TY - JOUR

T1 - Malaria Pigment Crystals

T2 - The Achilles ' Heel of the Malaria Parasite

AU - Kapishnikov, Sergey

AU - Hempelmann, Ernst

AU - Elbaum, Michael

AU - Als-Nielsen, Jens

AU - Leiserowitz, Leslie

PY - 2021/3/19

Y1 - 2021/3/19

N2 - The biogenic formation of hemozoin crystals, a crucial process in heme detoxification by the malaria parasite, is reviewed as an antimalarial drug target. We first focus on the in-vivo formation of hemozoin. A model is presented, based on native-contrast 3D imaging obtained by X-ray and electron microscopy, that hemozoin nucleates at the inner membrane leaflet of the parasitic digestive vacuole, and grows in the adjacent aqueous medium. Having observed quantities of hemoglobin and hemozoin in the digestive vacuole, we present a model that heme liberation from hemoglobin and hemozoin formation is an assembly-line process. The crystallization is preceded by reaction between heme monomers yielding hematin dimers involving fewer types of isomers than in synthetic hemozoin; this is indicative of protein-induced dimerization. Models of antimalarial drugs binding onto hemozoin surfaces are reviewed. This is followed by a description of bromoquine, a chloroquine drug analogue, capping a significant fraction of hemozoin surfaces within the digestive vacuole and accumulation of the drug, presumably a bromoquine-hematin complex, at the vacuole's membrane.

AB - The biogenic formation of hemozoin crystals, a crucial process in heme detoxification by the malaria parasite, is reviewed as an antimalarial drug target. We first focus on the in-vivo formation of hemozoin. A model is presented, based on native-contrast 3D imaging obtained by X-ray and electron microscopy, that hemozoin nucleates at the inner membrane leaflet of the parasitic digestive vacuole, and grows in the adjacent aqueous medium. Having observed quantities of hemoglobin and hemozoin in the digestive vacuole, we present a model that heme liberation from hemoglobin and hemozoin formation is an assembly-line process. The crystallization is preceded by reaction between heme monomers yielding hematin dimers involving fewer types of isomers than in synthetic hemozoin; this is indicative of protein-induced dimerization. Models of antimalarial drugs binding onto hemozoin surfaces are reviewed. This is followed by a description of bromoquine, a chloroquine drug analogue, capping a significant fraction of hemozoin surfaces within the digestive vacuole and accumulation of the drug, presumably a bromoquine-hematin complex, at the vacuole's membrane.

KW - crystal growth

KW - crystal structure

KW - malaria

KW - hemozoin nucleation

KW - mode of action

KW - X-ray imaging

U2 - 10.1002/cmdc.202000895

DO - 10.1002/cmdc.202000895

M3 - Review

C2 - 33523575

JO - Farmaco

JF - Farmaco

SN - 1860-7179

ER -