Plasmodium falciparum heme and redox-metabolic protein complex (PfHeme-Proteome)

The target complex consisting of Plasmodium falciparum heme and various redox and metabolic proteins represents the primary site of action for artemisinin-based antimalarial drugs. During the intraerythrocytic stage, the malaria parasite digests host hemoglobin, releasing free heme (protoporphyrin IX containing Fe2+), which is normally sequestered into inert hemozoin crystals (Meshnick, 2002, Int J Parasitol). Artemisinins react with this heme-derived iron to undergo reductive cleavage of their internal endoperoxide bridge, generating highly reactive carbon-centered radicals and reactive oxygen species (Wang et al., 2015, Nat Commun). These radicals subsequently form covalent adducts with a broad spectrum of parasite proteins, effectively bombarding the parasite's metabolic machinery. Key proteins targeted include those involved in glycolysis (e.g., GAPDH), protein folding (e.g., HSP70), and antioxidant defense (e.g., Thioredoxin reductase), leading to a rapid collapse of cellular homeostasis (Tilley et al., 2016, Trends Parasitol). This multi-target mechanism explains the high potency and rapid action of artemisinins against various life stages of the parasite. Resistance to this mechanism is primarily mediated by mutations in the PfKelch13 protein, which reduces the parasite's hemoglobin uptake and enhances its stress response, thereby decreasing the activation of the drug (Ismail et al., 2016, Malar J).

Other names

Heme-artemisinin targetsParasite redox proteomeArtemisinin-binding proteinsHeme-activated protein targets

Heme-mediated activation of the drug's endoperoxide bridge generates reactive carbon-centered radicals that covalently alkylate and inhibit multiple essential parasite proteins.