Dataset Information

Comprehensive map of the Artemisia annua proteome and quantification of differential protein expression in chemotypes producing high vs low content of artemisinin

ABSTRACT: Artemisia annua is well known for biosynthesizing artemisinin, which is the primary therapeutic approach against malaria. It was reported that treatment with leaf of A. annua showed better effect and less tendency of developing drug resistance than purified artemisinin, suggesting other components in A. annua may contribute to the therapeutic efficacy. Here, we conducted a global proteomic profiling of A. annua with identification of a total of 13,403 proteins based on the genome sequence annotation database. Furthermore, we generated a spectral library to perform quantitative proteomic analysis using data independent acquisition mass spectrometry (DIA-MS). Specifically, we comprehensively quantified and compared proteins between two chemotypes that produce high (HAP) and low (LAP) artemisinin content, respectively. 182 proteins were identified with abundance significantly different between these two chemotypes. Overall, our current study globally identified the proteome of A. annua and quantitatively compared the targeted sub-proteomes between the two cultivars of HAP and LAP, providing systematic information on metabolic pathways of A. annua and facilitating identification of good chemotypes for producing anti-malaria compounds.

INSTRUMENT(S): Orbitrap Fusion, Q Exactive

ORGANISM(S): Artemisia Annua (sweet Wormwood)

TISSUE(S): Plant Cell, Flower Bud, Leaf

DISEASE(S): Malaria

SUBMITTER: MINGHUI CHEN

LAB HEAD: Kexuan Tang

PROVIDER: PXD015547 | Pride | 2020-04-27

REPOSITORIES: Pride

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Publications

Comprehensive Map of the Artemisia annua Proteome and Quantification of Differential Protein Expression in Chemotypes Producing High versus Low Content of Artemisinin.

Chen Minghui M Yan Tingxiang T Ji Liyun L Dong Yu Y Sidoli Simone S Yuan Zuofei Z Cai Chunlin C Chen Jiwei J Tang Yueli Y Shen Qian Q Pan Qifang Q Fu Xueqing X Ku Xin X Liao Lujian L Garcia Benjamin A BA Yan Wei W Tang Kexuan K

Proteomics 20200518 10

Artemisia annua is well known for biosynthesizing the antimalarial drug artemisinin. Here, a global proteomic profiling of A. annua is conducted with identification of a total of 13 403 proteins based on the genome sequence annotation database. Furthermore, a spectral library is generated to perform quantitative proteomic analysis using data independent acquisition mass spectrometry. Specifically, proteins between two chemotypes that produce high (HAP) and low (LAP) artemisinin content, respecti ...[more]

PMID: 32311217

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Project 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.

Dataset Information

Comprehensive map of the Artemisia annua proteome and quantification of differential protein expression in chemotypes producing high vs low content of artemisinin

Publications

Comprehensive Map of the Artemisia annua Proteome and Quantification of Differential Protein Expression in Chemotypes Producing High versus Low Content of Artemisinin.

Similar Datasets

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