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Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei
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, sur...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Federation of American Societies for Experimental Biology
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602898/ https://www.ncbi.nlm.nih.gov/pubmed/28679527 http://dx.doi.org/10.1096/fj.201700311R |
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author | Macedo, Juan P. Currier, Rachel B. Wirdnam, Corina Horn, David Alsford, Sam Rentsch, Doris |
author_facet | Macedo, Juan P. Currier, Rachel B. Wirdnam, Corina Horn, David Alsford, Sam Rentsch, Doris |
author_sort | Macedo, Juan P. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5602898 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Federation of American Societies for Experimental Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-56028982017-09-25 Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei Macedo, Juan P. Currier, Rachel B. Wirdnam, Corina Horn, David Alsford, Sam Rentsch, Doris FASEB J Research 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. Federation of American Societies for Experimental Biology 2017-10 2017-07-05 /pmc/articles/PMC5602898/ /pubmed/28679527 http://dx.doi.org/10.1096/fj.201700311R Text en © The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Macedo, Juan P. Currier, Rachel B. Wirdnam, Corina Horn, David Alsford, Sam Rentsch, Doris Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei |
title | Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei |
title_full | Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei |
title_fullStr | Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei |
title_full_unstemmed | Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei |
title_short | Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei |
title_sort | ornithine uptake and the modulation of drug sensitivity in trypanosoma brucei |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602898/ https://www.ncbi.nlm.nih.gov/pubmed/28679527 http://dx.doi.org/10.1096/fj.201700311R |
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