Effect of Artemisinin on the Redox System of NADPH/FNR/Ferredoxin from Malaria Parasites

Abstract

FNR and ferredoxin constitute a redox cascade, which provides reducing power in the plastid of malaria parasites. Recently, mutation of ferredoxin (D97Y) was reported to be strongly related to the parasite’s resistance to the front-line antimalarial drug artemisinin. In order to gain insight into the mechanism for the resistance, we studied the effect of dihydroartemisinin (DHA), the active compound of artemisinin, on the redox cascade of NADPH/FNR/ferredoxin in in vitro reconstituted systems. DHA partially inhibited the diaphorase activity of FNR by decreasing the affinity of FNR for NADPH. The activity of the electron transfer from FNR to wild-type or D97Y mutant ferredoxin was not significantly affected by DHA. An in silico docking analysis indicated possible binding of DHA molecule in the binding cavity of 2′5′ADP, a competitive inhibitor for NADPH, on FNR. We previously showed that the D97Y mutant of ferredoxin binds to FNR more strongly than wild-type ferredoxin, and ferredoxin and FNR are generally known to be involved in the oxidative stress response. Thus, these results suggest that ferredoxin is not a direct target of artemisinin, but its mutation may be involved in the protective response against the oxidative stress caused by artemisinin.

Apicoplast Journey and Its Essentiality as a Compartment for Malaria Parasite Survival

“…Based on the similarity with prokaryotic and plant MEP pathways, other enzymes of the MEP pathway were also mapped and studied as a target for various inhibitors ( Wang et al., 2010 ; Saggu et al., 2016 ). This pathway provides multiple opportunities to develop a valuable combination therapy that could be either the various enzymes of this pathway or the redox environment created for the functioning of this pathway ( Saggu et al., 2016 ; Kimata-Ariga and Morihisa, 2022 ).…”

Naturally Acquired Kelch13 Mutations in Plasmodium falciparum Strains Modulate In Vitro Ring-Stage Artemisinin-Based Drug Tolerance and Parasite Survival in Response to Hyperoxia

“…However, the role of the apicoplast in ART tolerance is generating significant interest. Genetic mutations associated with ART tolerance include fd ( 32 , 73 – 75 ) and arps10 ( 32 ), which are localized to the apicoplast, and ATG18, which, although it is not localized to the apicoplast, is associated with apicoplast biogenesis ( 76 ), suggestive of an integral role of the apicoplast in ART tolerance. In comparison, fd mutations (D193Y) inserted and removed from K13 mutant and WT strains by Stokes and colleagues ( 77 ) using gene insertion techniques exhibited no apparent effect on parasite survival.…”

Redox-Based Strategies against Infections by Eukaryotic Pathogens

“…Transcriptomic and proteomic data analysis of A. fumigatus indicated that an oxidative phosphorylation pathway, as well as an ergosterol synthesis pathway, is consequently misregulated upon exposure to artemisinin [ 64 ], suggesting again that oxidative stress is produced during treatment by artemisinin. Interestingly, a stabilizing mutation in the ferredoxin, known to be involved in the oxidative stress response, confers resistance to parasites treated with artemisinin, in accordance with a protective role of ferredoxin against artemisinin [ 66 ].…”