C-terminal aromatic residue of Plasmodium ferredoxin important for the interaction with ferredoxin: NADP(H) oxidoreductase: possible involvement for artemisinin resistance of human malaria parasites.

The malaria parasite (Plasmodium sp.) contains a plastid-derived organelle called the apicoplast, which is essential for the growth of the parasite. In this organelle, a redox system comprising plant-type ferredoxin (Fd) and Fd: NADP(H) oxidoreductase (FNR) supplies reducing power for the crucial metabolic pathways. Electron transfer between Plasmodium falciparum Fd (PfFd) and FNR (PfFNR) is performed with higher affinity and specificity than those of plant Fd and FNR. We investigated the structural basis for such superior protein-protein interaction by focussing on the Plasumodium-specific regions of PfFd. Significant contribution of the C-terminal region of PfFd for the electron transfer with PfFNR was revealed by exchanging the C-terminal three residues between plant Fd and PfFd. Further site-directed mutagenesis of the PfFd C-terminal residues indicated that the presence of aromatic residue at Positions 96 and 97 contributes to the lower Km for PfFNR. Physical binding analyses using fluorescence and calorimetric measurements supported the results. A mutation from Asp to Tyr at position 97 of PfFd was recently reported to be strongly associated with P. falciparum resistance to artemisinin, the front line anti-malarial drug. Thus, the enhanced interaction of PfFd D97Y protein with PfFNR could be involved in artemisinin resistance of human malaria parasites. © The Author(s) 2020. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

Citation

Yoko Kimata-Ariga, Asako Sakamoto, Miho Kamatani, Takashi Saitoh, Toshiharu Hase. C-terminal aromatic residue of Plasmodium ferredoxin important for the interaction with ferredoxin: NADP(H) oxidoreductase: possible involvement for artemisinin resistance of human malaria parasites. Journal of biochemistry. 2020 Oct 01;168(4):427-434

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PMID: 32470136

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