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primary topic: Artemisinin-resistant Plasmodium falciparum Kelch13 mutant proteins display reduced heme-binding affinity and decreased artemisinin activation

Artemisinin-resistant Plasmodium falciparum Kelch13 mutant proteins display reduced heme-binding affinity and decreased artemisinin activation
type: AcademicArticle
type: Article
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.
date: 2024-11
volume: 7
issue: 1
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository

Springer Science and Business Media LLC
type: Organization

Commun. Biol.
type: Collection

Kasturi Haldar
type: Person
given name: Kasturi
family name: Haldar

Mohammad Faaiz
type: Person
given name: Mohammad
family name: Faaiz

Abdur Rahman
type: Person
given name: Abdur
family name: Rahman

Ashish
type: Person
family name: Ashish

Nawaal Khan
type: Person
given name: Nawaal
family name: Khan

Harshita Rastogi
type: Person
given name: Harshita
family name: Rastogi

Souvik Bhattacharjee
type: Person
given name: Souvik
family name: Bhattacharjee

Pramit Chowdhury
type: Person
given name: Pramit
family name: Chowdhury

Smritikana Dutta
type: Person
given name: Smritikana
family name: Dutta

Jyoti Rani Nath
type: Person
given name: Jyoti Rani
family name: Nath

Sabahat Tamseel
type: Person
given name: Sabahat
family name: Tamseel

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primary topic: Artemisinin-resistant Plasmodium falciparum Kelch13 mutant proteins display reduced heme-binding affinity and decreased artemisinin activation