<> "The repository administrator has not yet configured an RDF license."^^ . <> . . . "Artemisinin-resistant Plasmodium falciparum Kelch13 mutant proteins display reduced heme-binding affinity and decreased artemisinin activation"^^ . "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."^^ . "2024-11" . "7" . "1" . . "Springer Science and Business Media LLC"^^ . . . "Commun. Biol."^^ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . "Kasturi"^^ . "Haldar"^^ . "Kasturi Haldar"^^ . . "Mohammad"^^ . "Faaiz"^^ . "Mohammad Faaiz"^^ . . "Abdur"^^ . "Rahman"^^ . "Abdur Rahman"^^ . . ""^^ . "Ashish"^^ . " Ashish"^^ . . "Nawaal"^^ . "Khan"^^ . "Nawaal Khan"^^ . . "Harshita"^^ . "Rastogi"^^ . "Harshita Rastogi"^^ . . "Souvik"^^ . "Bhattacharjee"^^ . "Souvik Bhattacharjee"^^ . . "Pramit"^^ . "Chowdhury"^^ . "Pramit Chowdhury"^^ . . "Smritikana"^^ . "Dutta"^^ . "Smritikana Dutta"^^ . . "Jyoti Rani"^^ . "Nath"^^ . "Jyoti Rani Nath"^^ . . "Sabahat"^^ . "Tamseel"^^ . "Sabahat Tamseel"^^ . . . . . "HTML Summary of #3331 \n\nArtemisinin-resistant Plasmodium falciparum Kelch13 mutant proteins display reduced heme-binding affinity and decreased artemisinin activation\n\n" . "text/html" . .