Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum
| Autor: | Zi-Chun Hua, Yingke He, Jianbin Zhang, Chin Xia Liew, Chong-Jing Zhang, Jigang Wang, Min Liu, Teck Kwang Lim, Wan Ni Chia, Nianci Lu, Bin Liu, Han-Ming Shen, Kevin S. W. Tan, Li-Xia Yuan, Qingsong Lin, Zhengjun Li, Chiew Yee Loh, Chwee Teck Lim, Yan Quan Lee, Yew Mun Lee |
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| Rok vydání: | 2015 |
| Předmět: |
Multidisciplinary
biology Chemistry General Physics and Astronomy Plasmodium falciparum General Chemistry Plasma protein binding biology.organism_classification Proteomics General Biochemistry Genetics and Molecular Biology chemistry.chemical_compound Protein structure Mechanism of action Biochemistry Biotin parasitic diseases medicine medicine.symptom Artemisinin Heme medicine.drug |
| Zdroj: | Nature Communications. 6 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms10111 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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