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dc:title "HTML Summary of #3331 \n\nArtemisinin-resistant Plasmodium falciparum Kelch13 mutant proteins display reduced heme-binding affinity and decreased artemisinin activation\n\n";
foaf:primaryTopic .
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bibo:abstract "The potency of frontline antimalarial drug artemisinin (ART) derivatives is triggered by heme-induced cleavage of the endoperoxide bond to form reactive heme-ART alkoxy radicals and covalent heme-ART adducts, which are highly toxic to the parasite. ART-resistant (ART-R) parasites with mutations in the Plasmodium falciparum Kelch-containing protein Kelch13 (PfKekch13) exhibit impaired hemoglobin uptake, reduced yield of hemoglobin-derived heme, and thus decreased ART activation. However, any direct involvement of PfKelch13 in heme-mediated ART activation has not been reported. Here, we show that the purified recombinant PfKelch13 wild-type (WT) protein displays measurable binding affinity for iron and heme, the main effectors for ART activation. The heme-binding property is also exhibited by the native PfKelch13 protein from parasite culture. The two ART-R recombinant PfKelch13 mutants (C580Y and R539T) display weaker heme binding affinities compared to the ART-sensitive WT and A578S mutant proteins, which further translates into reduced yield of heme-ART derivatives when ART is incubated with the heme molecules bound to the mutant PfKelch13 proteins. In conclusion, this study provides the first evidence for ART activation via the heme-binding propensity of PfKelch13. This mechanism may contribute to the modulation of ART-R levels in malaria parasites through a novel function of PfKelch13."^^xsd:string;
bibo:authorList ;
bibo:issue "1";
bibo:volume "7";
dct:creator ,
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dct:date "2024-11";
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dct:publisher ;
dct:title "Artemisinin-resistant Plasmodium falciparum Kelch13 mutant proteins display reduced heme-binding affinity and decreased artemisinin activation"^^xsd:string;
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bibo:Article,
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ep:EPrint;
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foaf:name "Springer Science and Business Media LLC"^^xsd:string;
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foaf:givenName "Pramit"^^xsd:string;
foaf:name "Pramit Chowdhury"^^xsd:string;
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foaf:name "Abdur Rahman"^^xsd:string;
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foaf:name "Nawaal Khan"^^xsd:string;
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