Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum.,Nature Communications

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Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum.
Nature Communications ( IF 14.7 ) Pub Date : 2015-Dec-22 , DOI: 10.1038/ncomms10111
Jigang Wang _{1,

2,

3,

4} , Chong-Jing Zhang ₅ , Wan Ni Chia ₆ , Cheryl C Y Loh ₆ , Zhengjun Li ₇ , Yew Mun Lee ₁ , Yingke He ₈ , Li-Xia Yuan ₉ , Teck Kwang Lim ₁ , Min Liu ₃ , Chin Xia Liew ₇ , Yan Quan Lee ₆ , Jianbin Zhang ₄ , Nianci Lu ₁₀ , Chwee Teck Lim _{11,

12} , Zi-Chun Hua ₂ , Bin Liu ₅ , Han-Ming Shen ₄ , Kevin S W Tan ₆ , Qingsong Lin _{1,

7}

Affiliation

Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210023, China.
Interdisciplinary Research Group in Infectious Diseases, Singapore-MIT Alliance for Research &Technology (SMART), Singapore 138602, Singapore.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore 117585, Singapore.
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore.
NUS Environmental Research Institute, Singapore 117411, Singapore.
Department of Anaesthesiology, Singapore General Hospital, Singapore 169608, Singapore.
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
Department of Biomedical Engineering, National University of Singapore, Singapore 117583, Singapore.
Department of Mechanical Engineering, National University of Singapore, Singapore 117575, Singapore.

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.

中文翻译：

血红素激活的恶性疟原虫中青蒿素的混杂靶向。

青蒿素及其衍生物是最有效的抗疟疾药物，其作用机制尚不完全清楚。在这里，我们提出了一种无偏见的化学蛋白质组学分析，以直接探索恶性疟原虫中的这种机制。我们使用带有炔烃标记的青蒿素类似物与生物素结合来鉴定 124 种青蒿素共价结合蛋白靶标，其中许多与寄生虫的基本生物学过程有关。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，使用带有炔烃标记的青蒿素和荧光染料来监测蛋白质结合，我们发现血红素，而不是游离的亚铁，主要负责青蒿素的活化。血红素主要来自寄生虫' 环早期的血红素生物合成途径和后期的血红蛋白消化。我们的结果支持一个统一模型来解释青蒿素在杀死寄生虫中的作用和特异性。

更新日期：2015-12-25

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