Malaria Pigment Crystals: The Achilles′ Heel of the Malaria Parasite

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

Structural and morphological characterization of hemozoin produced by Schistosoma mansoni and Rhodnius prolixus

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2016-07-25T14:13:22Z No. of bitstreams: 1 Oliveira MF Structural and morphological......pdf: 426444 bytes, checksum: 7cef808ba81bac15d03cff11583556a5 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2016-07-25T14:25:37Z (GMT) No. of bitstreams: 1 Oliveira MF Structural and morphological......pdf: 426444 bytes, checksum: 7cef808ba81bac15d03cff11583556a5 (MD5)Made available in DSpace on 2016-07-25T14:25:37Z (GMT). No. of bitstreams: 1 Oliveira MF Structural and morphological......pdf: 426444 bytes, checksum: 7cef808ba81bac15d03cff11583556a5 (MD5) Previous issue date: 2005-11-07Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica. Programas de Biologia Molecular e Biotecnologia, Bioquímica e Biofísica Celular. Rio de Janeiro, RJ, BrasilUniversity of Guelph, Guelph. Department of Physics, MacNaughton Bldg, Gordon Street. Guelph, Ont. CanadaUniversity of Guelph, Guelph. Department of Physics, MacNaughton Bldg, Gordon Street. Guelph, Ont., CanadaMcGill University. Department of Chemistry. Montreal, Que., CanadaMcGill University. Department of Chemistry. Montreal, Que., CanadaTubingen University. Institute of Tropical Medicine. Department of Parasitology. Tubingen, GermanyFundação Gonçalo Moniz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilFundação Gonçalo Moniz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilUniversidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica. Programas de Biologia Molecular e Biotecnologia, Bioquímica e Biofísica Celular. Rio de Janeiro, RJ, BrasilUniversidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica. Programas de Biologia Molecular e Biotecnologia, Bioquímica e Biofísica Celular. Rio de Janeiro, RJ, Brasil / Laboratório Nacional de Luz Síncrotron. Campinas, SP, BrasilHemozoin (Hz) is a heme crystal produced upon the digestion of hemoglobin (Hb) by blood-feeding organisms as a main mechanism of heme disposal. The structure of Hz consists of heme dimers bound by reciprocal iron-carboxylate interactions and stabilized by hydrogen bonds. We have recently described heme crystals in the blood fluke, Schistosoma mansoni, and in the kissing bug, Rhodnius prolixus. Here, we characterized the structures and morphologies of the heme crystals from those two organisms and compared them to synthetic beta-hematin (betaH). Synchrotron radiation X-ray powder diffraction showed that all heme crystals share the same unit cell and structure. The heme crystals isolated from S. mansoni and R. prolixus consisted of very regular units assembled in multicrystalline spherical structures exhibiting remarkably distinct surface morphologies compared to betaH. In both organisms, Hz formation occurs inside lipid droplet-like particles or in close association to phospholipid membranes. These results show, for the first time, the structural and morphological characterization of natural Hz samples obtained from these two blood-feeding organisms. Moreover, Hz formation occurring in close association to a hydrophobic environment seems to be a common trend for these organisms and may be crucial to produce very regular shaped phases, allowing the formation of multicrystalline assemblies in the guts of S. mansoni and R. prolixus