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Malaria pigment crystals: The achilles′ heel of the malaria parasite

DOI: 10.1002/cmdc.202000895 DOI Help

Authors: Sergey Kapishnikov (Weizmann Institute of Science) , Ernst Hempelmann (Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP)) , Michael Elbaum (Weizmann Institute of Science) , Jens Als‐nielsen (Niels Bohr Institute, University of Copenhagen) , Leslie Leiserowitz (Weizmann Institute of Science)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemmedchem , VOL 4

State: Published (Approved)
Published: March 2021

Open Access Open Access

Abstract: 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.

Journal Keywords: crystal growth; crystal structure; malaria; hemozoin nucleation; mode of action; X-ray imaging

Diamond Keywords: Malaria

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

Other Facilities: U41‐TXM at Helmholtz‐Zentrum Berlin (HZB); MISTRAL at ALBA; ID16a at ESRF; microXAS at th Swiss Light Source (SLS); BW1 at HASYLAB, DESY

Added On: 19/04/2021 15:03

Discipline Tags:

Infectious Diseases Disease in the Developing World Health & Wellbeing Biochemistry Chemistry Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Microscopy Electron Microscopy (EM)