Chapter 16 : Proteases and Hemoglobin Degradation

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Proteases and Hemoglobin Degradation, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817558/9781555813307_Chap16-1.gif /docserver/preview/fulltext/10.1128/9781555817558/9781555813307_Chap16-2.gif


This chapter reviews the current understanding of the reasons for hemoglobin degradation, the mechanism of hemoglobin breakdown, the proteases that contribute to this process, and the potential for new antimalarial therapies that block hemoglobin hydrolysis. A large body of work suggests that a principal source of amino acids for erythrocytic parasites is the hydrolysis of globin. De novo synthesis of amino acids appears to play only a small role in supplying parasite amino acids. In , ring-stage parasites pinocytose the hemoglobin-rich erythrocyte cytosol into small vesicles. Upon its delivery to the food vacuole, and perhaps during vesicular transit to this organelle, hemoglobin is subjected to an acidic pH. Proteases of multiple catalytic classes appear to contribute to hemoglobin degradation. Biochemical characterizations of food vacuole aspartic and cysteine proteases and metalloproteases have shown that these enzymes hydrolyze hemoglobin or globin in vitro, supporting roles in hemoglobin hydrolysis. Evidence for a role for cysteine proteases in hemoglobin hydrolysis came from the observation that cysteine protease inhibitors cause a dramatic morphological abnormality in trophozoites, whereby food vacuoles swell and fill with undegraded hemoglobin. The processing of hemoglobin peptides in the cytosol is probably performed, at least in part, by a neutral metalloaminopeptidase. Homologs of proteases have been identified in other plasmodial species. Considering the selection of drug resistance, a recent study showed that parasites resistant to vinyl sulfone cysteine protease inhibitors could be selected by incubation of cultured parasites with stepwise increases in concentrations of inhibitor.

Citation: Rosenthal P. 2005. Proteases and Hemoglobin Degradation, p 311-326. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch16

Key Concept Ranking

Amino Acids
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


1. Allary, M.,, J. Schrevel,, and I. Florent. 2002. Properties, stage-dependent expression and localization of Plasmodium falciparum M1 family zinc-aminopeptidase. Parasitology 125: 1 10.
2. Asawamahasakda, W.,, I. Ittarat,, C. C. Chang,, P. McElroy,, and S. R. Meshnick. 1994. Effects of antimalarials and protease inhibitors on plasmodial hemozoin production. Mol. Biochem.Parasitol. 67: 183 191.
3. Asawamahasakda, W.,, and Y. Yuthavong. 1993. The methionine synthesis cycle and salvage of methyltetrahydrofolate from host red cells in the malaria parasite ( Plasmodium falciparum). Parasitology 107: 1 10.
4. Bailly, E.,, R. Jambou,, J. Savel,, and G. Jaureguiberry. 1992. Plasmodium falciparum: differential sensitivity in vitro to E-64 (cysteine protease inhibitor) and pepstatin A (aspartyl protease inhibitor). J. Protozool. 39: 593 599.
5. Banerjee, R.,, S. E. Francis,, and D. E. Goldberg. 2003. Food vacuole plasmepsins are processed at a conserved site by an acidic convertase activity in Plasmodium falciparum. Mol. Biochem. Parasitol. 129: 157 165.
6. Banerjee, R.,, J. Liu,, W. Beatty,, L. Pelosof,, M. Klemba,, and D. E. Goldberg. 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: 990 995.
7. Bendrat, K.,, B. J. Berger,, and A. Cerami. 1995. Haem polymerization in malaria. Nature 378: 138 139.
8. Bernstein, N. K.,, M. M. Cherney,, C. A. Yowell,, J. B. Dame,, and M. N. James. 2003. Structural insights into the activation of P. vivax plasmepsin. J.Mol. Biol. 329: 505 524.
9. Berry, C.,, M. J. Humphreys,, P. Matharu,, R. Granger,, P. Horrocks,, R. P. Moon,, U. Certa,, R. G. Ridley,, D. Bur,, and J. Kay. 1999. A distinct member of the aspartic proteinase gene family from the human malaria parasite Plasmodium falciparum. FEBS Lett. 447: 149 154.
10. Biagini, G. A.,, P. G. Bray,, D. G. Spiller,, M. R. White,, and S. A. Ward. 2003. The digestive food vacuole of the malaria parasite is a dynamic intracellular Ca2_ store. J. Biol.Chem. 278: 27910 27915.
11. Bohle, D. S.,, R. E. Dinnebier,, S. K. Madsen,, and P.W. Stephens. 1997. Characterization of the products of the heme detoxification pathway in malarial late trophozoites by X-ray diffraction. J. Biol. Chem. 272: 713 716.
12. Bohley, P.,, and P. O. Seglen. 1992. Proteases and proteolysis in the lysosome. Experientia 48: 151 157.
13. Bonday, Z. Q.,, S. Taketani,, P. D. Gupta,, and G. Padmanaban. 1997. Heme biosynthesis by the malarial parasite. Import of delta-aminolevulinate dehydrase from the host red cell. J. Biol. Chem. 272: 21839 21846.
14. Boss, C.,, S. Richard-Bildstein,, T. Weller,, W. Fischli,, S. Meyer,, and C. Binkert. 2003. Inhibitors of the Plasmodium falciparum parasite aspartic protease plasmepsin II as potential antimalarial agents. Curr. Med. Chem. 10: 883 907.
15. Bray, P.G.,, O. Janneh,, K. J. Raynes,, M. Mungthin,, H. Ginsburg,, and S.A. Ward. 1999. Cellular uptake of chloroquine is dependent on binding to ferriprotoporphyrin IX and is independent of NHE activity in Plasmodium falciparum. J. Cell Biol. 145: 363 376.
16. Curley, G. P.,, S. M. O’Donovan,, J. McNally,, M. Mullally,, H. O’Hara,, A. Troy,, S.A. O’Callaghan,, and J. P. Dalton. 1994. Aminopeptidases from Plasmodium falciparum, Plasmodium chabaudi chabaudi and Plasmodium berghei. J. Eukaryot. Microbiol. 41: 119 123.
17. Dahl, E. L.,, and P. J. Rosenthal. 2005. Biosynthesis, localization, and processing of falcipain cysteine proteases of Plasmodium falciparum. Mol. Biochem.Parasitol. 139: 205 212.
18. Dame, J. B.,, G. R. Reddy,, C. A. Yowell,, B. M. Dunn,, J. Kay,, and C. Berry. 1994. Sequence, expression and modeled structure of an aspartic proteinase from the human malaria parasite Plasmodium falciparum. Mol. Biochem. Parasitol. 64: 177 190.
19. Dame, J. B.,, C.A. Yowell,, L. Omara-Opyene,, J.M. Carlton,, R. A. Cooper,, and T. Li. 2003. Plasmepsin 4, the food vacuole aspartic proteinase found in all Plasmodium spp. infecting man. Mol. Biochem. Parasitol. 130: 1 12.
20. Dhanasekaran, S.,, N. R. Chandra,, B. K. Chandrasekhar Sagar,, P.N. Rangarajan,, and G. Padmanaban. 2004. Delta-aminolevulinic acid dehydratase from Plasmodium falciparum: indigenous versus imported. J. Biol. Chem. 279: 6934 6942.
21. Divo, A. A.,, T. G. Geary,, N. L. Davis,, and J. B. Jensen. 1985. Nutritional requirements of Plasmodium falciparum in culture. I.Exogenously supplied dialyzable components necessary for continuous growth. J. Protozool. 32: 59 64.
22. Dluzewski, A. R.,, K. Rangachari,, R. J. Wilson,, and W.B. Gratzer. 1986. Plasmodium falciparum:protease inhibitors and inhibition of erythrocyte invasion. Exp. Parasitol. 62: 416 422.
23. Dominguez, J. N.,, S. Lopez,, J. Charris,, L. Iarruso,, G. Lobo,, A. Semenov,, J. E. Olson,, and P. J. Rosenthal. 1997. Synthesis and antimalarial effects of phenothiazine inhibitors of a Plasmodium falciparum cysteine protease. J. Med. Chem. 40: 2726 2732.
24. Dorn, A.,, R. Stoffel,, H. Matile,, A. Bubendorf,, and R. G. Ridley. 1995. Malarial haemozoin/ beta-haematin supports haem polymerization in the absence of protein. Nature 374: 269 271.
25. Dua, M.,, P. Raphael,, P. S. Sijwali,, P. J. Rosenthal,, and M. Hanspal. 2001. Recombinant falcipain-2 cleaves erythrocyte membrane ankyrin and protein 4.1. Mol. Biochem. Parasitol. 116: 95 99.
26. Egan, T. J.,, W.W. Mavuso,, and K. K. Ncokazi. 2001. The mechanism of beta-hematin formation in acetate solution. Parallels between hemozoin formation and biomineralization processes. Biochemistry 40: 204 213.
27. Egan, T. J.,, D. C. Ross,, and P. A. Adams. 1994. Quinoline anti-malarial drugs inhibit spontaneous formation of beta-haematin (malaria pigment). FEBS Lett. 352: 54 57.
28. Eggleson, K. K.,, K. L. Duffin,, and D. E. Goldberg. 1999. Identification and characterization of falcilysin, a metallopeptidase involved in hemoglobin catabolism within the malaria parasite Plasmodium falciparum. J. Biol. Chem. 274: 32411 32417.
29. Eksi, S.,, B. Czesny,, D. C. Greenbaum,, M. Bogyo,, and K. C. Williamson. 2004. Targeted disruption of Plasmodium falciparum cysteine protease, falcipain 1, reduces oocyst production, not erythrocytic stage growth. Mol. Microbiol. 53: 243 250.
30. Elford, B. C.,, G. M. Cowan,, and D. J. Ferguson. 1995. Parasite-regulated membrane transport processes and metabolic control in malaria-infected erythrocytes. Biochem. J. 308: 361 374.
31. Ersmark, K.,, I. Feierberg,, S. Bjelic,, E. Hamelink,, F. Hackett,, M. J. Blackman,, J. Hulten,, B. Samuelsson,, J. Aqvist,, and A. Hallberg. 2004. Potent inhibitors of the Plasmodium falciparum enzymes plasmepsin I and II devoid of cathepsin D inhibitory activity. J. Med. Chem. 47: 110 122.
32. Fitch, C. D.,, and P. Kanjananggulpan. 1987. The state of ferriprotoporphyrin IX in malaria pigment. J. Biol. Chem. 262: 15552 15555.
33. Florent, I.,, Z. Derhy,, M. Allary,, M. Monsigny,, R. Mayer,, and J. Schrevel. 1998. A Plasmodium falciparum aminopeptidase gene belonging to the M1 family of zinc-metallopeptidases is expressed in erythrocytic stages. Mol. Biochem.Parasitol. 97: 149 160.
34. Foley, M.,, and L. Tilley. 1998. Quinoline antimalarials: mechanisms of action and resistance and prospects for new agents. Pharmacol.Ther. 79: 55 87.
35. Francis, S. E.,, R. Banerjee,, and D. E. Goldberg. 1997. Biosynthesis and maturation of the malaria aspartic hemoglobinases plasmepsins I and II. J. Biol. Chem. 272: 14961 14968.
36. Francis, S. E.,, I. Y. Gluzman,, A. Oksman,, A. Knickerbocker,, R. Mueller,, M. L. Bryant,, D. R. Sherman,, D. G. Russell,, and D. E. Goldberg. 1994. Molecular characterization and inhibition of a Plasmodium falciparum aspartic hemoglobinase. EMBO J. 13: 306 317.
37. Gabay, T.,, and H. Ginsburg. 1993. Hemoglobin denaturation and iron release in acidified red blood cell lysate—a possible source of iron for intraerythrocytic malaria parasites. Exp. Parasitol. 77: 261 272.
38. Gamboa de Dominguez, N. D.,, and P. J. Rosenthal. 1996. Cysteine proteinase inhibitors block early steps in hemoglobin degradation by cultured malaria parasites. Blood 87: 4448 4454.
39. Gavigan, C. S.,, J. P. Dalton,, and A. Bell. 2001. The role of aminopeptidases in haemoglobin degradation in Plasmodium falciparum-infected erythrocytes. Mol. Biochem. Parasitol. 117: 37 48.
40. Gluzman, I.Y.,, S. E. Francis,, A. Oksman,, C. E. Smith,, K. L. Duffin,, and D. E. Goldberg. 1994. Order and specificity of the Plasmodium falciparum hemoglobin degradation pathway. J. Clin Investig. 93: 1602 1608.
41. Goldberg, D. E.,, A. F. Slater,, R. Beavis,, B. Chait,, A. Cerami,, and G. B. Henderson. 1991. Hemoglobin degradation in the human malaria pathogen Plasmodium falciparum: a catabolic pathway initiated by a specific aspartic protease. J. Exp. Med. 173: 961 969.
42. Goldberg, D. E.,, A. F. Slater,, A. Cerami,, and G. B. Henderson. 1990. Hemoglobin degradation in the malaria parasite Plasmodium falciparum: an ordered process in a unique organelle. Proc. Natl. Acad. Sci. USA 87: 2931 2935.
43. Greenbaum, D. C.,, A. Baruch,, M. Grainger,, Z. Bozdech,, K. F. Medzihradszky,, J. Engel,, J. De- Risi,, A. A. Holder,, and M. Bogyo. 2002. A role for the protease falcipain 1 in host cell invasion by the human malaria parasite. Science 298: 2002 2006.
44. Haque, T. S.,, A. G. Skillman,, C. E. Lee,, H. Habashita,, I.Y. Gluzman,, T. J. Ewing,, D. E. Goldberg,, I. D. Kuntz,, and J.A. Ellman. 1999. Potent, low-molecular-weight non-peptide inhibitors of malarial aspartyl protease plasmepsin II. J. Med. Chem. 42: 1428 1440.
45. Hempelmann, E.,, and T. J. Egan. 2002. Pigment biocrystallization in Plasmodium falciparum. Trends Parasitol. 18: 11.
46. Hempelmann, E.,, C. Motta,, R. Hughes,, S. A. Ward,, and P.G. Bray. 2003. Plasmodium falciparum: sacrificing membrane to grow crystals? Trends Parasitol. 19: 23 26.
47. Hill, J.,, L. Tyas,, L. H. Phylip,, J. Kay,, B. M. Dunn,, and C. Berry. 1994. High level expression and characterisation of plasmepsin II, an aspartic proteinase from Plasmodium falciparum. FEBS Lett. 352: 155 158.
48. Hodder, A. N.,, D. R. Drew,, V. C. Epa,, M. Delorenzi,, R. Bourgon,, S. K. Miller,, R. L. Moritz,, D. F. Frecklington,, R. J. Simpson,, T. P. Speed,, R. N. Pike,, and B. S. Crabb. 2003. Enzymic, phylogenetic, and structural characterization of the unusual papain-like protease domain of Plasmodium falciparum SERA5. J. Biol. Chem. 278: 48169 48177.
49. Humphreys, M. J.,, R. P. Moon,, A. Klinder,, S. D. Fowler,, K. Rupp,, D. Bur,, R. G. Ridley,, and C. Berry. 1999. The aspartic proteinase from the rodent parasite Plasmodium berghei as a potential model for plasmepsins from the human malaria parasite, Plasmodium falciparum. FEBS Lett. 463: 43 48.
50. Jiang, S.,, S.T. Prigge,, L. Wei,, Y. Gao,, T. H. Hudson,, L. Gerena,, J. B. Dame,, and D. E. Kyle. 2001. New class of small nonpeptidyl compounds blocks Plasmodium falciparum development in vitro by inhibiting plasmepsins. Antimicrob.Agents Chemother. 45: 2577 2584.
51. Johansson, P. O.,, Y. Chen,, A. K. Belfrage,, M. J. Blackman,, I. Kvarnstrom,, K. Jansson,, L. Vrang,, E. Hamelink,, A. Hallberg,, A. Rosenquist,,and B. Samuelsson. 2004. Design and synthesis of potent inhibitors of the malaria aspartyl proteases plasmepsin I and II.Use of solid-phase synthesis to explore novel statine motifs. J.Med.Chem. 47: 3353 3366.
52. Kamchonwongpaisan, S.,, E. Samoff,, and S. R. Meshnick. 1997. Identification of hemoglobin degradation products in Plasmodium falciparum. Mol. Biochem. Parasitol. 86: 179 186.
53. Kirk, K. 2001. Membrane transport in the malaria-infected erythrocyte. Physiol. Rev. 81: 495 537.
54. Klemba, M.,, W. Beatty,, I. Gluzman,, and D. E. Goldberg. 2004a. Trafficking of plasmepsin II to the food vacuole of the malaria parasite Plasmodium falciparum. J. Cell Biol. 164: 47 56.
55. Klemba, M.,, I. Gluzman,, and D. E. Goldberg. 2004b. A Plasmodium falciparum dipeptidyl aminopeptidase I participates in vacuolar hemoglobin degradation. J. Biol. Chem. 279: 43000 43007.
56. Kolakovich, K. A.,, I.Y. Gluzman,, K. L. Duffin,, and D. E. Goldberg. 1997. Generation of hemoglobin peptides in the acidic digestive vacuole of Plasmodium falciparum implicates peptide transport in amino acid production. Mol. Biochem. Parasitol. 87: 123 135.
57. Krugliak, M.,, J. Zhang,, and H. Ginsburg. 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: 249 256.
58. Langreth, S. G.,, J. B. Jensen,, R.T. Reese,, and W. Trager. 1978. Fine structure of human malaria in vitro. J. Protozool. 25: 443 452.
59. Lauer, S. A.,, P. K. Rathod,, N. Ghori,, and K. Haldar. 1997. A membrane network for nutrient import in red cells infected with the malaria parasite. Science 276: 1122 1125.
60. Le Bonniec, S.,, C. Deregnaucourt,, V. Redeker,, R. Banerjee,, P. Grellier,, D. E. Goldberg,, and J. Schrevel. 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 14223.
61. Lee, B. J.,, A. Singh,, P. Chiang,, S. J. Kemp,, E. A. Goldman,, M. I. Weinhouse,, G. P. Vlasuk,, and P. J. Rosenthal. 2003. Antimalarial activities of novel synthetic cysteine protease inhibitors. Antimicrob. Agents Chemother. 47: 3810 3814.
62. Lew, V. L.,, L. Macdonald,, H. Ginsburg,, M. Krugliak,, and T. Tiffert. 2004. Excess haemoglobin digestion by malaria parasites: a strategy to prevent premature host cell lysis. Blood Cells Mol. Dis. 32: 353 359.
63. Lew, V. L.,, T. Tiffert,, and H. Ginsburg. 2003. Excess hemoglobin digestion and the osmotic stability of Plasmodium falciparum-infected red blood cells. Blood 101: 4189 4194.
64. Li, T.,, C.A. Yowell,, B.B. Beyer,, S. H. Hung,, J. Westling,, M.T. Lam,, B. M. Dunn,, and J. B. Dame. 2004. Recombinant expression and enzymatic subsite characterization of plasmepsin 4 from the four Plasmodium species infecting man. Mol. Biochem.Parasitol. 135: 101 109.
65. Liu, J.,, I.Y. Gluzman,, M. E. Drew,, and D. E. Goldberg. 2005. The role of Plasmodium falciparum food vacuole plasmepsins. J. Biol. Chem. 280: 1432 1437.
66. Lynn, A.,, S. Chandra,, P. Malhotra,, and V. S. Chauhan. 1999. Heme binding and polymerization by Plasmodium falciparum histidine rich protein II: influence of pH on activity and conformation. FEBS Lett. 459: 267 271.
67. Mabeza, G. F.,, M. Loyevsky,, V.R. Gordeuk,, and G. Weiss. 1999. Iron chelation therapy for malaria: a review. Pharmacol.Ther. 81: 53 75.
68. McKerrow, J. H.,, E. Sun,, P. J. Rosenthal,, and J. Bouvier. 1993. The proteases and pathogenicity of parasitic protozoa. Annu.Rev. Microbiol. 47: 821 853.
69. Meshnick, S. R. 2002. Artemisinin: mechanisms of action, resistance and toxicity. Int. J. Parasitol. 32: 1655 1660.
70. Moon, R. P.,, L. Tyas,, U. Certa,, K. Rupp,, D. Bur,, C. Jacquet,, H. Matile,, H. Loetscher,, F. Grueninger- Leitch,, J. Kay,, B. M. Dunn,, C. Berry,, and R. G. Ridley. 1997. Expression and characterisation of plasmepsin I from Plasmodium falciparum. Eur. J. Biochem. 244: 552 560.
71. Mu, J.,, M.T. Ferdig,, X. Feng,, D. A. Joy,, J. Duan,, T. Furuya,, G. Subramanian,, L. Aravind,, R. A. Cooper,, J.C. Wootton,, M. Xiong,, and X. Z. Su. 2003. Multiple transporters associated with malaria parasite responses to chloroquine and quinine. Mol. Microbiol. 49: 977 989.
72. Murata, C. E.,, and D. E. Goldberg. 2003a. Plasmodium falciparum falcilysin: a metalloprotease with dual specificity. J. Biol. Chem. 278: 38022 38028.
73. Murata, C. E.,, and D. E. Goldberg. 2003b. Plasmodium falciparum falcilysin: an unprocessed food vacuole enzyme. Mol. Biochem. Parasitol. 129: 123 126.
74. Na, B. K.,, B. R. Shenai,, P. S. Sijwali,, Y. Choe,, K. C. Pandey,, A. Singh,, C. S. Craik,, and P. J. Rosenthal. 2004. Identification and biochemical characterization of vivapains, cysteine proteases of the malaria parasite Plasmodium vivax. Biochem. J. 378: 529 538.
75. Nezami, A.,, I. Luque,, T. Kimura,, Y. Kiso,, and E. Freire. 2002. Identification and characterization of allophenylnorstatine-based inhibitors of plasmepsin II, an antimalarial target. Biochemistry 41: 2273 2280.
76. Noteberg, D.,, E. Hamelink,, J. Hulten,, M. Wahlgren,, L. Vrang,, B. Samuelsson,, and A. Hallberg. 2003. Design and synthesis of plasmepsin I and plasmepsin II inhibitors with activity in Plasmodium falciparum-infected cultured human erythrocytes. J. Med. Chem. 46: 734 746.
77. Olliaro, P. L.,, and D. E. Goldberg. 1995. The Plasmodium falciparum digestive vacuole: metabolic headquarters and choice drug target. Parasitol.Today 11: 294 297.
78. Olson, J. E.,, G. K. Lee,, A. Semenov,, and P. J. Rosenthal. 1999. Antimalarial effects in mice of orally administered peptidyl cysteine protease inhibitors. Bioorg. Med. Chem. 7: 633 638.
79. Omara-Opyene, A. L.,, P. A. Moura,, C. R. Sulsona,, J. A. Bonilla,, C. A. Yowell,, H. Fujioka,, D. A. Fidock,, and J. B. Dame. 2004. Genetic disruption of the Plasmodium falciparum digestive vacuole plasmepsins demonstrates their functional redundancy. J. Biol. Chem. 279: 54088 54096.
80. Orjih, A. U.,, H. S. Banyal,, R. Chevli,, and C. D. Fitch. 1981. Hemin lyses malaria parasites. Science 214: 667 669.
81. Pagola, S.,, P.W. Stephens,, D. S. Bohle,, A.D. Kosar,, and S. K. Madsen. 2000. The structure of malaria pigment beta-haematin. Nature 404: 307 310.
82. Pandey, K.C.,, P. S. Sijwali,, A. Singh,, B. K. Na,, and P. J. Rosenthal. 2004. Independent intramolecular mediators of folding, activity, and inhibition for the Plasmodium falciparum cysteine protease falcipain-2. J. Biol. Chem. 279: 3484 3491.
83. Pandey, K. C.,, S.X. Wang,, P. S. Sijwali,, A. L. Lau,, J. H. McKerrow,, and P. J. Rosenthal. The Plasmodium falciparum cysteine protease falcipain-2 captures its substrate, hemoglobin, via a unique motif. Proc. Natl.Acad. Sci. USA, in press.
84. Ring, C. S.,, E. Sun,, J. H. McKerrow,, G. K. Lee,, P. J. Rosenthal,, I. D. Kuntz,, and F. E. Cohen. 1993. Structure-based inhibitor design by using protein models for the development of antiparasitic agents. Proc. Natl. Acad. Sci. USA 90: 3583 3587.
85. Rockett, K. A.,, J. H. Playfair,, F. Ashall,, G. A. Targett,, H. Angliker,, and E. Shaw. 1990. Inhibition of intraerythrocytic development of Plasmodium falciparum by proteinase inhibitors. FEBS Lett. 259: 257 259.
86. Rosenthal, P. J. 1995. Plasmodium falciparum: effects of proteinase inhibitors on globin hydrolysis by cultured malaria parasites. Exp. Parasitol. 80: 272 281.
87. Rosenthal, P. J. 2004. Cysteine proteases of malaria parasites. Int. J. Parasitol. 34: 1489 1499.
88. Rosenthal, P. J.,, G. K. Lee,, and R. E. Smith. 1993. Inhibition of a Plasmodium vinckei cysteine proteinase cures murine malaria. J. Clin Investig. 91: 1052 1056.
89. Rosenthal, P. J.,, J. H. McKerrow,, M. Aikawa,, H. Nagasawa,, and J. H. Leech. 1988. A malarial cysteine proteinase is necessary for hemoglobin degradation by Plasmodium falciparum. J. Clin Investig. 82: 1560 1566.
90. Rosenthal, P. J.,, J. E. Olson,, G. K. Lee,, J.T. Palmer,, J. L. Klaus,, and D. Rasnick. 1996. Antimalarial effects of vinyl sulfone cysteine proteinase inhibitors. Antimicrob.Agents Chemother. 40: 1600 1603.
91. Rosenthal, P. J.,, P. S. Sijwali,, A. Singh,, and B. R. Shenai. 2002. Cysteine proteases of malaria parasites: targets for chemotherapy. Curr. Pharm. Des. 8: 1659 1672.
92. Rosenthal, P. J.,, W. S. Wollish,, J.T. Palmer,, and D. Rasnick. 1991. Antimalarial effects of peptide inhibitors of a Plasmodium falciparum cysteine proteinase. J. Clin Investig. 88: 1467 1472.
93. Saliba, K. J.,, R. J. Allen,, S. Zissis,, P. G. Bray,, S. A. Ward,, and K. Kirk. 2003. Acidification of the malaria parasite’s digestive vacuole by a H_- ATPase and a H_-pyrophosphatase. J. Biol. Chem. 278: 5605 5612.
94. Scheibel, L.W.,, and I.W. Sherman,. 1988. Plasmodial metabolism and related organellar function during various stages of the life-cycle: proteins, lipids, nucleic acids and vitamins, p. 219 252. In W. H. Wernsdorfer, and I. McGregor (ed.), Malaria: Principles and Practice of Malariology. Churchill Livingstone, Ltd., Edinburgh, United Kingdom.
95. Semenov, A.,, J. E. Olson,, and P. J. Rosenthal. 1998. Antimalarial synergy of cysteine and aspartic protease inhibitors. Antimicrob. Agents Chemother. 42: 2254 2258.
96. Shenai, B. R.,, B. J. Lee,, A. Alvarez-Hernandez,, P. Y. Chong,, C. D. Emal,, R. J. Neitz,, W. R. Roush,, and P. J. Rosenthal. 2003. Structure-activity relationships for inhibition of cysteine protease activity and development of Plasmodium falciparum by peptidyl vinyl sulfones. Antimicrob. Agents Chemother. 47: 154 160.
97. Shenai, B. R.,, and P. J. Rosenthal. 2002. Reducing requirements for hemoglobin hydrolysis by Plasmodium falciparum cysteine proteases. Mol. Biochem.Parasitol. 122: 99 104.
98. Shenai, B. R.,, P. S. Sijwali,, A. Singh,, and P. J. Rosenthal. 2000. Characterization of native and recombinant falcipain-2, a principal trophozoite cysteine protease and essential hemoglobinase of Plasmodium falciparum. J. Biol. Chem. 275: 29000 29010.
99. Sherman, I.W. 1977. Transport of amino acids and nucleic acid precursors in malarial parasites. Bull. W. H. O. 55: 211 225.
100. Sijwali, P. S.,, K. Kato,, K. B. Seydel,, J. Gut,, J. Lehman,, M. Klemba,, D. E. Goldberg,, L. H. Miller,, and P. J. Rosenthal. 2004. Plasmodium falciparum cysteine protease falcipain-1 is not essential in erythrocytic stage malaria parasites. Proc. Natl. Acad. Sci. USA 101: 8721 8726.
101. Sijwali, P. S.,, and P. J. Rosenthal. 2004. Gene disruption confirms a critical role for the cysteine protease falcipain-2 in hemoglobin hydrolysis by Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 101: 4384 4389.
102. Sijwali, P. S.,, B. R. Shenai,, J. Gut,, A. Singh,, and P. J. Rosenthal. 2001. Expression and characterization of the Plasmodium falciparum haemoglobinase falcipain-3. Biochem. J. 360: 481 489.
103. Sijwali, P. S.,, B. R. Shenai,, and P. J. Rosenthal. 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 14915.
104. Silva, A. M.,, A.Y. Lee,, S.V. Gulnik,, P. Maier,, J. Collins,, T.N. Bhat,, P. J. Collins,, R. E. Cachau,, K. E. Luker,, I.Y. Gluzman,, S. E. Francis,, A. Oksman,, D. E. Goldberg,, and J.W. Erickson. 1996. Structure and inhibition of plasmepsin II, a hemoglobin-degrading enzyme from Plasmodium falciparum. Proc. Natl.Acad. Sci.USA 93: 10034 10039.
105. Singh, A.,, and P. J. Rosenthal. 2004. Selection of cysteine protease inhibitor-resistant malaria parasites is accompanied by amplification of falcipain genes and alteration in inhibitor transport. J. Biol. Chem. 279: 35236 35241.
106. Singh, A.,, B. R. Shenai,, Y. Choe,, J. Gut,, P. S. Sijwali,, C. S. Craik,, and P. J. Rosenthal. 2002. Critical role of amino acid 23 in mediating activity and specificity of vinckepain-2, a papain-family cysteine protease of rodent malaria parasites. Biochem. J. 368: 273 281.
107. Slater, A. F.,, and A. Cerami. 1992. Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature 355: 167 169.
108. Slater, A. F.,, W. J. Swiggard,, B. R. Orton,, W.D. Flitter,, D. E. Goldberg,, A. Cerami,, and G. B. Henderson. 1991. An iron-carboxylate bond links the heme units of malaria pigment. Proc. Natl.Acad. Sci. USA 88: 325 329.
109. Slomianny, C. 1990. Three-dimensional reconstruction of the feeding process of the malaria parasite. Blood Cells 16: 369 378.
110. Spiller, D.G.,, P.G. Bray,, R. H. Hughes,, S.A. Ward,, and M. R. White. 2002. The pH of the Plasmodium falciparum digestive vacuole: holy grail or deadend trail? Trends Parasitol. 18: 441 444.
111. Stocks, P. A.,, K. J. Raynes,, and S. A. Ward,. 2001. Novel quinoline antimalarials, p. 235 253. In P. J. Rosenthal (ed.), Antimalarial Chemotherapy: Mechanisms of Action, Resistance, and New Directions in Drug Discovery. Humana Press, Totowa,N.J.
112. Sullivan, D. J. 2002. Theories on malarial pigment formation and quinoline action. Int. J. Parasitol. 32: 1645 1653.
113. Sullivan, D. J., Jr.,, I.Y. Gluzman,, and D. E. Goldberg. 1996. Plasmodium hemozoin formation mediated by histidine-rich proteins. Science 271: 219 222.
114. Tilley, L.,, P. Loria,, and M. Foley,. 2001. Chloroquine and other quinoline antimalarials, p. 87 121. In P. J. Rosenthal (ed.), Antimalarial Chemotherapy: Mechanisms of Action, Resistance, and New Directions in Drug Discovery. Humana Press, Totowa,N.J.
115. Turk, D.,, V. Janjic,, I. Stern,, M. Podobnik,, D. Lamba,, S.W. Dahl,, C. Lauritzen,, J. Pedersen,, V. Turk,, and B. Turk. 2001. Structure of human dipeptidyl peptidase I (cathepsin C): exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases. EMBO J. 20: 6570 6582.
116. White, N. J. 2004. Antimalarial drug resistance. J. Clin. Investig. 113: 1084 1092.
117. Withers-Martinez, C.,, L. Jean,, and M. J. Blackman. 2004. Subtilisin-like proteases of the malaria parasite. Mol Microbiol. 53: 55 63.
118. Wu, Y.,, X. Wang,, X. Liu,, and Y. Wang. 2003. Datamining approaches reveal hidden families of proteases in the genome of malaria parasite. Genome Res. 13: 601 616.
119. Zarchin, S.,, M. Krugliak,, and H. Ginsburg. 1986. Digestion of the host erythrocyte by malaria parasites is the primary target for quinoline-containing antimalarials. Biochem. Pharmacol. 35: 2435 2442.


Generic image for table

Features of proteases that may play roles in hemoglobin hydrolysis

Citation: Rosenthal P. 2005. Proteases and Hemoglobin Degradation, p 311-326. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch16

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error