Malaria: Drugs, Disease and Post-genomic Biology pp 275-291

Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 295)

Hemoglobin Degradation

  • D. E. Goldberg

Abstract

Hemoglobin degradation by Plasmodium is a massive catabolic process within the parasite food vacuole that is important for the organism’s survival in its host erythrocyte. A proteolytic pathway is responsible for generating amino acids from hemoglobin. Each of the enzymes involved has its own peculiarities to be exploited for development of antimalarial agents that will starve the parasite or result in build-up of toxic intermediates. There are a number of unanswered questions concerning the cell biology, biochemistry and metabolic roles of this crucial pathway.

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References

  1. 1.
    Morrison DB, Jeskey HA (1948) Alterations in some constituents of the monkey erythrocyte infected with Plasmodium knowlesi as related to pigment formation. J Nat Malar Soc 7:259–264Google Scholar
  2. 2.
    Ball EG, et al. (1948) Studies on malarial parasites: ix. chemical and metabolic changes during growth and multiplication in vivo and in vitro. J Biol Chem 175:547–571PubMedGoogle Scholar
  3. 3.
    Loria P, et al. (1999) Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials. Biochem J 339:363–370PubMedCrossRefGoogle Scholar
  4. 4.
    McCormick GJ (1970) Amino acid transport and incorporation in red blood cells of normal and Plasmodium knowlesi-infected rhesus monkeys. Exp Parasitol 27:143–149PubMedGoogle Scholar
  5. 5.
    Sherman IW, Tanigoshi L (1970) Incorporation of 14C-amino acids by malaria. Int J Biochem 1:635–637CrossRefGoogle Scholar
  6. 6.
    Divo AA, et al. (1985) Nutritional requirements of Plasmodium falciparum in culture. I. Exogenously supplied dialyzable components necessary for continuous growth. J Protozool 32:59–64PubMedGoogle Scholar
  7. 7.
    Francis SE, et al. (1994) Molecular characterization and inhibition of a Plasmodium falciparum aspartic hemoglobinase. EMBO J 13:306–317PubMedGoogle Scholar
  8. 8.
    Zarchin S, Krugliak M, Ginsburg H (1986) Digestion of the host erythrocyte by malaria parasites is the primary target for quinolone-containing antimalarials. Biochem Pharmacol 35:2435–2442PubMedCrossRefGoogle Scholar
  9. 9.
    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
  10. 10.
    Ginsburg H (1990) Some reflections concerning host erythrocyte-malarial parasite interrelationships. Blood Cells 16:225–235PubMedGoogle Scholar
  11. 11.
    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
  12. 12.
    Hempelmann E, et al. (2003) Plasmodium falciparum: sacrificing membrane to grow crystals? Trends Parasitol 19:23–26PubMedGoogle Scholar
  13. 13.
    Banerjee R, Sullivan DJ Jr, Goldberg DE (2001) The Plasmodium food vacuole. In: Rosenthal PJ (ed.) ntimalarial chemotherapy: mechanisms of action, resistance and new directions in drug discovery. Humana Press: Totowa, NJ, ch 4Google Scholar
  14. 14.
    Goldberg DE, et al. (1991) Hemoglobin degradation in the human malaria pathogen Plasmodium falciparum: A catabolic pathway initiated by a specific aspartic protease. J Exp Med 173:961–969PubMedCrossRefGoogle Scholar
  15. 15.
    Coombs GH, et al. (2001) Aspartic proteases of Plasmodium falciparum and other parasitic protozoa as drug targets. Trends Parasitol 17:532–537PubMedCrossRefGoogle Scholar
  16. 16.
    Dame JB, et al. (2003) Plasmepsin 4, the food vacuole aspartic proteinase found in all Plasmodium spp. infecting man. Mol Biochem Parasitol 130:1–12PubMedCrossRefGoogle Scholar
  17. 17.
    Banerjee R, et al. (2002) Four plasmepsins are active in the Plasmodium falciparum food vacuole, including a protease with an active-site histidine. Proc Natl Acad Sci USA 99:990–995PubMedCrossRefGoogle Scholar
  18. 18.
    Francis SE, Banerjee R, Goldberg DE (1997) Biosynthesis and maturation of the malaria aspartic hemoglobinases plasmepsins I and II. J Biol Chem 272:14961–14968PubMedCrossRefGoogle Scholar
  19. 19.
    Bozdech Z, et al. (2003) The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum. PLoS Biol 1:E5PubMedCrossRefGoogle Scholar
  20. 20.
    Le Bonniec S, et al. (1999) Plasmepsin II, an acidic hemoglobinase from the Plasmodium falciparum food vacuole, is active at neutral pH on the host erythrocyte membrane skeleton. J Biol Chem 274:14218–14223PubMedGoogle Scholar
  21. 21.
    Wyatt DM, Berry C (2002) Activity and inhibition of plasmepsin IV, a new aspartic proteinase from the malaria parasite, Plasmodium falciparum. FEBS Lett 513:159–162PubMedCrossRefGoogle Scholar
  22. 22.
    Gluzman IY, et al. (1994) Order and specificity of the Plasmodium falciparum hemoglobin degradation pathway. J Clin Invest 93:1602–1608PubMedGoogle Scholar
  23. 23.
    Westling J, et al. (1999) Active site specificity of plasmepsin II. Protein Sci 8:2001–2009PubMedCrossRefGoogle Scholar
  24. 24.
    Luker KE, et al. (1996) Kinetic analysis of plasmepsins I and II, aspartic proteases of the Plasmodium falciparum digestive vacuole. Mol Biochem Parasitol 79:71–78PubMedCrossRefGoogle Scholar
  25. 25.
    DiIanni Carroll C, et al. (1998) Identification of potent inhibitors of Plasmodium falciparum plasmepsin II from an encoded statine combinatorial library. Bioorg Med Chem Lett 8:2315–2320Google Scholar
  26. 26.
    Siripurkpong P, et al. (2002) Active site contribution to specificity of the aspartic proteases plasmepsins I and II. J Biol Chem 277:41009–41013PubMedCrossRefGoogle Scholar
  27. 27.
    Westling J, et al. (1997) Plasmodium falciparum, P. vivax, and P. malariae: a comparison of the active site properties of plasmepsins cloned and expressed from three different species of the malaria parasite. Exp Parasitol 87:185–193PubMedCrossRefGoogle Scholar
  28. 28.
    Dame JB, et al. (1994) Sequence, expression and modeled structure of an aspartic proteinase from the human malaria parasite Plasmodium falciparum. Mol Biol Parasitol 64:177–190Google Scholar
  29. 29.
    Nezami A, et al. (2003) High-affinity inhibition of a family of Plasmodium falciparum proteases by a designed adaptive inhibitor. Biochemistry 42:8459–8464PubMedCrossRefGoogle Scholar
  30. 30.
    Moon RP, et al. (1997) Expression and characterization of plasmepsin I from Plasmodium falciparum. Eur J Biochem 244:552–560PubMedCrossRefGoogle Scholar
  31. 31.
    Silva AM, et al. (1996) Structure and inhibition of plasmepsin II, a hemoglobin-degrading enzyme from Plasmodium falciparum. Proc Natl Acad Sci USA 93:10034–10039PubMedCrossRefGoogle Scholar
  32. 32.
    Bernstein NK, et al. (2003) Structural insights into the activation of P. vivax plasmepsin. J Mol Biol 329:505–524PubMedCrossRefGoogle Scholar
  33. 33.
    Bernstein NK, et al. (1999) Crystal structure of the novel aspartic proteinase zymogen proplasmepsin II from plasmodium falciparum. Nat Struct Biol 6:32–37PubMedGoogle Scholar
  34. 34.
    Xie D, et al. (1997) Dissection of the pH dependence of inhibitor binding energetics for an aspartic protease: direct measurement of the protonation states of the catalytic aspartic acid residues. Biochemistry 36:16166–16172PubMedGoogle Scholar
  35. 35.
    Asojo OA, et al. (2003) Novel uncomplexed and complexed structures of plasmepsin II, an aspartic protease from Plasmodium falciparum. J Mol Biol 327:173–181PubMedCrossRefGoogle Scholar
  36. 36.
    Istvan ES, Goldberg DE (2003) Dimerization of P. falciparum plasmepsins: implications for catalysis and drug design. Molecular Parasitology Meeting XIV, Woods Hole, MA, p.16EGoogle Scholar
  37. 37.
    Boss C, et al. (2003) Inhibitors of the Plasmodium falciparum parasite aspartic protease plasmepsin II as potential antimalarial agents. Curr Med Chem 10:883–907PubMedCrossRefGoogle Scholar
  38. 38.
    Klemba M, Goldberg DE (2002) Biological roles of proteases in parasitic protozoa. Annu Rev Biochem 71:275–305PubMedCrossRefGoogle Scholar
  39. 39.
    Haque TS, et al. (1999) Potent, low-molecular-weight non-peptide inhibitors of malarial aspartyl protease plasmepsin II. J Med Chem 42:1428–1440PubMedCrossRefGoogle Scholar
  40. 40.
    Jiang S, et al. (2001) New class of small nonpeptidyl compounds blocks Plasmodium falciparum development in vitro by inhibiting plasmepsins. Antimicrob Agents Chemother 45:2577–2584PubMedCrossRefGoogle Scholar
  41. 41.
    Dame JB, et al. (2003) Molecular and phenotypic characterization of gene knock-outs of each of the four food vacuole plasmepsins of Plasmodium falciparum. Molecular Parasitology Meeting XIV, Woods Hole, MA, p.277CGoogle Scholar
  42. 42.
    Liu J, Drew M, Goldberg DE (in preparation, 2004)Google Scholar
  43. 43.
    Rosenthal PJ, et al. (1988) A malarial cysteine proteinase is necessary for hemoglobin degradation by Plasmodium falciparum. J Clin Invest 82:1560–1566PubMedGoogle Scholar
  44. 44.
    Rosenthal PJ, et al. (1989) Plasmodium falciparum: inhibitors of lysosomal cysteine proteinases inhibit a trophozoite proteinase and block parasite development. Mol Biochem Parasitol 35:177–184PubMedCrossRefGoogle Scholar
  45. 45.
    Sijwali PS, et al. (2001) Expression and characterization of the Plasmodium falciparum haemoglobinase falcipain-3. Biochem J 360:481–489PubMedGoogle Scholar
  46. 46.
    Rosenthal PJ, Lee GK (1993) Inhibition of a Plasmodium vinkei cysteine proteinase cures murine malaria. J Clin Invest 91:1052–1056PubMedCrossRefGoogle Scholar
  47. 47.
    Rosenthal PJ (1993) A Plasmodium vinckei cysteine proteinase shares unique features with its Plasmodium falciparum analogue. Biochem Biophys Acta 1173:91–93PubMedGoogle Scholar
  48. 48.
    Rosenthal PJ (1996) Conservation of key amino acids among the cysteine proteinases of multiple malarial species. Mol Biochem Parasitol 75:255–260PubMedCrossRefGoogle Scholar
  49. 49.
    Shenai BR, et al. (2000) Characterization of native and recombinant falcipain-2, a principal trophozoite cysteine protease and essential hemoglobinase of Plasmodium falciparum. J Biol Chem 275:29000–29010PubMedCrossRefGoogle Scholar
  50. 50.
    Dhawan S, et al. (2003) Ankyrin peptide blocks falcipain-2-mediated malaria parasite release from red blood cells. J Biol Chem 278:30180–30186PubMedCrossRefGoogle Scholar
  51. 51.
    Dua M, et al. (2001) Recombinant falcipain-2 cleaves erythrocyte membrane ankyrin and protein 4.1. Mol Biochem Parasitol 116:95–99PubMedCrossRefGoogle Scholar
  52. 52.
    Greenbaum DC, et al. (2002) A role for the protease falcipain 1 in host cell invasion by the human malaria parasite. Science 298:2002–2006PubMedCrossRefGoogle Scholar
  53. 53.
    Shenai BR, Rosenthal PJ (2002) Reducing requirements for hemoglobin hydrolysis by Plasmodium falciparum cysteine proteases. Mol Biochem Parasitol 122:99–104PubMedCrossRefGoogle Scholar
  54. 54.
    Atamna H, Ginsburg H (195) 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
  55. 55.
    Gamboa de Dominguez ND, Rosenthal PJ (1996) Cysteine proteinase inhibitors block early steps in hemoglobin degradation by cultured malaria parasites. Blood 87:4448–4454Google Scholar
  56. 56.
    Bray PG, et al. (1998) Access to hematin: the basis of chloroquine resistance. Mol Parmacol 54:170–179Google Scholar
  57. 57.
    Mungthin M, et al. (1998) Central role of hemoglobin degradation in mechanisms of action of 4-aminoquinolines, quinoline methanols, and phenanthrene methanols. Antimicrob Agents Chemother 42:2973–2977PubMedGoogle Scholar
  58. 58.
    Bray PG, et al. (1999) Cellular uptake of chloroquine is dependent on binding to ferriprotoporphyrin IX and is independent of NHE activity in Plasmodium falciparum.Google Scholar
  59. 59.
    Francis SE, et al. (1996) Characterization of native falcipain, an enzyme involved in Plasmodium falciparum hemoglobin degradation. Mol Biochem Parasitol 83:189–200PubMedCrossRefGoogle Scholar
  60. 60.
    Ring CS, et al. (1993) Structure-based inhibitor design by using protein models for the development of antiparasitic agents. Proc Natl Acad Sci USA 90:3583–3587PubMedGoogle Scholar
  61. 61.
    Rosenthal PJ, et al. (2002) Cysteine proteases of malaria parasites: targets for chemotherapy. Curr Pharm Des8:1659–1672PubMedCrossRefGoogle Scholar
  62. 62.
    Bailly E, et al. (1992) Plasmodium falciparum: differential sensitivity in vitro to E-64 (cysteine protease inhibitor) and pepstatin (aspartic protease inhibitor). J Protozool 39:593–599PubMedGoogle Scholar
  63. 63.
    Semenov A, Olson JE, Rosenthal PJ (1998) Antimalarial synergy of cysteine and aspartic protease inhibitors. Antimicrob Agents Chemother 42:2254–2258PubMedGoogle Scholar
  64. 64.
    Ridley RG (2002) Medical need, scientific opportunity and the drive for antimalarial drugs. Nature 415:686–693PubMedCrossRefGoogle Scholar
  65. 65.
    Sijwali PS, Lee BJ, Rosenthal PJ (2003) Knock-down of falcipain-2 supports a cooperative role for cysteine and aspartic proteases in hemoglobin hydrolysis by P. falciparum. Molecular Parasitology Meeting XIV, Woods Hole, MA, p 277CGoogle Scholar
  66. 66.
    Eggleson KK, Duffin KL, Goldberg DE (1999) Identification and characterization of falcilysin, a metallopeptidase involved in hemoglobin catabolism within the malaria parasite Plasmodium falciparum. J Biol Chem 274Google Scholar
  67. 67.
    Wu Y, et al. (2003) Data-mining approaches reveal hidden families of proteases in the genome of malaria parasite. Genome Res 13:601–616PubMedCrossRefGoogle Scholar
  68. 68.
    van Dooren GG, et al. (2002) Processing of an apicoplast leader sequence in Plasmodium falciparum and the identification of a putative leader cleavage enzyme. J Biol Chem 277:23612–23619PubMedGoogle Scholar
  69. 69.
    Murata CE, Goldberg DE (2003) Plasmodium falciparum falcilysin: an unprocessed food vacuole enzyme. Mol Biochem Parasitol 129:123–126PubMedCrossRefGoogle Scholar
  70. 70.
    Murata CE, Goldberg DE (2003) Plasmodium falciparum falcilysin: a metalloprotease with dual specificity. J Biol Chem 278:38022–38028PubMedGoogle Scholar
  71. 71.
    Taylor AB, et al. (2001) Crystal structures of mitochondrial processing peptidase reveal the mode for specific cleavage of import signal sequences. Structure(Camb) 9:615–625Google Scholar
  72. 72.
    Gavigan CS, Dalton JP, Bell A (2001) The role of aminopeptidases in haemoglobin degradation in Plasmodium falciparum-infected erythrocytes. Mol Biochem Parasitol 117:37–48PubMedCrossRefGoogle Scholar
  73. 73.
    Florent I, et al. (1998) A Plasmodium falciparum aminopeptidase gene belonging to the M1 family of zinc-metallopeptidases is expressed in erythrocytic stages. Mol Biochem Parasitol 97:149–160PubMedCrossRefGoogle Scholar
  74. 74.
    Allary M, Schrevel J, Florent I (2002) Properties, stage-dependent expression and localization of Plasmodium falciparum M1 family zinc-aminopeptidase. Parasitology 125:1–10PubMedCrossRefGoogle Scholar
  75. 75.
    Kolakovich KA, et al. (1997) Generation of hemoglobin peptides in the acidic digestive vacuole of Plasmodium falciparum implicates peptide transport in amino acid production. Mol Biochem Parasitol 87:123–135PubMedCrossRefGoogle Scholar
  76. 76.
    Klemba M, et al. (2004) Trafficking of plasmepsin II to the food vacuole of the malaria parasite Plasmodium falciparum. J Cell Biol (in press)Google Scholar
  77. 77.
    Banerjee R, Francis SE, Goldberg DE (2003) Food vacuole plasmepsins are processed at a conserved site by an acidic convertase activity in Plasmodium falciparum. Mol Biochem Parasitol 129:157–165PubMedCrossRefGoogle Scholar
  78. 78.
    Sijwali PS, Shenai BR, Rosenthal PJ (2002) Folding of the Plasmodium falciparum cysteine protease falcipain-2 is mediated by a chaperone-like peptide and not the prodomain. J Biol Chem 277:14910–14915PubMedCrossRefGoogle Scholar
  79. 79.
    Pandey KC, et al. (2003) Independent intramolecular mediators of folding, activity, and inhibition for the Plasmodium falciparum cysteine protease falcipain-2. J Biol ChemGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2005

Authors and Affiliations

  • D. E. Goldberg
    • 1
  1. 1.Howard Hughes Medical Institute. Departments of Medicine and Molecular MicrobiologyWashington UniversitySt. LouisUSA

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