Macedo Juan P, Currier Rachel B, Wirdnam Corina, Horn David, Alsford Sam, Rentsch Doris
Institute of Plant Sciences, University of Bern, Bern, Switzerland.
London School of Hygiene and Tropical Medicine, London, United Kingdom.
FASEB J. 2017 Oct;31(10):4649-4660. doi: 10.1096/fj.201700311R. Epub 2017 Jul 5.
, 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 , 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 , 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 .
导致人类非洲锥虫病（HAT）的原生动物寄生虫依靠鸟氨酸脱羧酶（ODC）摄取和代谢鸟氨酸来生存。实际上，ODC是世界卫生组织“基本药物”依氟鸟氨酸的作用靶点，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[此处原文缺失相关寄生虫名称]中具有重要影响，但相关转运蛋白尚未被鉴定出来。我们描述了这些氨基酸转运蛋白（AATs）。在异源表达系统中，TbAAT10 - 1对鸟氨酸具有选择性，而TbAAT2 - 4既能转运鸟氨酸也能转运组氨酸。这些AATs对于维持[此处原文缺失相关寄生虫名称]细胞内鸟氨酸和多胺水平也是必需的，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。与对组氨酸的竞争一致，这种氨基酸的高细胞外浓度模拟了TbAAT2 - 4基因缺陷。我们的研究结果确定了TbAAT10 - 1和TbAAT2 - 4为寄生虫鸟氨酸转运蛋白，其中一种可被组氨酸调节，但两者均影响对重要抗HAT药物的敏感性。——马塞多，J.P.，柯里尔，R.B.，维尔登姆，C.，霍恩，D.，阿尔斯福德，S.，伦奇，D. [此处原文缺失相关寄生虫名称]中的鸟氨酸摄取与药物敏感性调节
