Elucidation of the role of ferredoxin mutations in maltial resistance to artemisinin

The purpose of this study is to prevent the spread of resistance to artemisinin, a specific drug for malaria parasites, and to elucidate the mechanism by which the ferredoxin (Fd) mutation (Asp97Tyr), which is strongly associated with this resistance, leads to drug resistance. Aim to In the first year, this Fd mutation was found to greatly increase the affinity for Fd’s major partner enzyme, Fd-NADPH oxidase (FNR), while decreasing its electron transfer activity (Journal of biochemistry, 2021). It was thought that this Fd functional change would affect the reducing power supply system of malaria parasites and the response to artemisinin in its downstream metabolism. I checked. The redox cascade of NADPH/FNR/Fd/Fd-dependent metabolic enzymes supplies reducing power to various metabolic systems of malaria parasites. Of this cascade, 1) the electron transfer activity from NADPH to FNR was mildly inhibited by artemisinin, mainly due to the decreased affinity of NADPH for FNR. In silico docking analysis supported that artemisinin inhibited NADPH binding to FNR. 2) The electron transfer activity from FNR to Fd (wild-type and Asp97Tyr mutant) was not significantly inhibited by artemisinin. 3) No electron transfer from FNR and Fd) to artemisinin was detected. These findings suggest that Fd is not a direct target of artemisinin, and that mutations in Fd affect FNR and Fd-related metabolism and suppress the oxidative stress response induced by artemisinin, leading to tolerance. These results were presented at academic conferences and published a paper (Antioxidants, 2022).

Project details

Basic Science
Drug Resistance

Apr 2020 — Mar 2023

$38,109

Japan