Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum.
Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum.
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DOI：
10.1038/ncomms10111
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发表时间：
2015-12-22
影响因子：
16.6
通讯作者：
Lin Q
中科院分区：
文献类型：
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作者：
Wang J;Zhang CJ;Chia WN;Loh CC;Li Z;Lee YM;He Y;Yuan LX;Lim TK;Liu M;Liew CX;Lee YQ;Zhang J;Lu N;Lim CT;Hua ZC;Liu B;Shen HM;Tan KS;Lin Q
青蒿素及其衍生物是最有效的抗疟疾药物，其作用机制尚未完全了解。在这里，我们提出了一个公正的化学蛋白质组学分析，直接探讨这一机制在恶性疟原虫。我们使用一个炔标记的青蒿素类似物加上生物素，以确定124青蒿素共价结合蛋白的目标，其中许多是参与寄生虫的基本生物过程。如此广泛的靶向谱破坏了寄生虫的生化景观并导致其死亡。此外，使用炔标记的青蒿素加上荧光染料监测蛋白质结合，我们表明，血红素，而不是游离亚铁，主要负责青蒿素激活。血红素主要来源于寄生虫的血红素生物合成途径在早期的环阶段和血红蛋白消化在后期阶段。我们的研究结果支持一个统一的模型来解释青蒿素在杀寄生虫中的作用和特异性。 抗疟药青蒿素的作用机制尚不清楚。在这里，作者使用了一种标记的青蒿素类似物来表明这种药物主要被血红素激活，然后与疟疾寄生虫中的120多种蛋白质共价结合，影响其许多细胞过程。
The mechanism of action of artemisinin and its derivatives, the most potent of the anti-malarial drugs, is not completely understood. Here we present an unbiased chemical proteomics analysis to directly explore this mechanism in Plasmodium falciparum. We use an alkyne-tagged artemisinin analogue coupled with biotin to identify 124 artemisinin covalent binding protein targets, many of which are involved in the essential biological processes of the parasite. Such a broad targeting spectrum disrupts the biochemical landscape of the parasite and causes its death. Furthermore, using alkyne-tagged artemisinin coupled with a fluorescent dye to monitor protein binding, we show that haem, rather than free ferrous iron, is predominantly responsible for artemisinin activation. The haem derives primarily from the parasite's haem biosynthesis pathway at the early ring stage and from haemoglobin digestion at the latter stages. Our results support a unifying model to explain the action and specificity of artemisinin in parasite killing. The mechanism of action of artemisinin, an antimalarial drug, is not well understood. Here, the authors use a labelled artemisinin analogue to show that the drug is mainly activated by haem and then binds covalently to over 120 proteins in the malaria parasite, affecting many of its cellular processes.