Synthetic Hemozoin (β-Hematin) Crystals Nucleate at the Surface of Neutral Lipid Droplets That Control Their Sizes

Overview

Journal Cryst Growth Des

Publisher American Chemical Society

Date 2013 Nov 19

PMID 24244110

Citations 13

Authors

Melvin A Ambele

B Trevor Sewell

Franscious R Cummings

Peter J Smith

Timothy J Egan

Affiliations

Soon will be listed here.

Abstract

Emulsions of monopalmitoylglycerol (MPG) and of a neutral lipid blend (NLB), consisting of MPG, monostearoylglycerol, dipalmitoylglycerol, dioleoylglycerol and dilineoylglycerol (4:2:1:1:1), the composition associated with hemozoin from the malaria parasite , have been used to mediate the formation of β-hematin microcrystals. Transmission electron microscopy (TEM), electron diffraction and electron spectroscopic imaging/electron energy loss spectroscopy (ESI/EELS) have been used to characterize both the lipid emulsion and β-hematin crystals. The latter have been compared with β-hematin formed at a pentanol/aqueous interface and with hemozoin both within parasites and extracted from the parasites. When lipid and ferriprotoporphyrin IX solutions in 1:9 v/v acetone/methanol were thoroughly pre-mixed either using an extruder or ultrasound, β-hematin crystals were found formed in intimate association with the lipid droplets. These crystals resembled hemozoin crystals, with prominent {100} faces. Lattice fringes in TEM indicated that these faces made contact with the lipid surface. The average length of these crystals was 0.62 times the average diameter of NLB droplets and their size distributions were statistically equivalent after 10 min incubation, suggesting that the lipid droplets also controlled the sizes of the crystals. This most closely resembles hemozoin formation in the helminth worm , while in , crystal formation appears to be associated with the much more gently curved digestive vacuole membrane which apparently leads to formation of much larger hemozoin crystals, similar to those formed at the flat pentanol-water interface.

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References

Pisciotta J, Coppens I, Tripathi A, Scholl P, Shuman J, Bajad S . The role of neutral lipid nanospheres in Plasmodium falciparum haem crystallization. Biochem J. 2006; 402(1):197-204. PMC: 1783988. DOI: 10.1042/BJ20060986. View

Kapishnikov S, Berthing T, Hviid L, Dierolf M, Menzel A, Pfeiffer F . Aligned hemozoin crystals in curved clusters in malarial red blood cells revealed by nanoprobe X-ray Fe fluorescence and diffraction. Proc Natl Acad Sci U S A. 2012; 109(28):11184-7. PMC: 3396539. DOI: 10.1073/pnas.1118134109. View

Slater A, Cerami A . Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature. 1992; 355(6356):167-9. DOI: 10.1038/355167a0. View

EGAN T, Mavuso W, Ncokazi K . The mechanism of beta-hematin formation in acetate solution. Parallels between hemozoin formation and biomineralization processes. Biochemistry. 2001; 40(1):204-13. DOI: 10.1021/bi0013501. View

Egan T, Combrinck J, Egan J, Hearne G, Marques H, Ntenteni S . Fate of haem iron in the malaria parasite Plasmodium falciparum. Biochem J. 2002; 365(Pt 2):343-7. PMC: 1222701. DOI: 10.1042/BJ20020793. View

Jani D, Nagarkatti R, Beatty W, Angel R, Slebodnick C, Andersen J . HDP-a novel heme detoxification protein from the malaria parasite. PLoS Pathog. 2008; 4(4):e1000053. PMC: 2291572. DOI: 10.1371/journal.ppat.1000053. View

Hoang A, Sandlin R, Omar A, Egan T, Wright D . The neutral lipid composition present in the digestive vacuole of Plasmodium falciparum concentrates heme and mediates β-hematin formation with an unusually low activation energy. Biochemistry. 2010; 49(47):10107-16. PMC: 2996888. DOI: 10.1021/bi101397u. View

Hoang A, Ncokazi K, de Villiers K, Wright D, Egan T . Crystallization of synthetic haemozoin (beta-haematin) nucleated at the surface of lipid particles. Dalton Trans. 2010; 39(5):1235-44. PMC: 2889375. DOI: 10.1039/b914359a. View

EGAN T, Ross D, Adams P . Quinoline anti-malarial drugs inhibit spontaneous formation of beta-haematin (malaria pigment). FEBS Lett. 1994; 352(1):54-7. DOI: 10.1016/0014-5793(94)00921-x. View

10.

Oliveira M, Silva J, Dansa-Petretski M, De Souza W, Lins U, Braga C . Haem detoxification by an insect. Nature. 1999; 400(6744):517-8. DOI: 10.1038/22910. View

11.

TRAGER W, Jensen J . Human malaria parasites in continuous culture. Science. 1976; 193(4254):673-5. DOI: 10.1126/science.781840. View

12.

Noland G, Briones N, Sullivan Jr D . The shape and size of hemozoin crystals distinguishes diverse Plasmodium species. Mol Biochem Parasitol. 2003; 130(2):91-9. DOI: 10.1016/s0166-6851(03)00163-4. View

13.

Chen M, Shi L, Sullivan Jr D . Haemoproteus and Schistosoma synthesize heme polymers similar to Plasmodium hemozoin and beta-hematin. Mol Biochem Parasitol. 2001; 113(1):1-8. DOI: 10.1016/s0166-6851(00)00365-0. View

14.

Ambele M, Egan T . Neutral lipids associated with haemozoin mediate efficient and rapid β-haematin formation at physiological pH, temperature and ionic composition. Malar J. 2012; 11:337. PMC: 3479076. DOI: 10.1186/1475-2875-11-337. View

15.

Correa Soares J, Maya-Monteiro C, Bittencourt-Cunha P, Atella G, Lara F, dAvila J . Extracellular lipid droplets promote hemozoin crystallization in the gut of the blood fluke Schistosoma mansoni. FEBS Lett. 2007; 581(9):1742-50. DOI: 10.1016/j.febslet.2007.03.054. View

16.

Bellemare M, Bohle D, Brosseau C, Georges E, Godbout M, Kelly J . Autofluorescence of condensed heme aggregates in malaria pigment and its synthetic equivalent hematin anhydride (beta-hematin). J Phys Chem B. 2009; 113(24):8391-401. DOI: 10.1021/jp8104375. View

17.

Sullivan Jr D, Gluzman I, Goldberg D . Plasmodium hemozoin formation mediated by histidine-rich proteins. Science. 1996; 271(5246):219-22. DOI: 10.1126/science.271.5246.219. View

18.

Bendrat K, Berger B, Cerami A . Haem polymerization in malaria. Nature. 1995; 378(6553):138-9. DOI: 10.1038/378138a0. View

19.

Chugh M, Sundararaman V, Kumar S, Reddy V, Siddiqui W, Stuart K . Protein complex directs hemoglobin-to-hemozoin formation in Plasmodium falciparum. Proc Natl Acad Sci U S A. 2013; 110(14):5392-7. PMC: 3619337. DOI: 10.1073/pnas.1218412110. View

20.

Egan T, Chen J, de Villiers K, Mabotha T, Naidoo K, Ncokazi K . Haemozoin (beta-haematin) biomineralization occurs by self-assembly near the lipid/water interface. FEBS Lett. 2006; 580(21):5105-10. DOI: 10.1016/j.febslet.2006.08.043. View