Bioavailable Iron and Heme Metabolism in Plasmodium falciparum

  • P. F. Scholl
  • A. K. Tripathi
  • D. J. Sullivan
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 295)


Iron metabolism is essential for cell function and potentially toxic because iron can catalyze oxygen radical production. Malaria-attributable anemia and iron deficiency anemia coincide as being treatable diseases in the developing world. In absolute amounts, more than 95% of Plasmodium metal biochemistry occurs in the acidic digestive vacuole where heme released from hemoglobin catabolism forms heme crystals. The antimalarial quinolines interfere with crystallization. Despite the completion of the Plasmodium genome, many ‘gene gaps’ exist in components of the metal pathways described in mammalian or yeast cells. Present evidence suggests that parasite bioavailable iron originates from a labile erythrocyte cytosolic pool rather than from abundant heme iron. Indeed the parasite has to make its own heme within two separate organelles, the mitochondrion and the apicomplast. Paradoxically, despite the abundance of iron within the erythrocyte, iron chelators are cytocidal to the Plasmodium parasite. Hemozoin has become a sensitive biomarker for laser desorption mass spectrometry detection of Plasmodium infection in both mice and humans.


Matrix Assisted Laser Desorption Ionization Plasmodium Falciparum Infected Erythrocyte Iron Chelation Therapy Bioavailable Iron 
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.


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  1. Arese P, Schwarzer E (1997) Malarial pigment (haemozoin): A very active ‘inert’ substance. Ann Trop Med Parasitol 91:501–516PubMedGoogle Scholar
  2. Atamna H, Ginsburg H (1995) Heme degradation in the presence of glutathione: A proposed mechanism to account for the high levels of non-heme iron found in the membranes of hemoglobinopathic red blood cells. J Biol Chem 42:24876–24883Google Scholar
  3. Atkinson CT, Bayne MT, Gordeuk VR, Brittenham GM, Aikawa M (1991) Stage-specific ultrastructural effects of desferrioxamine on Plasmodium falciparum in vitro. Am J Trop Med Hyg 45:593–601PubMedGoogle Scholar
  4. Bahl A, Brunk B, Coppel RL, Crabtree J, Diskin SJ, Fraunholz MJ, Grant GR, Gupta D, Huestis RL, Kissinger JC, Labo P, Li L, McWeeney SK, Milgram AJ, Roos DS, Schug J, Stoeckert CJ, Jr. (2002) Plasmodb: The Plasmodium genome resource. An integrated database providing tools for accessing, analyzing and mapping expression and sequence data (both finished and unfinished). Nucl Acids Res 30:87–90PubMedCrossRefGoogle Scholar
  5. Basilico N, Pagani E, Monti D, Olliaro P, Taramelli D (1998) A microtitre-based method for measuring the haem polymerization inhibitory activity (hpia) of antimalarial drugs. J Antimicrob Chemother 42:55–60PubMedCrossRefGoogle Scholar
  6. Bendrat K, Berger BJ, Cerami A (1995) Haem polymerization in malaria. Nature 378:138PubMedCrossRefGoogle Scholar
  7. Berger J, Dyck JL, Galan P, Aplogan A, Schneider D, Traissac P, Hercberg S (2000) Effect of daily iron supplementation on iron status, cell-mediated immunity, and incidence of infections in 6-36 month old Togolese children Eur J Clin Nutr 54:29–35PubMedCrossRefGoogle Scholar
  8. Blauer G, Akkawi M (1997) Investigations of b-and β-hematin. J Inorg Chem 66:145–152Google Scholar
  9. Blauer G, Akkawi M (2000) On the preparation of beta-haematin. Biochem J 346:249–250PubMedCrossRefGoogle Scholar
  10. Bohle DS, Helms JB (1993) Synthesis of β-hematin by dehydrohalogenation of hemin. Biochem Biophys Res Comm 193:504–508PubMedCrossRefGoogle Scholar
  11. Bozdech Z, Llinas M, Pulliam BL, Wong ED, Zhu J, DeRisi JL (2003) The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum. PLoS Biol 1:86–100CrossRefGoogle Scholar
  12. Brooker S, Peshu N, Warn PA, Mosobo M, Guyatt HL, Marsh K, Snow RW (1999) The epidemiology of hookworm infection and its contribution to anaemia among pre-school children on the Kenyan coast. Trans R Soc Trop Med Hyg 93:240–246PubMedGoogle Scholar
  13. Buller R, Peterson ML, Almarsson O, Leiserowitz L (2002) Quinoline binding site on malaria pigment crystal:A rational pathway for antimalaria drug design. Cryst Growth Des 2:553–562CrossRefGoogle Scholar
  14. Carbone T (1891) Sulla natura chimica del pigmento malarico G. Accad Med Torino 39:901Google Scholar
  15. Choi YHC, Cerda FJ, Chu H-a, Babcock TG, Marletta AM (1999) Spectroscopic characterization of the heme-binding sites in Plasmodium falciparum histidine-rich protein 2. Biochemistry 38:16916–16924PubMedGoogle Scholar
  16. Chong CR, Sullivan DJ (2003) Inhibition of heme crystal growth by antimalarials and other compounds:Implications for drug discovery. Biochem Pharm 66:2201–2212PubMedCrossRefGoogle Scholar
  17. Cotter RJ (1997) Time-of-flightmass spectrometry: Instrumentation and applications in biological research. American Chemical Society, Washington, D.CGoogle Scholar
  18. Deharo E, Barkan D, Krugliak M, Golenser J, Ginsburg H (2003) Potentiation of the antimalarial action of chloroquine in rodent malaria by drugs known to reduce cellular glutathione levels. Biochem Pharm 66:809–817PubMedCrossRefGoogle Scholar
  19. DeHoffman E, Charette J, Stroobant V (1996) Mass spectrometry: Principles and applications. JohnWiley and Sons, Chichester, UKGoogle Scholar
  20. Demirev PA, Feldman AB, Kongkasuriyachai D, Scholl P, Sullivan D, Jr., Kumar N (2002) Detection of malaria parasites in blood by laser desorption mass spectrometry. Anal Chem 74:3262–3266PubMedCrossRefGoogle Scholar
  21. Desai MR, Dhar R, Rosen DH, Kariuki SK, Shi YP, Kager PA, Ter Kuile FO (2004) Daily iron supplementation is more efficacious than twice weekly iron supplementation for the treatment of childhood anemia in western Kenya. J Nutr 134:1167–1174PubMedGoogle Scholar
  22. Desai MR, Mei JV, Kariuki SK, Wannemuehler KA, Phillips-Howard PA, Nahlen BL, Kager PA, Vulule JM, ter Kuile FO (2003) Randomized, controlled trial of daily iron supplementation and intermittent sulfadoxine-pyrimethamine for the treatment of mild childhood anemia in western Kenya. J Infect Dis 187:658–666PubMedCrossRefGoogle Scholar
  23. Dorn A, Stoffel R, Matile H, Bubendorf A, Ridley RG (1995) Malarial haemozoin/betahaematin supports haem polymerization in the absence of protein. Nature 374:269–271PubMedCrossRefGoogle Scholar
  24. Dorn A, Vippagunta SR, Matile H, Bubendorf A, Vennerstrom JL, Ridley RG (1998a) A comparison and analysis of several ways to promote haematin (haem) polymerisation and an assessment of its initiation in vitro. Biochem Pharm 55:737–747PubMedGoogle Scholar
  25. Dorn A, Vippagunta SR, Matile H, Jaquet C, Vennerstrom JL, Ridley RG (1998b) An assessment of drug-haematin binding as amechanism for inhibition of haematin polymerisation by quinoline antimalarials Biochem Pharm 55:727–736PubMedGoogle Scholar
  26. Eckstein-Ludwig U, Webb RJ, VanGoethem ID, East JM, Lee AG, Kimura M, O’Neill PM, Bray PG, Ward SA, Krishna S (2003) Artemisinins target the SERCA of Plasmodium falciparum. Nature 424:957–961PubMedCrossRefGoogle Scholar
  27. Egan T, Ross D, Adams P (1994a) Quinoline anti-malarial drugs inhibit spontaneous formation of beta-haematin (malaria pigment). FEBS Letters 352:54–57PubMedCrossRefGoogle Scholar
  28. Egan TJ (2002) Physico-chemical aspects of hemozoin (malaria pigment) structure and formation. J Inorg Biochem 91:19–26PubMedCrossRefGoogle Scholar
  29. Egan TJ (2004) Haemozoin formation as a target for the rational design of new antimalarials. Drug Design Reviews Online 1:93–110Google Scholar
  30. Egan TJ, Combrinck JM, Egan J, Hearne GR, Marques HM, Ntenteni S, Sewell BT, Smith PJ, Taylor D, Van Schalkwyk DA, Walden JC (2002) Fate of haem iron in the malaria parasite Plasmodium falciparum. Biochem J 365: 343–347PubMedCrossRefGoogle Scholar
  31. Egan TJ, Hunter R, Kaschula CH, Marques HM, Misplon A, Walden J (2000) Structurefunction relationships in aminoquinolines: Effect of amino and chloro groups on quinoline-hematin complex formation, inhibition of beta-hematin formation, and antiplasmodial activity. J Med Chem 43:283–291PubMedGoogle Scholar
  32. 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
  33. Egan TJ, Mavuso WW, Ross DC, Marques HM (1997) Thermodynamic factors controlling the interaction of quinoline antimalarial drugs with ferriprotoporphyrin IX. J Inorg Biochem 68:137–145PubMedCrossRefGoogle Scholar
  34. Egan TJ, Ross DC, Adams PA (1994b) Quinoline anti-malarial drugs inhibit spontaneous formation of beta-haematin (malaria pigment). FEBS Lett 352:54–57PubMedCrossRefGoogle Scholar
  35. Ekvall H, Premji Z, Bjorkman A (2000) Micronutrient and iron supplementation and effective antimalarial treatment synergistically improve childhood anaemia. Trop Med Int Health 5:696–705PubMedCrossRefGoogle Scholar
  36. Fairbanks Vf, Beutler E. (1995a) Iron deficiency. In: Beutler E, Lichtman M, Coller B, Kipps T (eds) Williams hematology, McGraw-Hill, New York, pp490–511Google Scholar
  37. Fairbanks Vf, Beutler E. (1995b). Iron metabolism. In: Beutler E, Lichtman M, Coller B, Kipps T (eds) Williams hematology, McGraw-Hill, New York, pp369–379Google Scholar
  38. Famin O, Ginsburg H (2003) The treatment of plasmodium falciparum-infected erythrocytes with chloroquine leads to accumulation of ferriprotoporphyrin IX bound to particular parasite proteins and to the inhibition of the parasite’s 6-phosphogluconate dehydrogenase. Parasite 10:39–50PubMedGoogle Scholar
  39. Famin O, Krugliak M, Ginsburg H (1999) Kinetics of inhibitionof glutathione-mediated degradation of ferriprotoporphyrin IX by antimalarial drugs. Biochem Pharm 58:59–68PubMedCrossRefGoogle Scholar
  40. Fitch C, Cai G, Chen Y, Shoemaker J (1999) Involvement of lipids inferriprotoporphyrin IX polymerization in malaria. Biochim Biophys Acta 1454:31–37PubMedGoogle Scholar
  41. Fitch CD (1998) Involvement of heme in the antimalarial action of chloroquine. Trans Am Clin Climatol Assoc 109:97–105; discussion 105–106PubMedGoogle Scholar
  42. Fitch CD, Chen YF, Cai GZ (2003) Chloroquine-induced masking of a lipid that promotes ferriprotoporphyrin IX dimerization in malaria. J Biol Chem 278:22596–22599PubMedGoogle Scholar
  43. Fitch CD, Chou AC (1996) Heat-labile and heat-stimulable heme polymerase activities in Plasmodium berghei. Mol Biochem Parasitol 82:261–264PubMedCrossRefGoogle Scholar
  44. Fitch CD, Kanjananggulpan P (1987) The state of ferriprotoporphyrin IX in malaria pigment. J Biol Chem 262:15552–15555PubMedGoogle Scholar
  45. Francis SE, Sullivan DJ Jr, Goldberg DE (1997) Hemoglobin metabolism in the malaria parasite Plasmodium falciparum Annu Rev Microbiol 51:97–123PubMedCrossRefGoogle Scholar
  46. Fry M, Beesley JE (1991) Mitochondria of mammalian Plasmodium spp. Parasitology 102:17–26PubMedCrossRefGoogle Scholar
  47. Gabay T, Ginsburg H (1993) Hemoglobin denaturation and iron release in acidified red blood cell lysate-a possible source of iron for intraerthrocytic malaria parasites. Exp Parisitol 77:261–272Google Scholar
  48. Gabay T, Krugliak M, Shalmiev G, Ginsburg H (1994) Inhibition by anti-malarial drugs of haemoglobin denaturation and iron release in acidified red blood cell lysates-a possible mechanism of their anti-malarial effect? Parasitology 108:371–381PubMedGoogle Scholar
  49. Garrick MD, Nunez MT, Olivares M, Harris ED (2003) Parallels and contrasts between iron and copper metabolism. Biometals 16:1–8PubMedGoogle Scholar
  50. Gera T, Sachdev HP (2002) Effect of iron supplementation on incidence of infectious illness in children: Systematic review. BMJ 325:1142PubMedCrossRefGoogle Scholar
  51. Ginsburg H, Famin O, Zhang J, Krugliak M (1998) Inhibition of glutathione-dependant degradation of heme by chloroquine and amodiaquine as a possible basis for their antimalarials mode of action. Biochem Pharmacol 56:1305–1313PubMedCrossRefGoogle Scholar
  52. Ginsburg H, Gorodetsky R, Krugliak M (1986) The status of zinc in malaria (Plasmodium falciparum) infected human red blood cells: Stage dependent accumulation, compartmentation and effect of dipicolinate. Biochimica et Biophysica Acta 886:337–344PubMedGoogle Scholar
  53. Ginsburg H, Krugliak M (1999) Chloroquine—someopen questions on its antimalarial mode of action and resistance. Drug Resist Update 2:180–187Google Scholar
  54. Goldberg DE, Slater AFG, Cerami A, Henderson GB (1990) Hemoglobin degradation in the malaria parasite Plasmodium falciparum: An ordered process in a unique organelle. Proc Natl Acad Sci USA 87:2931–2935PubMedGoogle Scholar
  55. Gordeuk V, Thuma P, Brittenham G, McLaren C, Parry D, Backenstose A, Biemba G, Msiska R, Holmes L, McKinley E, et al. (1992) Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria. N Engl J Med 327:1473–1477PubMedCrossRefGoogle Scholar
  56. Gushin H, Mackenzie B, Berger UV, Gushin Y, Romero MR, Boron WF, Nussberger S, Gollan JL, Hediger MA (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388:482–487Google Scholar
  57. Haddad S, Restieri C, Krishnan K (2001) Characterization of age-related changes in body weight and organ weights from birth to adolescence in humans. J Toxicol Environ Health A 64:453–464PubMedCrossRefGoogle Scholar
  58. Haldar K, Henderson CL, Cross GAM (1986) Identification of the parasite transferrin receptor of Plasmodium falciparim-infected erythrocytes and its acylation via 1,2-diacyl-sn-glycerol. Proc Natl Acad Sci USA 83:8565–8569PubMedGoogle Scholar
  59. Hastka J, Lasserre J, Schwarzbeck A, Strauch M, Hehlmann R (1993) Zinc protoporphyrin in anemia of chronic disorders. Blood 81:1200–1204PubMedGoogle Scholar
  60. Hawley SR, Bray PG, Mungthin M, Atkinson JD, O’Neill PM, Ward SA (1998) Relationship between antimalarial drug activity, accumulation, and inhibition of heme polymerization in Plasmodium falciparum in vitro Antimicrob Agents Chemother 42:682–686PubMedGoogle Scholar
  61. Hempelmann E, Egan TJ (2002) Pigment biocrystallization in Plasmodium falciparum. Trends Parasitol 18:11PubMedCrossRefGoogle Scholar
  62. Hempelmann E, Motta C, Hughes R, Ward SA, Bray PG (2003) Plasmodium falciparum: Sacrificing membrane to grow crystals? Trends Parasitol 19:23–26PubMedGoogle Scholar
  63. Hentze MW, Muckenthaler MU, Andrews NC (2004) Balancing acts:Molecular control of mammalian iron metabolism. Cell 117:285–297PubMedCrossRefGoogle Scholar
  64. Hershko C, Peto TE (1988) Deferoxamine inhibition of malaria is independent of host iron status. J Exp Med 168:375–387PubMedCrossRefGoogle Scholar
  65. Huy NT, Kamei K, Yamamoto T, Kondo Y, Kanaori K, Takano R, Tajima K, Hara S (2002) Clotrimazole binds to heme and enhances heme-dependent hemolysis: Proposed antimalarial mechanism of clotrimazole. J Biol Chem 277:4152–4158PubMedCrossRefGoogle Scholar
  66. Iyer JK, Shi L, Shankar AH, Sullivan DJ, Jr. (2003) Zinc protoporphyrin IX binds heme crystals to inhibit the process of crystallization in Plasmodium falciparum. Mol Med 9:175–182PubMedGoogle Scholar
  67. Kalkanidis M, Klonis N, Tilley L, Deady LW (2002) Novel phenothiazine antimalarials: Synthesis, antimalarial activity, and inhibition of the formation of beta-haematin. Biochem Pharmacol 63:833–842PubMedCrossRefGoogle Scholar
  68. Kaplan J, O’Halloran TV (1996) Iron metabolism in eukaryotes: Mars and venus at it again. Science 271:1510–1512PubMedGoogle Scholar
  69. Kristiansen JE, Jepsen S (1985) The susceptibility of Plasmodium falciparum in vitro to chlorpromazine and the stereo-isomeric compounds cis (z)-and trans (e)-clopenthixol. Acta Pathol Microbiol Immunol Scand [B] 93:249–251Google Scholar
  70. Krugliak M, Zhang J, Ginsburg H (2002) Intraerythrocytic Plasmodium falciparum utilizes only a fraction of the amino acids derived from the digestion of host cell cytosol for the biosynthesis of its proteins. Mol Biochem Parasitol 119:249–256PubMedCrossRefGoogle Scholar
  71. Kurosawa Y, Dorn A, Kitsuji-Shirane M, Shimada H, Satoh T, Matile H, Hofheinz W, Masciadri R, Kansy M, Ridley RG (2000) Hematin polymerization assay as a highthroughput screen for identification of new antimalarial pharmacophores. Antimicrob Agents Chemother 44:2638–2644PubMedCrossRefGoogle Scholar
  72. Lamola AA, Yamane T (1974) Zinc protoporphyrin in the erythrocytes of patientswith lead intoxication and iron deficiency anemia. Science 186:936–938PubMedGoogle Scholar
  73. Lawrence C, Olson JA (1986) Birefringent hemozoin identifies malaria. Am J Clin Pathol 86:360–363PubMedGoogle Scholar
  74. Leed A, DuBay K, Ursos LM, Sears D, DeDios AC, Roepe PD (2002) Solution structures of antimalarial drug-heme complexes Biochemistry 41:10245–10255PubMedCrossRefGoogle Scholar
  75. Leenstra T, Kariuki SK, Kurtis JD, Oloo AJ, Kager PA, ter Kuile FO (2004) Prevalence and severity of anemia and iron deficiency: Cross-sectional studies in adolescent schoolgirls in western Kenya. Eur J Clin Nutr 58:681–691PubMedCrossRefGoogle Scholar
  76. Levesque MA, Sullivan AD, Meshnick SR (1999) Splenic and hepatic hemozoin in mice after malaria parasite clearance. J Parasitol 85:570–573PubMedGoogle Scholar
  77. 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
  78. Loyevsky M, John C, Dickens B, Hu V, Miller JH, Gordeuk VR (1999a) Chelation of iron within the erythrocytic Plasmodium falciparum parasite by iron chelators. Mol Biochem Parasitol 101:43–59PubMedCrossRefGoogle Scholar
  79. Loyevsky M, LaVaute T, Allerson CR, Stearman R, Kassim OO, Cooperman S, Gordeuk VR, Rouaul TA (2001) An IRP-like protein from Plasmodium falciparum binds to a mammalian iron-responsive element. Blood 98:2555–2562PubMedCrossRefGoogle Scholar
  80. Loyevsky M, Lytton SD, Mester B, Libman J, Shanzer A, Cabantchik ZI (1993) The antimalarial action of desferal involves a direct access route to erythrocytic (Plasmodium falciparum parasites. J Clin Invest 91:218–224PubMedCrossRefGoogle Scholar
  81. Loyevsky M, Mompoint F, Yikilmaz E, Altschul SF, Madden T, Wootton JC, Kurantsin-Mills J, Kassim OO, Gordeuk VR, Rouault TA (2003) Expression of a recombinant IRP-like Plasmodium falciparum protein that specifically binds putative plasmodial ires. Mol Biochem Parasitol 126:231–238PubMedCrossRefGoogle Scholar
  82. Loyevsky M, Sacci JB, Jr., Boehme P, Weglicki W, John C, Gordeuk VR (1999b) Plasmodium falciparum and Plasmodium yoelii: Effect of the iron chelation prodrug dexrazoxane on in vitro cultures. Exp Parasitol 91:105–114PubMedCrossRefGoogle Scholar
  83. Mabeza GF, Loyevsky M, Gordeuk VR, Weiss G (1999) Iron chelation therapy for malaria: A review. Pharmacol Ther 81:53–75PubMedCrossRefGoogle Scholar
  84. Mann S, Bannister JV, Williams RJP (1986) Structure and composition of ferritin cores isolated from human spleen, limpet (Patella vulgata) hemolymph and bacterial (Pseudomonas aeruginosa) cells. J Mol Biol 188:225–232PubMedCrossRefGoogle Scholar
  85. Marques HM, Voster K, Egan TJ (1996) The interaction of the heme-octapeptide, nacetylmicroperoxidase-8 with antimalarial drugs: Solution studies and modeling by molecular mechanics methods. J Inorgan Biochem 64:7–23CrossRefGoogle Scholar
  86. Massaga JJ, Kitua AY, Lemnge MM, Akida JA, Malle LN, Ronn AM, Theander TG, Bygbjerg IC (2003) Effect of intermittent treatmentwith amodiaquine on anaemia and malarial fevers in infants in Tanzania: A randomised placebo-controlled trial Lancet 361:1853–1860PubMedCrossRefGoogle Scholar
  87. McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F, Hediger MA, Hentze MW, Simpson RJ (2000) A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5:299–309PubMedCrossRefGoogle Scholar
  88. Mebrahtu T, Stoltzfus RJ, Chwaya HM, Jape JK, Savioli L, Montresor A, Albonico M, Tielsch JM (2004) Low-dose daily iron supplementation for 12 months does not increase the prevalence of malarial infection or density of parasites in young Zanzibari children J Nutr 134:3037–3041PubMedGoogle Scholar
  89. Menendez C, Kahigwa E, Hirt R, Vounatsou P, Aponte JJ, Font F, Acosta CJ, Schellenberg DM, Galindo CM, Kimario J, Urassa H, Brabin B, Smith TA, Kitua AY, Tanner M, Alonso PL (1997) Randomised placebo-controlled trial of iron supplementation and malaria chemoprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants. Lancet 350:844–85PubMedGoogle Scholar
  90. Menendez C, Schellenberg D, Quinto L, Kahigwa E, Alvarez L, Aponte JJ, Alonso PL (2004) The effects of short-term iron supplementation on iron status in infants in malaria-endemic areas. Am J Trop Med Hyg 71:434–440PubMedGoogle Scholar
  91. Miyajima H (2002) Genetic disorders affecting proteins of iron and copper metabolism: Clinical implications. Intern Med 41:762–769PubMedGoogle Scholar
  92. Monti D, Vodopivec B, Basilico N, Olliaro P, Taramelli D (1999) A novel endogenous antimalarial: Fe (ii)-protoporphyrin IX alpha (heme) inhibits hematin polymerization to beta-hematin (malaria pigment) and kills malaria parasites. Biochemistry 38:8858–8863PubMedCrossRefGoogle Scholar
  93. Moody A (2002) Rapid diagnostic tests for malaria parasites. Clin Microbiol Rev 15:66–78PubMedCrossRefGoogle Scholar
  94. Moreau S, Perly B, Chachaty C, and Deleuze C (1985) A nuclear magnetic resonance study of the interactions of antimalarial drugs with porphyrins. Biochem Biophys Acta 840:107–116PubMedGoogle Scholar
  95. Murray MJ, Murray NJ, Murray AB, Murray MB (1975) Refeeding-malaria and hyperferraemia. Lancet 1:653–654PubMedGoogle Scholar
  96. Noland GS, Briones N, Sullivan DJ (2003) The shape and size of hemozoin crystals distinguishes diverse Plasmodium species. Mol Biochem Parasitol 130:91–99PubMedCrossRefGoogle Scholar
  97. Nyakeriga AM, Troye-Blomberg M, Dorfman JR, Alexander ND, Back R, Kortok M, Chemtai AK, Marsh K, Williams TN (2004) Iron deficiency and malaria among children living on the coast of Kenya. J Infect Dis 190:439–447PubMedCrossRefGoogle Scholar
  98. O’Neill PM, Willock DJ, Hawley SR, Bray PG, Storr RC, Ward SA, Park BK (1997) Synthesis, antimalarial activity, and molecularmodeling of tebuquine analogues. J Med Chem 40:437–448PubMedGoogle Scholar
  99. Oppenheimer SJ (2001) Iron and its relation to immunity and infectious disease. J Nutr 131:616S-633S; discussion 633S-635SGoogle Scholar
  100. Pagola S, Stephens PW, Bohle DS, Kosar AD, Madsen SK (2000) The structure of malaria pigment beta-hematin. Nature 404:307–310PubMedGoogle Scholar
  101. Pandey AV, Babbarwal VK, Okoyeh JN, Joshi RM, Puri SK, Singh RL, Chauhan VS (2003) Hemozoin formation in malaria: A two-step process involving histidinerich proteins and lipids. Biochem Biophys Res Commun 308:736–743PubMedCrossRefGoogle Scholar
  102. Panek H, O’Brian MR (2002) A whole genome view of prokaryotic haem biosynthesis. Microbiology 148:2273–2282PubMedGoogle Scholar
  103. Papalexis V, Siomos MA, Campanale N, Guo X, Kocak G, Foley M, Tilley L (2001) Histidine-rich protein 2 of the malaria parasite, Plasmodium falciparum, is involved in detoxification of the by-products of haemoglobin degradation. Mol Biochem Parasitol 115:77–86PubMedCrossRefGoogle Scholar
  104. Peto TE, Thompson JL (1986) A reappraisal of the effects of iron and desferrioxamine on the growth of Plasmodium falciparum ‘in vitro’: The unimportance of serum iron Br J Haematol 63:273–280PubMedGoogle Scholar
  105. Rasoloson D, Shi L, Chong CR, Kafsack BF, Sullivan DJ (2004) Copper pathways in Plasmodium falciparum infected erythrocytes indicate an efflux role for the copper P-ATPase. Biochem JGoogle Scholar
  106. Raventos-Suarez C, Pollack S, Nagel RL (1982) Plasmodium falciparum: Inhibition of in vitro growth by desferrioxamine. Am J Trop Med Hyg 31:919–922PubMedGoogle Scholar
  107. Ridley RG (1996) Hemozoin formation in malaria parasites: Is there a haem polymerase? Trends Microbiol 4:253–254PubMedCrossRefGoogle Scholar
  108. Rodriguez MH, Jungery M (1986) A protein on Plasmodium falciparum-infected erythrocytes functions as a transferrin receptor. Nature 324:388–391PubMedCrossRefGoogle Scholar
  109. Sanchez-Lopez R, Haldar K (1992) A transferrin-independent iron uptake activity in Plasmodium falciparum-infected and uninfected erythrocytes. Mol Biochem Parasitol 55:9–20PubMedCrossRefGoogle Scholar
  110. Sato S, Wilson RJ (2003) Proteobacteria-like ferrochelatase in the malaria parasite Curr Genet 42:292–300PubMedGoogle Scholar
  111. Scholl PF, Kongkasuriyachai D, Demirev PA, Feldman AB, Lin JS, Sullivan DJ, Kumar N (2004) Rapid detection of malaria infection in vivo by laser desorption mass spectrometry. Am J Trop Med Hyg 71:546–551PubMedGoogle Scholar
  112. Schwarzer E, Datteis DF, Giribaldi G, Ulliers D, Valente E, Arese P (1999a) Hemozoin stability and dormant induction of heme oxygenase in hemozoin-fed human monocytes. Mol Biochem Parasitol 100:61–72PubMedCrossRefGoogle Scholar
  113. Schwarzer E, Turrini F, Ulliers D, Giribaldi G, Ginsburg H, Arese P (1992) Impairment of macrophage functions after ingestion of Plasmodium falciparum-infected erythrocytes or isolated malarial pigment. J Exp Med 176:1033–1041PubMedCrossRefGoogle Scholar
  114. Scott MD, Ranz A, Kuypers FA, Lubin BH, Meshnick SR (1990) Parasite uptake of desferroxamine: A prerequisite for antimalarial activity Br J Haematol 75:598–602PubMedGoogle Scholar
  115. Slater AF (1993) Chloroquine:Mechanism of drug action and resistance in Plasmodium falciparum. Pharmacol Ther 57:203–235PubMedCrossRefGoogle Scholar
  116. Slater AF, Cerami A (1992) Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature 355:167–169PubMedCrossRefGoogle Scholar
  117. Slater AF, Swiggard WJ, Orton BR, Flitter WD, Goldberg DE, Cerami A, Henderson GB (1991) An iron-carboxylate bond links the heme units of malaria pigment. Proc Natl Acad Sci USA 88:325–329PubMedGoogle Scholar
  118. Slater AFG (1992) Malarial pigment. Experim Parasitol 74:362–365Google Scholar
  119. Spivak JL (2002) Iron and the anemia of chronic disease. Oncology (Huntingt) 16:25–33Google Scholar
  120. Stoltzfus RJ, Chwaya HM, Montresor A, Tielsch JM, Jape JK, Albonico M, Savioli L (2004) Low dose daily iron supplementation improves iron status and appetite but not anemia, whereas quarterly anthelminthic treatment improves growth, appetite and anemia in Zanzibari preschool children. J Nutr 134:348–356PubMedGoogle Scholar
  121. Stoltzfus RJ, Chwaya HM, Montresor A, Albonico M, Savioli L, Tielsch JM (2000) Malaria, hookworms and recent fever are related to anemia and iron status indicators in 0-to 5-y old Zanzibari choldren and these relationships change with age. J Nutr 130:1724–1733PubMedGoogle Scholar
  122. Sullivan D (2002a) Hemozoin: A biocrystal synthesized during the degradation of hemoglobin. In Matsumura S, Steinbüchel A (eds) Miscellaneous biopolymers, biodegradation of synthetic polymers, Wiley-VCHVerlagGmbH&Co, Weinheim, Germany, pp129–163Google Scholar
  123. Sullivan DJ (2002b) Theories onmalarial pigment formation and quinoline action. Int J Parasitol 32:1645–1653PubMedGoogle Scholar
  124. Sullivan DJ Jr, Gluzman IY, Goldberg DE (1996a) Plasmodium hemozoin formation mediated by histidine-rich proteins. Science 271:219–222PubMedGoogle Scholar
  125. Sullivan DJ Jr, Gluzman IY, Russell DG, Goldberg DE (1996b) On the molecular mechanism of chloroquine’s antimalarial action. Proc Natl Acad Sci USA 93:11865–11870PubMedGoogle Scholar
  126. Sullivan DJ Jr, Matile H, Ridley RG, Goldberg DE (1998) A common mechanism for blockade of heme polymerization by antimalarial quinolines. J Biol Chem 273:31103–31107PubMedCrossRefGoogle Scholar
  127. Surolia N, Padmanaban G (1992) De novo biosynthesis of heme offers a new chemotherapeutic target in the human malarial parasite. Biochem Biophys Res Commun 187:744–750PubMedCrossRefGoogle Scholar
  128. Taliaferro WH, Mulligan HW (1937) The histopathology of malaria with special reference to the function and origin of macrophages in defense. Indian Med Mem 29:1–12Google Scholar
  129. Tatala S, Svanberg U, Mduma B (1998) Low dietary iron availability is a major cause of anemia: A nutrition survey in the Lindi district of Tanzania. Am J Clin Nutr 68:171–178PubMedGoogle Scholar
  130. Thuma PE, Mabeza GF, Biemba G, Bhat GJ, McLaren CE, Moyo VM, Zulu S, Khumalo H, Mabeza P, M’Hango A, Parry D, Poltera AA, Brittenham GM, Gordeuk VR (1998) Effect of iron chelation therapy on mortality in zambian children with cerebral malaria. Trans R Soc Trop Med Hyg 92:214–218PubMedCrossRefGoogle Scholar
  131. Tripathi AK, Garg SK, Tekwani BL (2002) A physiochemical mechanism of hemozoin (beta-hematin) synthesis by malaria parasite Biochem Biophys Res Commun 290:595–601PubMedCrossRefGoogle Scholar
  132. Tripathi AK, Khan SI, Walker LA, Tekwani BL (2004) Spectrophotometric determination of de novo hemozoin/beta-hematin formation in an in vitro assay. Anal Biochem 325:85–91PubMedCrossRefGoogle Scholar
  133. Vennerstrom JL, Ager AL Jr, Andersen SL, Grace JM, Wongpanich V, Angerhofer CK, Hu JK, Wesche DL (2000) Assessment of the antimalarial potential of tetraoxane WR 148999. Am J Trop Med Hyg 62:573–578PubMedGoogle Scholar
  134. Verhoef H, West CE, Nzyuko SM, de Vogel S, van der Valk R, Wanga MA, Kuijsten A, Veenemans J, Kok FJ (2002) Intermittent administration of iron and sulfadoxinepyrimethamine to control anaemia in Kenyan children: A randomised controlled trial. Lancet 360:908–914PubMedGoogle Scholar
  135. Weaver J, Zhan H, Pollack S (1993) Erythrocyte haemolysate interacts with atp-fe to forma complex containing iron, ATP and 13 800MWpolypeptide. Br J Haematol 83:138–144PubMedGoogle Scholar
  136. Wilson CM, Smith AB, Baylon RV (1996) Characterization of the delta-aminolevulinate synthase gene homologue in P. falciparum. Mol Biochem Parasitol 79:135–140PubMedCrossRefGoogle Scholar
  137. Yip R (1998) Iron deficiency. Bull WHO 76:121–123PubMedGoogle Scholar
  138. Zhan H, Gupta RK, Weaver J, Pollack S (1990) Iron bound to low MW ligands: Interactions with mitochondria and cytosolic proteins. Eur J Haematol 44:125–131PubMedGoogle Scholar
  139. Zhang J, Krugliak M, Ginsburg H (1999) The fate of ferriprotoporphyrin IX in malaria infected erythrocytes in conjunction with the mode of action of antimalarial drugs. Mol Biochem Parasitol 99:129–141PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • P. F. Scholl
    • 1
  • A. K. Tripathi
    • 2
  • D. J. Sullivan
    • 2
  1. 1.Department of Environmental Health SciencesBaltimoreUSA
  2. 2.W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public HealthJohns Hopkins UniversityBaltimoreUSA

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