Malaria Pigment Crystals, the Achilles Heel of the Malaria Parasite.

Biogenic formation of hemozoin crystals, a crucial metabolic process of heme detoxification by the malaria parasite, is reviewed as an antimalarial drug target. Starting from a historical description of malaria pigment, the original term for hemozoin, this Perspective first focuses on hemozoin's in-vivo formation. A model is presented, based on native-contrast three-dimensional imaging achieved by X-ray and electron microscopy, that hemozoin nucleates at the inner membrane leaflet of the digestive vacuole, growing in the adjacent aqueous medium. We present observation of quantities of hemozoin found in the digestive vacuole and our model whereby heme liberation from hemoglobin and hemozoin formation is an assembly-line process. The crystallization is preceded by reaction between heme monomers yielding hematin dimers, which constitute hemozoin. Biogenic hemozoin embodies fewer types of dimeric hematin isomers than synthetic hemozoin, indicative of protein-activated heme dimerization. This assembly-line process has implications on the drug types, which inhibit hemozoin formation. We review antimalarial drugs and models of their adsorption onto hemozoin surfaces. Finally, we present our observation of bromoquine, a chloroquine drug analogue, capping a significant fraction of hemozoin crystal surfaces within Plasmodium -infected red blood cells and accumulation of the drug, presumably a bromoquine-hematin dimer complex, at the digestive vacuole membrane.