PXD002611 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Heme-activated Promiscuous Targeting of Artemisinin in Plasmodium falciparum |
Description | Plasmodium falciparum, the most pathogenic human malaria parasite, infects millions of human beings and causes a serious public health threat. Currently, the most potent anti-malarial drugs are artemisinin and its derivatives1,2. Artemisinin is a sesquiterpene lactone with an endoperoxide bridge3. The activation of artemisinin requires the cleavage of the endoperoxide bridge in the presence of iron sources4. Once activated, artemisinins are converted into highly reactive carbon-centered radicals5,6 that attack macromolecules through alkylation and propagate a series of damages, eventually leading to parasite death7,8. Even though several parasite proteins have been reported as the targets of artemisinin9,10, the exact mechanism of artemisinin action is still controversial and its high potency and specificity against the malaria parasite could not be fully accounted. Here, we have developed an unbiased chemical proteomics approach to directly probe the mechanism of action of artemisinin in P. falciparum in situ. An alkyne-tagged artemisinin analogue coupled with biotin enables selective purification and identification of 124 artemisinin covalent-binding protein targets, many of which are involved in essential biological processes of the parasite. In vitro assays confirm the specific artemisinin binding and inhibition of selected targets. Such a broad targeting spectrum disrupts the biochemical landscape of the parasite and causes its death. Furthermore, using the alkyne-tagged artemisinin coupled with a fluorescent dye to monitor its protein binding, we showed that heme, rather than free ferrous iron, is predominantly responsible for artemisinin activation. The extremely high level of heme released from the hemoglobin digestion by the parasite make artemisinin exceptionally potent against late-stage parasites (trophozoite and schizont stages) compared to parasites at early ring stage, which have low level of heme, mainly from endogenous synthesis. The ‘blood eating’ nature of the parasite with the release of large amounts of heme confers artemisinin with extremely high specificity against the parasites, with minimum side effects towards healthy red blood cells. Taken together, our results established a unifying model to explain the action and specificity of artemisinin in parasite killing. Our findings could facilitate the development of better alternative strategies to treat malaria in times of emerging artemisinin resistance11,12. |
HostingRepository | PRIDE |
AnnounceDate | 2015-12-17 |
AnnouncementXML | Submission_2016-01-05_15:12:46.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Qingsong Lin |
SpeciesList | scientific name: Plasmodium falciparum (isolate 3D7); NCBI TaxID: 36329; |
ModificationList | monohydroxylated residue; acetylated residue; methylthiolated residue |
Instrument | TripleTOF 5600 |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2015-07-28 01:17:10 | ID requested | |
1 | 2015-12-17 00:38:42 | announced | |
⏵ 2 | 2016-01-05 15:12:47 | announced | Updated publication reference for PubMed record(s): 26694030. |
Publication List
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, Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum. Nat Commun, 6():10111(2015) [pubmed] |
Keyword List
curator keyword: Biomedical |
submitter keyword: Artemisinin, chemical proteomics, target, mechanism of action |
Contact List
Dr Lin Qingsong |
contact affiliation | Department of Bioloigcal Science, National University of Singapore |
contact email | dbslinqs@nus.edu.sg |
lab head | |
Qingsong Lin |
contact affiliation | Biological Sciences |
contact email | dbslinqs@nus.edu.sg |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD002611
- Label: PRIDE project
- Name: Heme-activated Promiscuous Targeting of Artemisinin in Plasmodium falciparum