The Antimalarial Drug Quinine Disrupts Tat2p-mediated Tryptophan Transport and Causes Tryptophan Starvation
The Antimalarial Drug Quinine Disrupts Tat2p-mediated Tryptophan Transport and Causes Tryptophan Starvation
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DOI：
10.1074/jbc.m109.005843
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发表时间：
2009-07-03
影响因子：
4.8
通讯作者：
Avery, Simon V.
中科院分区：
文献类型：
--
作者：
Khozoie, Combiz;Pleass, Richard J.;Avery, Simon V.
奎宁是治疗疟疾的主要药物。然而，奎宁作用的主要方式尚不清楚，其疗效因患者的不良反应而受到损害。为了帮助解决这些问题，使用酵母缺失菌株收集进行了奎宁敏感性的全基因组筛选。在筛选中鉴定的奎宁敏感突变体包括几种色氨酸生物合成缺陷型（色氨酸菌株）。这种敏感性在独立的测定中得到证实，并且可以用外源性色氨酸抑制，表明奎宁引起色氨酸饥饿。因此，奎宁被发现抑制[H-3]色氨酸摄取细胞，和奎宁的敏感性的一个trp 1 δ突变体可以获救的过表达的色氨酸渗透酶，编码的TAT 1和TAT 2。奎宁作用的位点被特别确定为高亲和力的色氨酸/酪氨酸通透酶，Tat 2 p，奎宁与色氨酸抑制的方式。对Tyr水平的所得作用也反映在aro 7 Delta缺失菌株的Tyr-可抑制的奎宁超敏性上，所述aro 7 Delta缺失菌株是Tyr（和Phe）营养缺陷型的。目前的全基因组数据集为发现奎宁毒性模式提供了重要资源。我们证明，通过Tat 2 p摄取Trp和Tyr是细胞奎宁毒性的主要靶点，这一潜力得到了验证。研究结果还表明，膳食色氨酸补充剂可以帮助避免奎宁的毒性作用。
Quinine is a major drug of choice for the treatment of malaria. However, the primary mode of quinine action is unclear, and its efficacy is marred by adverse reactions among patients. To help address these issues, a genome-wide screen for quinine sensitivity was carried out using the yeast deletion strain collection. Quinine-sensitive mutants identified in the screen included several that were defective for tryptophan biosynthesis (trp strains). This sensitivity was confirmed in independent assays and was suppressible with exogenous Trp, suggesting that quinine caused Trp starvation. Accordingly, quinine was found to inhibit [H-3] Trp uptake by cells, and the quinine sensitivity of a trp1 Delta mutant could be rescued by overexpression of Trp permeases, encoded by TAT1 and TAT2. The site of quinine action was identified specifically as the high affinity Trp/Tyr permease, Tat2p, with which quinine associated in a Trp-suppressible manner. A resultant action also on Tyr levels was reflected by the Tyr-suppressible quinine hypersensitivity of an aro7 Delta deletion strain, which is auxotrophic for Tyr (and Phe). The present genome-wide dataset provides an important resource for discovering modes of quinine toxicity. That potential was validated with our demonstration that Trp and Tyr uptake via Tat2p is a major target of cellular quinine toxicity. The results also suggest that dietary tryptophan supplements could help to avert the toxic effects of quinine.