Ferrous heme protoporphyrin IX (Fe(II)-PPIX)

Ferrous heme protoporphyrin IX (Fe(II)-PPIX) is a critical byproduct of hemoglobin degradation within the digestive vacuole of Plasmodium parasites during the intraerythrocytic stage of malaria (Klonis et al., 2011, PNAS). During this stage, the parasite consumes host hemoglobin to obtain amino acids, releasing free heme which is toxic due to its ability to generate reactive oxygen species (Tilley et al., 2016, Trends in Parasitology). To survive, the parasite typically detoxifies this heme by sequestering it into an insoluble crystalline form known as hemozoin. Ferrous heme serves as the primary activator for artemisinin-based antimalarial drugs; the ferrous iron center reacts with the drug's pharmacophore, an internal endoperoxide bridge, to produce highly reactive carbon-centered radicals (Wang et al., 2015, Cell). These radicals subsequently alkylate multiple parasite targets, including the PfATP6 calcium pump and various metabolic enzymes, leading to rapid parasite death. Consequently, the availability of ferrous heme is a prerequisite for the clinical efficacy of artemisinin combination therapies (ACTs), and its role is central to the treatment of Plasmodium falciparum infections (Heller & Roepe, 2019, Molecules).

Other names

Ferrous hemeHeme bFe(II)-protoporphyrin IXReduced hemeUnbound ferrous heme

Reductive activation of the endoperoxide bridge in artemisinin-class drugs by the ferrous iron center, leading to the generation of toxic carbon-centered free radicals that alkylate parasite proteins and lipids.