Heme and endoperoxide activation pathway

The heme and endoperoxide activation pathway is the fundamental biochemical mechanism through which artemisinin and its derivatives exert their potent antimalarial effects against Plasmodium falciparum. This pathway is triggered when the endoperoxide bridge of the drug molecule reacts with ferrous heme (Fe2+), which is released in high concentrations during the parasite's digestion of host hemoglobin (Meshnick, 2002). The heme iron catalyzes the reductive cleavage of the peroxide bond, leading to the formation of highly reactive carbon-centered radicals and reactive oxygen species (O'Neill et al., 2010). These intermediates subsequently alkylate a broad spectrum of parasite proteins and lipids, disrupting essential cellular processes and causing rapid parasite death (Wang et al., 2015). This mechanism is highly selective for the parasite's intraerythrocytic stages due to their unique heme-rich environment. Resistance to drugs targeting this pathway is primarily mediated by mutations in the PfKelch13 protein, which reduce the rate of hemoglobin endocytosis and thus the availability of heme for drug activation (Tilley et al., 2016).

Other names

Artemisinin activation pathwayHeme-dependent endoperoxide cleavageEndoperoxide-heme interactionHeme-mediated drug activation

The pathway involves the reductive cleavage of the endoperoxide bridge by ferrous heme (Fe2+), which generates reactive carbon-centered radicals and reactive oxygen species that alkylate parasite biomolecules (Meshnick, 2002).