Crystallization of Synthetic Hemozoin (Beta-Hematin) Nucleated at the Surface of Synthetic Neutral Lipid Bodies
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Crystallization of Synthetic Hemozoin (Beta-Hematin) ucleated at the Surface of Synthetic eutral Lipid Bodies Anh N. Hoang,a Kanyile K. Ncokazi,b Katherine A. de Villiers,†b , David W. Wright,*a Timothy J. Egan*b a
Department of Chemistry, Vanderbilt University, Station B351822, Nashville, TN 37235, USA. E-mail: [email protected] b Department of Chemistry, University of Cape Town, Private Bag, Rondebosch 7701, South Africa. E-mail. [email protected] ABSTRACT: The mechanism of formation of hemozoin, a detoxification by-product of several bloodfeeding organisms including malaria parasites, has been a subject of debate; however, recent studies suggest that neutral lipids may serve as a catalyst. In this study, a model system consisting of an emulsion of synthetic lipid bodies, resembling their in vivo counterpart in composition and size, was employed to investigate the formation of β-hematin, synthetic hemozoin, at the lipid-water interface. The introduction of heme (Fe(III)PPIX) to this synthetic neutral lipid bodies system under biomimetic conditions (37 °C, pH 4.8) produced beta-hematin with apparent first order kinetics and an average half life of 0.5 min. TEM of monoglycerides (MPG) extruded through a 200 nm filter with heme produced beta-hematin crystals aligned and parallel to the lipid/water interface. TEM data suggests that beta-hematin crystallizes via epitaxial nucleation at the lipid-water interface through interaction of Fe(III)PPIX with the polar head group and elongation occurs parallel this interface. ITRODUCTIO: During the pathogenic blood stage of a malaria infection, the Plasmodium parasites enter the host’s red blood cell (RBC) and degrade hemoglobin as a source of nutrition. As a consequence, free heme, known to be capable of causing lipid peroxidation1 and to destabilize membranes through a colloid osmotic mechanism2, is released. It is believed that the parasite circumvents heme toxicity by sequestering the heme molecules into a dark brown crystalline material known as the malaria pigment or hemozoin. Hemozoin is a microcrystalline cyclic dimer of ferriprotoporphyrin IX (Fe(III)PPIX) in which the propionate side chain of one protoporphyrin coordinates to the iron(III) centre of the other3,4. The dimers hydrogen bond to their neighbours via the second propionic acid group, forming extended chains through the crystal. This crystal was first recognized as the discoloration of internal organs of malaria victims in 1717. Despite its early identification, the chemical and structural properties of hemozoin have only been resolved in the last two decades. The molecular mechanism that drives this crystallization remains a topic of debate. However, it is believed that this process is inhibited by chloroquine and other quinoline and related antimalarials5. Therefore, understanding the molecular mechanism behind its formation may help in the elucidation of new strategies for the design of antimalarials. A recent popular hypothesis for hemozoin formation centers on neutral li
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