Using cell fractionation and measurement of Fe(III)heme-pyridine, the antimalarial chloroquine (CQ) has been shown to cause a dose-dependent decrease in hemozoin and concomitant increase in toxic “free” heme in cultured Plasmodium falciparum that is directly correlated with parasite survival. Transmission electron microscopy techniques have further shown that heme is redistributed from the parasite digestive vacuole to the cytoplasm and that CQ disrupts hemozoin crystal growth, resulting in mosaic boundaries in the crystals formed in the parasite. Extension of the cell fractionation study to other drugs has shown that artesunate, amodiaquine, lumefantrine, mefloquine and quinine, all clinically important antimalarials, also inhibit hemozoin formation in the parasite cell, while the antifolate pyrimethamine and its combination with sulfadoxine do not. This study finally provides direct evidence in support of the hemozoin inhibition hypothesis for the mechanism of action of CQ and shows that other quinoline and related antimalarials inhibit cellular hemozoin formation.
Several blood-feeding organisms, including the malaria parasite detoxify haem released from host haemoglobin by conversion to the insoluble crystalline ferriprotoporphyrin IX dimer known as haemozoin. To date the mechanism of haemozoin formation has remained unknown, although lipids or proteins have been suggested to catalyse its formation. We have found that beta-haematin (synthetic haemozoin) forms rapidly under physiologically realistic conditions near octanol/water, pentanol/water and lipid/water interfaces. Molecular dynamics simulations show that a precursor of the haemozoin dimer forms spontaneously in the absence of the competing hydrogen bonds of water, demonstrating that this substance probably self-assembles near a lipid/water interface in vivo.
The nucleation of malaria pigment (hemozoin) and β-hematin crystals (synthetic hemozoin) can be promoted by lipid molecules. To determine the orientation of β-hematin crystals nucleated by 1-myristoyl-glycerol (MMG) on the water surface, we undertook a grazing incidence synchrotron X-ray diffraction and X-ray reflectivity study. Our results indicate that premixed R-hematin with MMG yielded β-hematin nanocrystals oriented with the {100} face parallel to water surface, which we explain insofar that the spreading solution allows MMG molecular aggregation into clusters exposing OH groups and oxygen lone-pair electrons that interact with hematin molecules. Hematin molecules, which did not interact with MMG clusters, do not yield β-hematin, but rather an unknown crystalline phase. Independently, evidence is presented that self-assembled functionalized alkanethiol monolayers (SAMs) exposing OH groups induce β-hematin nucleation primarily via its {100} face, whereas those exposing CH 3 induce nucleation of either the {100} or {010} face, preferentially {010}. The results can be explained in terms of a difference in affinity of the SAMs to these two crystal faces. The two sets of β-hematin nucleation experiments, conducted under different conditions, strengthen the notion that MMG molecules, mimicking a digestive vacuole lipid surface, induce, via stereospecific interactions, oriented nucleation of β-hematin at the {100} face.
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