Parasitology Research

, Volume 100, Issue 4, pp 671–676 | Cite as

Hemozoin Biocrystallization in Plasmodium falciparum and the antimalarial activity of crystallization inhibitors

  • Ernst HempelmannEmail author
Quinine extracted from the bark of the South American Cinchona spp tree was the first of all antimalarials in western medicine and had been used since the 17th century. For more than 300 years, quinine was the only specific treatment for malaria. It was synthesized in 1944 (Woodward and Doering 1945) and has again become the antimalarial drug of choice in some parts of the world, both for uncomplicated and complicated forms of the disease and as monotherapy or as the backbone of combination therapy. The drug is a powerful schizonticide, active only against malaria pigment (hemozoin) producing stages (Warhurst et al. 2003). The drug has no activity against the sporozoites and exo-erythrocytic stages of the parasites (liver schizonts) which do not consume hemoglobin. Other blood schizontocidal antimalarial drugs (chloroquine, amodiaquine, mefloquine, halofantrine, and lumefantrine) are also likely to be inhibitors of heme detoxification (see Fig.  1) (Ezzet et al. 2000; Chong and...


Malaria Methylene Blue Chloroquine Antimalarial Drug Halofantrine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Electron micrographs (Figs. 3 and 4) were imaged by Lawrence Bannister and John Hopkins, Department of Anatomy and Human Science, Guy’s, King’s and St Thomas’ Medical School, London. The freeze fracture replica was prepared by Anthony Brain, Centre for Ultrastructural Imaging, King’s College London. The advice and support of Graham H. Mitchell, Guy’s Hospital London, is gratefully acknowledged.


  1. Atamna H, Krugliak M, Shalmiev G, Deharo E, Pescarmona G, Ginsburg H (1996) Mode of antimalarial effect of methylene blue and some of its analoques on Plasmodium falciparum in culture and their inhibition of P. vinckei petteri and P. yoelli nigeriensis in vivo. Biochem Pharmacol 51:693–700PubMedCrossRefGoogle Scholar
  2. Ball EG, McKee RW, Anfinsen CB, Cruz WO, Geiman QM (1948) Studies on malarial parasites. IX. Chemical and metabolic changes during growth and multiplication in vivo and in vitro. J Biol Chem 175:547–571Google Scholar
  3. Bäuerlein E (ed) (2004) Biomineralization. Wiley-VCH Verlag GmbH, WeinheimGoogle Scholar
  4. Bray PG, Mungthin M, Ridley RG, Ward SA (1998) Access to hematin: the basis of chloroquine resistance. Mol Pharmacol 54:170–179PubMedGoogle Scholar
  5. Bray PG, Ward SA, O’Neill PM (2005) Quinolines and artemisinin: chemistry, biology and history. Curr Top Microbiol Immunol 295:3–38PubMedGoogle Scholar
  6. Brown WH (1911) Malarial pigment (so-called melanin): its nature and mode of production. J Exp Med 13:290–300CrossRefGoogle Scholar
  7. Carbone T (1891) Sulla natura chimica del pigmento malarico. G R Accad Med Torino 39:901–906Google Scholar
  8. Chong CR, Sullivan DJ (2003) Inhibition of heme crystal growth by antimalarials and other compounds: implication for drug discovery. Biochem Pharmacol 66:2201–2212PubMedCrossRefGoogle Scholar
  9. Coatney GR (1963) Pitfalls in a discovery: the chronicle of chloroquine. Am J Trop Med Hyg 12:121–128PubMedGoogle Scholar
  10. Dascombe MJ, Drew MG, Morris H, Wilairat P, Auparakkitanon S, Moule WA, Alizadeh-Shekalgourabi S, Evans PG, Lloyd M, Dyas AM, Carr P, Ismail FM (2005) Mapping antimalarial pharmacophores as a useful tool for the rapid discovery of drugs effective in vivo: design, construction, characterization, and pharmacology of metaquine. J Med Chem 48:5423–5436PubMedCrossRefGoogle Scholar
  11. Deegan T, Maegraith BG (1956) Studies on the nature of malarial pigment (hemozoin). Ann Trop Med Parasitol 50:194–211PubMedGoogle Scholar
  12. Deharo E, Garcia RN, Oporto P, Gimenez A, Sauvain M, Jullian V, Ginsburg H (2002) A non-radiolabelled ferriprotoporphyrin IX biomineralisation inhibition test for the high throughput screening of antimalarial compounds. Exp Parasitol 100:252–2566PubMedCrossRefGoogle Scholar
  13. Dünschede H-B (1971) Tropenmedizinische Forschung bei Bayer. Michael Triltsch Verlag, DüsseldorfGoogle Scholar
  14. Egan TJ (2002) Physico-chemical aspects of hemozoin (malaria pigment) structure and formation. J Inorg Biochem 91:19–26PubMedCrossRefGoogle Scholar
  15. Egan TJ (2006) Interactions of quinoline antimalarials with hematin in solution. J Inorg Biochem 100:916–926PubMedCrossRefGoogle Scholar
  16. Egan TJ, Hempelmann E, Mavuso WW (1999) Characterisation of synthetic beta-haematin and effects of the antimalarial drugs quinidine, halofantrine, desbutylhalofantrine and mefloquine on its formation. J Inorg Biochem 73:101–107PubMedCrossRefGoogle Scholar
  17. Egan TJ, Mavuso WW, Ncokazi KK (2001) The mechanism of beta-hematin formation in acetate solution. Parallels between hemozoin formation and biomineralization processes. Biochemistry 40:204–213PubMedCrossRefGoogle Scholar
  18. Ezzet F, van Vugt M, Nosten F, Looareesuwan S, White NJ (2000) Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria. Antimicrob Agents Chemother 44:697–704PubMedCrossRefGoogle Scholar
  19. Fitch CD (2004) Ferriprotoporphyrin IX, phospholipids, and the antimalarial actions of quinoline drugs. Life Sci 74:1957–1972PubMedCrossRefGoogle Scholar
  20. Fitch CD, Kanjananggulpan P (1987) The state of ferriprotoporphyrin IX in malaria pigment. J Biol Chem 262:15552–15555PubMedGoogle Scholar
  21. Frerichs FT (1858) Pathologisch-anatomischer Atlas zur Klinik der Leberkrankheiten Band I: Klinik der Leberkrankheiten, Kapitel VIII Die Pigmentleber. Melanämische Leber. Veränderungen der Leber bei Intermittens. 325–368, F. Vieweg und Sohn, BraunschweigGoogle Scholar
  22. Guttmann P, Ehrlich P (1891) Ueber die Wirkung desMethylenblau bei Malaria. Berliner Klinische Wochenschrift 39:953–956Google Scholar
  23. Hamsik A (1925) Zur Darstellung des Oxyhämins. Hoppe-Seyler Z Physiol Chem 148:99–110Google Scholar
  24. Harinasuta T, Migasen S, Bunnag D (1962) Chloroquine resistance in Plasmodium falciparum in Thailand. In: UNESCO First Regional Symposium on Scientific Knowledge of Tropical Parasites pp. 148–153, University of Singapore, SingaporeGoogle Scholar
  25. Hempelmann E, Egan TJ (2002) Pigment biocrystallization in Plasmodium falciparum. Trends Parasitol 18:11PubMedCrossRefGoogle Scholar
  26. Hempelmann E, Marques HM (1994) Analysis of malaria pigment from Plasmodium falciparum. J Pharmacol Toxicol Methods 32:25–30PubMedCrossRefGoogle Scholar
  27. Hempelmann E, Motta C, Hughes R, Ward SA, Bray PG (2003) Plasmodium falciparum: sacrificing membrane to grow crystals? Trends Parasitol 19:23–26PubMedCrossRefGoogle Scholar
  28. Homewood CA, Moore GA, Warhurst DC, Atkinson EM (1975) Purification and some properties of malarial pigment. Ann Trop Med Parasitol 69:283–287PubMedGoogle Scholar
  29. Kaufman TS, Ruveda EA (2005) The quest for quinine: those who won the battles and those who won the war. Angew Chem Int Ed 44:854–885CrossRefGoogle Scholar
  30. Laveran CLA (1880) A newly discovered parasite in the blood of patients suffering from malaria. Parasitic etiology of attacks of malaria. Translated from the French and reprinted. In: Kean BH, Mott KE, Russell AJ (eds) Tropical Medicine and Parasitology. Classic Investigations. Vol. 1, 1978: Cornell University Press, Ithaca, New YorkGoogle Scholar
  31. Leed A, DuBay K, Ursos LM, Sears D, De Dios AC, Roepe PD (2002) Solution structures of antimalarial drug–heme complexes. Biochemistry 41:10245–10255PubMedCrossRefGoogle Scholar
  32. Lemberg R, Legge JW (1949) Hematin compounds and bile pigments. Interscience, New YorkGoogle Scholar
  33. Lew VL, Tiffert T, Ginsburg H (2003) Excess hemoglobin digestion and the osmotic stability of Plasmodium falciparum infected red blood cells. Blood 101:4189–4194PubMedCrossRefGoogle Scholar
  34. Lowenstam HA, Weiner S (1989) On biomineralization. Oxford University Press, New YorkGoogle Scholar
  35. Macomber PB, Sprinz H, Tousimis AJ (1967) Morphological effects of chloroquine on Plasmodium berghei in mice. Nature 214:937–939PubMedCrossRefGoogle Scholar
  36. Mann S (2002) Biomineralization. Oxford University Press, New YorkGoogle Scholar
  37. Meckel H (1847) Ueber schwarzes Pigment in der Milz und dem Blute einer Geisteskranken. Zeitschr f Psychiatrie IV:198–226Google Scholar
  38. Moore DV, Lanier JE (1961) Observations on two Plasmodium falciparum infections with an abnormal response to chloroquine. Am J Trop Med Hyg 10:5–9PubMedGoogle Scholar
  39. Omodeo-Sale F, Motti A, Dondorp A, White NJ, Taramelli D (2005) Destabilisation and subsequent lysis of human erythrocytes induced by Plasmodium falciparum haem products. Eur J Haematol 74:324–332PubMedCrossRefGoogle Scholar
  40. Pagola S, Stephens PW, Bohle DS, Kosar AD, Madsen SK (2000) The structure of malaria pigment beta-haematin. Nature 404:307–310PubMedCrossRefGoogle Scholar
  41. Peters W (1964) Pigment formation and nuclear division in chloroquine-resistant malaria parasites (Plasmodium berghei, Vincke and Lips, 1948). Nature 203:1290–1291PubMedCrossRefGoogle Scholar
  42. Scholl PF, Tripathi AK, Sullivan DJ (2005) Bioavailable iron and heme metabolism in Plasmodium falciparum. Curr Top Microbiol Immunol 295:293–324PubMedCrossRefGoogle Scholar
  43. Schulemann W (1932) Synthetic anti-malarial preparations. Proc R Soc Med 25:897–905Google Scholar
  44. Sharma V (2005) Therapeutic drugs for targeting chloroquine resistance in malaria. Mini-Reviews in Medical Chemistry 5:337–351CrossRefGoogle Scholar
  45. Slater AFG, Cerami A (1992) Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature 355:167–169PubMedCrossRefGoogle Scholar
  46. Slater AFG, Swiggard WJ, Orton BR, Flitter WD, Goldberg DE, Cerami A, Henderson GB (1991) An iron-carboxylate bond links the heme units of malaria pigment. PNAS 88:325–329PubMedCrossRefGoogle Scholar
  47. Smith DC, Sanford LB (1985) Laveran’s germ: the reception and use of a medical discovery. Am J Trop Med Hyg 34:2–20PubMedGoogle Scholar
  48. Sullivan DJ (2002) Hemozoin, a biocrystal synthesized during the degradation of hemoglobin. In: Matsumura S, Steinbüchel A (eds) Biopolymers, vol. 9, Wiley-VCH Verlag GmbH, Weinheim pp 129–163Google Scholar
  49. Tekwani BL, Walker LA (2005) Targeting the hemozoin synthesis pathway for new antimalarial drug discovery: technologies for in vitro β-hematin formation assay. Comb Chem High Throughput Screen 8:61–67CrossRefGoogle Scholar
  50. Vennerstrom JL, Makler MT, Angerhofer CK, William JA (1995) Antimalarial dyes revisited: xanthenes, azines, oxazines and thiazines. Antimicrob Agents Chemother 39:2671–2677PubMedGoogle Scholar
  51. Virchow R (1849) Zur pathologischen Physiologie des Blutes. Arch Pathol Anatomie 2:587–598CrossRefGoogle Scholar
  52. Wainwright M, Amaral L (2005) The phenothiazinium chromophore and the evolution of antimalarial drugs. Trop Med Int Health 10:501–511PubMedCrossRefGoogle Scholar
  53. Warhurst DC, Hockley DJ (1967) Mode of action of chloroquine on Plasmodium berghei and P. cynomolgi. Nature 214:935–936PubMedCrossRefGoogle Scholar
  54. Warhurst DC, Craig JC, Adagu IS, Meyer DJ, Lee SY (2003) The relationship of physico-chemical properties and structure of the differential antiplasmodial activity of the cinchona alkaloids. Malar J 2:26PubMedCrossRefGoogle Scholar
  55. Wellems TE, Plowe CV (2001) Chloroquine-resistant malaria. J Infect Dis 184:770–776PubMedCrossRefGoogle Scholar
  56. Woodward RB, Doering WE (1945) The total synthesis of quinine. J Am Chem Soc 67:860–874CrossRefGoogle Scholar
  57. Ziegler J, Linck R, Wright DW (2001) Heme aggregation inhibitors: antimalarial drugs targeting an essential biomineralization process. Curr Med Chem 8:171–189PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  1. 1.School of Biochemistry, Genetics, Microbiology and Plant PathologyUniversity of KwaZulu-NatalPietermaritzburgSouth Africa

Personalised recommendations