Artemisinin is among the most efficient antimalarial treatments to date that promote quick clearance of Plasmodium parasitemia and a significant decrease in malarial symptoms. Despite its success in fighting the malaria burden, the precise molecular mechanism of artemisinin in the parasite is still unresolved. Prior research demonstrates fluorescent artemisinin derivatives localize to digestive vacuole-associated neutral lipid bodies in the parasite, and artemisinin application to parasite cultures leads to peroxidation of a BODIPY lipid peroxyl radical indicator probe. Furthermore, in vitro assays reacting artemisinin and heme in the presence of neutral lipids and phospholipid results in the formation of fluorescent degradation products that may be indicative of lipid peroxidation. Other leading theories suggest alkylation and/or inhibition of parasite proteins and enzymatic pathways as a mechanism by which artemisinin and related trioxanes kill the parasite. To further explore artemisinin metabolite-induced peroxidation as a killing mechanism in the parasite we sought to investigate the effect of fluorescent reaction metabolites on native activity of a constitutively expressed enzyme in vitro. Hexokinase is the first enzyme to be involved in glucose catabolism in many eukaryotic organisms, including Plasmodium parasites. Here the inhibitory effects of fluorescent artemisinin-heme reaction products on a model hexokinase system are discussed, as well as the implications for the proposed mechanism of parasite killing through artemisinin-induced lipid peroxidation.

Determining the inhibitory effect of heme-artemisinin-lipid metabolites on enzyme activity

251st National Meeting (2016)

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