Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei.
Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei.
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DOI：
10.1096/fj.201700311r
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Rentsch D
中科院分区：
文献类型：
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作者：
Macedo JP;Currier RB;Wirdnam C;Horn D;Alsford S;Rentsch D
布氏锥虫是引起人类非洲锥虫病（HAT）的原生动物寄生虫，其生存依赖于鸟氨酸脱羧酶（ODC）对鸟氨酸的摄取和代谢。事实上，ODC是WHO“基本药物”依氟鸟氨酸的目标，依氟鸟氨酸与另一种抗HAT药物苏拉明具有拮抗作用。因此，鸟氨酸摄取在T.但运输者尚未查明。我们描述这些氨基酸转运蛋白（AAT）。在异源表达系统中，TbAAT 10 -1对鸟氨酸具有选择性，而TbAAT 2 -4转运鸟氨酸和组氨酸。这些AAT也是维持T细胞内鸟氨酸和多胺水平所必需的。布氏杆菌，从而降低对依氟鸟氨酸的敏感性并增加对苏拉明的敏感性。与组氨酸的竞争一致，这种氨基酸的高细胞外浓度表型TbAAT 2 -4遗传缺陷。我们的研究结果确定了TbAAT 10 -1和TbAAT 2 -4作为寄生虫的鸟氨酸转运蛋白，其中之一可以通过组氨酸调节，但两者都影响对重要抗HAT药物的敏感性。Macedo，J. P.，库里耶河B.，Wirdnam，C.，霍恩，D.，Alsford，S.，Rentsch，D.布氏锥虫对鸟氨酸的摄取及药物敏感性的调节。
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.