Chapter 16 : Proteases and Hemoglobin Degradation

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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

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1. Allary, M.,, J. Schrevel,, and I. Florent. 2002. Properties, stage-dependent expression and localization of Plasmodium falciparum M1 family zinc-aminopeptidase. Parasitology 125:110.
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. 67:183191.
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: 110.
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. 39:593599.
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: 157165.
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 99:990995.
7. Bendrat, K.,, B. J. Berger,, and A. Cerami. 1995. Haem polymerization in malaria. Nature 378:138139.
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. 329:505524.
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. 447:149154.
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. 278:2791027915.
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. 272:713716.
12. Bohley, P.,, and P. O. Seglen. 1992. Proteases and proteolysis in the lysosome. Experientia 48:151157.
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. 272:2183921846.
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. 10:883907.
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. 145:363376.
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. 41:119123.
17. Dahl, E. L.,, and P. J. Rosenthal. 2005. Biosynthesis, localization, and processing of falcipain cysteine proteases of Plasmodium falciparum. Mol. Biochem.Parasitol. 139:205212.
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. 64:177190.
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. 130:112.
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. 279:69346942.
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. 32:5964.
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. 62:416422.
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. 40:27262732.
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 374:269271.
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. 116:9599.
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 40:204213.
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. 352:5457.
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. 274:3241132417.
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. 53:243250.
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. 308:361374.
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. 47:110122.
32. Fitch, C. D.,, and P. Kanjananggulpan. 1987.The state of ferriprotoporphyrin IX in malaria pigment. J. Biol. Chem. 262:1555215555.
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. 97:149160.
34. Foley, M.,, and L. Tilley. 1998. Quinoline antimalarials: mechanisms of action and resistance and prospects for new agents. Pharmacol.Ther. 79:5587.
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. 272:1496114968.
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. 13:306317.
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. 77:261272.
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 87:44484454.
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. 117:3748.
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: 16021608.
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. 173:961969.
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 87:29312935.
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 298:20022006.
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. 42:14281440.
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. 19:2326.
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. 352:155158.
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. 278:4816948177.
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. 463:4348.
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. 45:25772584.
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. 47:33533366.
52. Kamchonwongpaisan, S.,, E. Samoff,, and S. R. Meshnick. 1997. Identification of hemoglobin degradation products in Plasmodium falciparum. Mol. Biochem. Parasitol. 86:179186.
53. Kirk, K. 2001. Membrane transport in the malaria-infected erythrocyte. Physiol. Rev. 81:495537.
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. 164:4756.
55. Klemba, M.,, I. Gluzman,, and D. E. Goldberg. 2004b.A Plasmodium falciparum dipeptidyl aminopeptidase I participates in vacuolar hemoglobin degradation. J. Biol. Chem. 279:4300043007.
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: 123135.
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. 119:249256.
58. Langreth, S. G.,, J. B. Jensen,, R.T. Reese,, and W. Trager. 1978. Fine structure of human malaria in vitro. J. Protozool. 25:443452.
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 276:11221125.
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. 274:1421814223.
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. 47:38103814.
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. 32:353359.
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 101:41894194.
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. 135:101109.
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. 280:14321437.
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. 459:267271.
67. Mabeza, G. F.,, M. Loyevsky,, V.R. Gordeuk,, and G. Weiss. 1999. Iron chelation therapy for malaria: a review. Pharmacol.Ther. 81:5375.
68. McKerrow, J. H.,, E. Sun,, P. J. Rosenthal,, and J. Bouvier. 1993.The proteases and pathogenicity of parasitic protozoa.Annu.Rev. Microbiol.47:821853.
69. Meshnick, S. R. 2002. Artemisinin: mechanisms of action, resistance and toxicity. Int. J. Parasitol. 32: 16551660.
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. 244:552560.
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. 49:977989.
72. Murata, C. E.,, and D. E. Goldberg. 2003a. Plasmodium falciparum falcilysin: a metalloprotease with dual specificity. J. Biol. Chem. 278:3802238028.
73. Murata, C. E.,, and D. E. Goldberg. 2003b. Plasmodium falciparum falcilysin: an unprocessed food vacuole enzyme. Mol. Biochem. Parasitol. 129:123126.
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: 529538.
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 41:22732280.
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. 46:734746.
77. Olliaro, P. L.,, and D. E. Goldberg. 1995.The Plasmodium falciparum digestive vacuole: metabolic headquarters and choice drug target. Parasitol.Today 11: 294297.
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. 7:633638.
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. 279:5408854096.
80. Orjih, A. U.,, H. S. Banyal,, R. Chevli,, and C. D. Fitch. 1981. Hemin lyses malaria parasites. Science 214:667669.
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 404:307310.
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. 279:34843491.
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 90:35833587.
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. 259:257259.
86. Rosenthal, P. J. 1995. Plasmodium falciparum: effects of proteinase inhibitors on globin hydrolysis by cultured malaria parasites. Exp. Parasitol. 80:272281.
87. Rosenthal, P. J. 2004. Cysteine proteases of malaria parasites. Int. J. Parasitol. 34:14891499.
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. 91:10521056.
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. 82:15601566.
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. 40:16001603.
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. 8:16591672.
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. 88:14671472.
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. 278:56055612.
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. 219252. 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. 42:22542258.
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. 47:154160.
97. Shenai, B. R.,, and P. J. Rosenthal. 2002. Reducing requirements for hemoglobin hydrolysis by Plasmodium falciparum cysteine proteases. Mol. Biochem.Parasitol. 122:99104.
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. 275:2900029010.
99. Sherman, I.W. 1977.Transport of amino acids and nucleic acid precursors in malarial parasites. Bull. W. H. O. 55:211225.
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 101:87218726.
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: 43844389.
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. 360:481489.
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. 277:1491014915.
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 93:1003410039.
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: 3523635241.
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. 368:273281.
107. Slater, A. F.,, and A. Cerami. 1992. Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites.Nature 355:167169.
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 88:325329.
109. Slomianny, C. 1990.Three-dimensional reconstruction of the feeding process of the malaria parasite. Blood Cells 16:369378.
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. 18:441444.
111. Stocks, P. A.,, K. J. Raynes,, and S. A. Ward,. 2001. Novel quinoline antimalarials, p. 235253. 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. 32:16451653.
113. Sullivan, D. J., Jr.,, I.Y. Gluzman,, and D. E. Goldberg. 1996. Plasmodium hemozoin formation mediated by histidine-rich proteins. Science 271:219222.
114. Tilley, L.,, P. Loria,, and M. Foley,. 2001. Chloroquine and other quinoline antimalarials, p. 87121. 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. 20:65706582.
116. White, N. J. 2004.Antimalarial drug resistance. J. Clin. Investig. 113:10841092.
117. Withers-Martinez, C.,, L. Jean,, and M. J. Blackman. 2004. Subtilisin-like proteases of the malaria parasite. Mol Microbiol.53:5563.
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. 13:601616.
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. 35:24352442.


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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

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