Alfred von Ballmoos-Haas

Date Deposited:

12 Dec 2017 17:08

Last Modified:

12 Dec 2017 17:08

Publisher DOI:

10.1096/fj.201700311R

PubMed ID:

28679527

BORIS DOI:

10.7892/boris.106868

URI:

https://boris.unibe.ch/id/eprint/106868

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