Targeting Trypanothione Metabolism in Trypanosomatid Human Parasites

Current Drug Targets

Volumn 11, Issue 12, 2010, Pages 1614-1630

  Olin Sandoval, Viridiana ^a   Moreno Sánchez, Rafael ^a   Saavedra, Emma ^a  

^a INSTITUTO NACIONAL DE CARDIOLOGÍA IGNACIO CHÁVEZ   (Mexico)

Author keywords

Drug targeting; Leishmania; Microbial antioxidant metabolism; Trypanosoma; Trypanothione

Indexed keywords

2 AMINO 5 (1 METHYL 5 NITRO 2 IMIDAZOLYL) 1,3,4 THIADIAZOLE; 5' [((Z) 4 AMINO 2 BUTENY)) METHYLAMINO] 5' DEOXYADENOSINE; ADENOSYLMETHIONINE DECARBOXYLASE; AMINO ACID TRANSPORTER; AMPHOTERICIN B; ANTIOXIDANT; ANTITRYPANOSOMAL AGENT; BENZNIDAZOLE; BUTHIONINE SULFOXIMINE; EFLORNITHINE; ENZYME INHIBITOR; GLUTAMATE CYSTEINE LIGASE; GLUTATHIONE; GLUTATHIONE PEROXIDASE; GLUTATHIONE THIOL TRANSFERASE; MELARSOPROL; NIFURTIMOX; NONSELENIUM GLUTATHIONE PEROXIDASE; ORNITHINE DECARBOXYLASE; PEROXIDE; POLYAMINE TRANSPORTER; PROTEIN P53; STIBOGLUCONATE SODIUM; THIOREDOXIN; TRANSFERASE; TRYPANOTHIONE; TRYPANOTHIONE REDUCTASE; TRYPANOTHIONE SYNTHETASE; TRYPAREDOXIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; ANTIMETABOLITE; DRUG DERIVATIVE; OXIDOREDUCTASE; PROTOZOAL PROTEIN; SPERMIDINE;

AFRICAN TRYPANOSOMIASIS; ANTIBIOTIC SENSITIVITY; DETOXIFICATION; DRUG POTENTIATION; DRUG STRUCTURE; DRUG TARGETING; ENZYME INHIBITION; ENZYME KINETICS; GENE INACTIVATION; GLUTATHIONE METABOLISM; HUMAN; IC 50; KINETOPLASTIDA; METABOLIC REGULATION; NONHUMAN; PARASITE SURVIVAL; PHENOTYPE; POLYAMINE METABOLISM; REVIEW; RNA INTERFERENCE; DRUG ANTAGONISM; DRUG DESIGN; DRUG EFFECT; GENETICS; METABOLISM; MOLECULARLY TARGETED THERAPY; PHYSIOLOGY; TRYPANOSOMATID INFECTION;

ANTIMETABOLITES; ANTIOXIDANTS; DRUG DESIGN; ENZYME INHIBITORS; EUGLENOZOA INFECTIONS; GLUTATHIONE; HUMANS; MOLECULAR TARGETED THERAPY; NADH, NADPH OXIDOREDUCTASES; PEROXIDES; PROTOZOAN PROTEINS; SPERMIDINE; TRYPANOCIDAL AGENTS; TRYPANOSOMATINA;

EID: 79952277996     PISSN: 13894501     EISSN: 18735592     Source Type: Journal    
DOI: 10.2174/1389450111009011614     Document Type: Review

References (120)

1. Croft SL, Barrett MP, Urbina JA. Chemotherapy of trypanosomiases and leishmaniasis. Trends Parasitol 2005; 21: 508-12.
2. Stuart K, Brun R, Croft S, et al. Kinetoplastids: related protozoan pathogens, different diseases. J Clin Invest 2008; 118: 1301-10.
3. Mansour TE. In: Chemotherapeutic Targets in Parasites. UK, The Press Syndicate of the University of Cambridge 2002; 90-101.
4. Liñares GE, Ravaschino EL, Rodriguez JB. Progresses in the field of drug design to combat tropical protozoan parasitic diseases. Curr Med Chem 2006; 13: 335-60.
5. Fairlamb AH, Cerami A. Metabolism and functions of trypanothione in the Kinetoplastida. Annu Rev Microbiol 1992; 46: 695-729.
6. Schmidt A, Krauth-Siegel RL. Enzymes of the trypanothione metabolism as targets for antitrypanosomal drug development. Curr Top Med Chem 2002; 2: 1239-59.
7. Jaeger T, Flohe L. The thiol-based redox networks of pathogens: unexploited targets in the search for new drugs. Biofactors 2006; 27: 109-20.
8. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007; 39: 44-84.
9. Borsook H, Keighley G. Oxidation-Reduction Potential of Ascorbic Acid (Vitamin C). Proc Natl Acad Sci USA 1933; 19: 875-8.
10. Krauth-Siegel LR, Comini MA, Schlecker T. The trypanothione system. Subcell Biochem 2007; 44: 231-51.
11. Krauth-Siegel RL, Comini MA. Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism. Biochim Biophys Acta 2008; 1780: 1236-48.
12. Ariyanayagam MR, Oza SL, Mehlert A, Fairlamb AH. Bis(glutathionyl)spermine and other novel trypanothione analogues in Trypanosoma cruzi. J Biol Chem 2003; 278: 27612-9.
13. Montrichard F, Le Guen F, Laval-Martin DL, Davioud-Charvet E. Evidence for the co-existence of glutathione reductase and trypanothione reductase in the non-trypanosomatid Euglenozoa: Euglena gracilis Z. FEBS Lett 1999; 442: 29-33.
14. Tamayo EM, Iturbe A, Hernandez E, et al. Trypanothione reductase from the human parasite Entamoeba histolytica: a new drug target. Biotechnol Appl Biochem 2005; 41: 105-15.
15. Griffith OW, Mulcahy RT. The enzymes of glutathione synthesis: gamma-glutamylcysteine synthetase. Adv Enzymol Relat Areas Mol Biol 1999; 73: 209-67, xii.
16. Lueder DV, Phillips MA. Characterization of Trypanosoma brucei gamma-glutamylcysteine synthetase, an essential enzyme in the biosynthesis of trypanothione (diglutathionylspermidine). J Biol Chem 1996; 271: 17485-90.
17. Richman PG, Meister A. Regulation of gamma-glutamyl-cysteine synthetase by nonallosteric feedback inhibition by glutathione. J Biol Chem 1975; 250: 1422-6.
18. Misra I, Griffith OW. Expression and purification of human gamma-glutamylcysteine synthetase. Protein Expr Purif 1998; 13: 268-76.
19. Grondin K, Haimeur A, Mukhopadhyay R, Rosen BP, Ouellette M. Co-amplification of the gamma-glutamylcysteine synthetase gene gsh1 and of the ABC transporter gene pgpA in arsenite-resistant Leishmania tarentolae. EMBO J 1997; 16: 3057-65.
20. Haimeur A, Brochu C, Genest P, Papadopoulou B, Ouellette M. Amplification of the ABC transporter gene PGPA and increased trypanothione levels in potassium antimonyl tartrate (SbIII) resistant Leishmania tarentolae. Mol Biochem Parasitol 2000; 108: 131-5.
21. Guimond C, Trudel N, Brochu C, et al. Modulation of gene expression in Leishmania drug resistant mutants as determined by targeted DNA microarrays. Nucleic Acids Res 2003; 31: 5886-96.
22. Fyfe PK, Alphey MS, Hunter WN. Structure of Trypanosoma brucei glutathione synthetase: domain and loop alterations in the catalytic cycle of a highly conserved enzyme. Mol Biochem Parasitol 2010; 170: 93-9.
23. Meierjohann S, Walter RD, Muller S. Glutathione synthetase from Plasmodium falciparum. Biochem J 2002; 363: 833-8.
24. Luo JL, Huang CS, Babaoglu K, Anderson ME. Novel kinetics of mammalian glutathione synthetase: characterization of gammaglutamyl substrate cooperative binding. Biochem Biophys Res Commun 2000; 275: 577-81.
25. Bitonti AJ, Kelly SE, McCann PP. Characterization of spermidine synthase from Trypanosoma brucei brucei. Mol Biochem Parasitol 1984; 13: 21-8.
26. Taylor MC, Kaur H, Blessington B, Kelly JM, Wilkinson SR. Validation of spermidine synthase as a drug target in African trypanosomes. Biochem J 2008; 409: 563-9.
27. Xiao Y, McCloskey DE, Phillips MA. RNA interference-mediated silencing of ornithine decarboxylase and spermidine synthase genes in Trypanosoma brucei provides insight into regulation of polyamine biosynthesis. Eukaryot Cell 2009; 8: 747-55.
28. Hereld D, Krakow JL, Bangs JD, Hart GW, Englund PT. A phospholipase C from Trypanosoma brucei which selectively cleaves the glycolipid on the variant surface glycoprotein. J Biol Chem 1986; 261: 13813-9.
29. Ariyanayagam MR, Oza SL, Guther ML, Fairlamb AH. Phenotypic analysis of trypanothione synthetase knockdown in the African trypanosome. Biochem J 2005; 391: 425-32.
30. Persson L. Ornithine decarboxylase and S-adenosylmethionine decarboxylase in trypanosomatids. Biochem Soc Trans 2007; 35: 314-7.
31. Selzer PM, Hesse F, Hamm-Kunzelmann B, Muhlstadt K, Echner H, Duszenko M. Down regulation of S-adenosyl-L-methionine decarboxylase activity of Trypanosoma brucei during transition from long slender to short stumpy-like forms in axenic culture. Eur J Cell Biol 1996; 69: 173-9.
32. Kinch LN, Scott JR, Ullman B, Phillips MA. Cloning and kinetic characterization of the Trypanosoma cruzi S-adenosylmethionine decarboxylase. Mol Biochem Parasitol 1999; 101: 1-11.
33. Le Quesne SA, Fairlamb AH. Regulation of a high-affinity diamine transport system in Trypanosoma cruzi epimastigotes. Biochem J 1996; 316 (Pt 2): 481-6.
34. Willert EK, Fitzpatrick R, Phillips MA. Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog. Proc Natl Acad Sci USA 2007; 104: 8275-80.
35. Beswick TC, Willert EK, Phillips MA. Mechanisms of allosteric regulation of Trypanosoma cruzi S-adenosylmethionine decarboxylase. Biochemistry 2006; 45: 7797-807.
36. Phillips MA, Coffino P, Wang CC. Trypanosoma brucei ornithine decarboxylase: enzyme purification, characterization, and expression in Escherichia coli. J Biol Chem 1988; 263: 17933-41.
37. Haimeur A, Guimond C, Pilote S, et al. Elevated levels of polyamines and trypanothione resulting from overexpression of the ornithine decarboxylase gene in arsenite-resistant Leishmania. Mol Microbiol 1999; 34: 726-35.
38. Burri C, Brun R. Eflornithine for the treatment of human African trypanosomiasis. Parasitol Res 2003; 90 (Suppl 1): S49-52.
39. Basselin M, Coombs GH, Barrett MP. Putrescine and spermidine transport in Leishmania. Mol Biochem Parasitol 2000; 109: 37-46.
40. Hasne MP, Ullman B. Identification and characterization of a polyamine permease from the protozoan parasite Leishmania major. J Biol Chem 2005; 280: 15188-94.
41. Hasne MP, Coppens I, Soysa R, Ullman B. A high-affinity putrescine-cadaverine transporter from Trypanosoma cruzi. Mol Microbiol 2010; 76: 78-91.
42. Oza SL, Tetaud E, Ariyanayagam MR, Warnon SS, Fairlamb AH. A single enzyme catalyses formation of Trypanothione from glutathione and spermidine in Trypanosoma cruzi. J Biol Chem 2002; 277: 35853-61.
43. Oza SL, Ariyanayagam MR, Aitcheson N, Fairlamb AH. Properties of trypanothione synthetase from Trypanosoma brucei. Mol Biochem Parasitol 2003; 131: 25-33.
44. Oza SL, Shaw MP, Wyllie S, Fairlamb AH. Trypanothione biosynthesis in Leishmania major. Mol Biochem Parasitol 2005; 139: 107-16.
45. Comini M, Menge U, Wissing J, Flohe L. Trypanothione synthesis in crithidia revisited. J Biol Chem 2005; 280: 6850-60.
46. Irigoín F, Cibilis L, Comini MA, Wilkinson SR, Flohé L, Radi R. Insights into the redox biology of Trypanosoma cruzi: Trypanothione metabolism and oxidant detoxification. Free Radic Biol Med 2008; 45: 733-742.
47. Castro H, Tomas AM. Peroxidases of trypanosomatids. Antioxid Redox Signal 2008; 10: 1593-606.
48. Wilkinson SR, Meyer DJ, Taylor MC, Bromley EV, Miles MA, Kelly JM. The Trypanosoma cruzi enzyme TcGPXI is a glycosomal peroxidase and can be linked to trypanothione reduction by glutathione or tryparedoxin. J Biol Chem 2002; 277: 17062-71.
49. Romao S, Castro H, Sousa C, Carvalho S, Tomas AM. The cytosolic tryparedoxin of Leishmania infantum is essential for parasite survival. Int J Parasitol 2009; 39: 703-11.
50. Alphey MS, Leonard GA, Gourley DG, Tetaud E, Fairlamb AH, Hunter WN. The high resolution crystal structure of recombinant Crithidia fasciculata tryparedoxin-I. J Biol Chem 1999; 274: 25613-22.
51. Hofmann B, Hecht HJ, Flohe L. Peroxiredoxins. Biol Chem 2002; 383: 347-64.
52. Nogoceke E, Gommel DU, Kiess M, Kalisz HM, Flohe L. A unique cascade of oxidoreductases catalyses trypanothionemediated peroxide metabolism in Crithidia fasciculata. Biol Chem 1997; 378: 827-36.
53. Trujillo M, Budde H, Pineyro MD, Stehr M, Robello C, Flohe L, Radi R. Trypanosoma brucei and Trypanosoma cruzi tryparedoxin peroxidases catalytically detoxify peroxynitrite via oxidation of fast reacting thiols. J Biol Chem 2004; 279: 34175-82.
54. Guerrero SA, Lopez JA, Steinert P, et al. His-tagged tryparedoxin peroxidase of Trypanosoma cruzi as a tool for drug screening. Appl Microbiol Biotechnol 2000; 53: 410-4.
55. Flohé L, Budde H, Bruns K, et al. Tryparedoxin peroxidase of Leishmania donovani: molecular cloning, heterologous expression, specificity, and catalytic mechanism. Arch Biochem Biophys 2002; 397: 324-35.
56. Schmidt H, Krauth-Siegel RL. Functional and physicochemical characterization of the thioredoxin system in Trypanosoma brucei. J Biol Chem 2003; 278: 46329-36.
57. Wilkinson SR, Temperton NJ, Mondragon A, Kelly JM. Distinct mitochondrial and cytosolic enzymes mediate trypanothionedependent peroxide metabolism in Trypanosoma cruzi. J Biol Chem 2000; 275: 8220-5.
58. Wilkinson SR, Meyer DJ, Kelly JM. Biochemical characterization of a trypanosome enzyme with glutathione-dependent peroxidase activity. Biochem J 2000; 352 Pt 3: 755-61.
59. Hillebrand H, Schmidt A, Krauth-Siegel RL. A second class of peroxidases linked to the trypanothione metabolism. J Biol Chem 2003; 278: 6809-15.
60. Schlecker T, Schmidt A, Dirdjaja N, Voncken F, Clayton C, Krauth-Siegel RL. Substrate specificity, localization, and essential role of the glutathione peroxidase-type tryparedoxin peroxidases in Trypanosoma brucei. J Biol Chem 2005; 280: 14385-94.
61. Konig J, Fairlamb AH. A comparative study of type I and type II tryparedoxin peroxidases in Leishmania major. FEBS J 2007; 274: 5643-58.
62. Wilkinson SR, Taylor MC, Touitha S, Mauricio IL, Meyer DJ, Kelly JM. TcGPXII, a glutathione-dependent Trypanosoma cruzi peroxidase with substrate specificity restricted to fatty acid and phospholipid hydroperoxides, is localized to the endoplasmic reticulum. Biochem J 2002; 364: 787-94.
63. Powis G, Montfort WR. Properties and biological activities of thioredoxins. Annu Rev Biophys Biomol Struct 2001; 30: 421-55.
64. Reckenfelderbaumer N, Ludemann H, Schmidt H, Steverding D, Krauth-Siegel RL. Identification and functional characterization of thioredoxin from Trypanosoma brucei brucei. J Biol Chem 2000; 275: 7547-52.
65. Krauth-Siegel RL, Ludemann H. Reduction of dehydroascorbate by trypanothione. Mol Biochem Parasitol 1996; 80: 203-8.
66. Wilkinson SR, Obado SO, Mauricio IL, Kelly JM. Trypanosoma cruzi expresses a plant-like ascorbate-dependent hemoperoxidase localized to the endoplasmic reticulum. Proc Natl Acad Sci USA 2002; 99: 13453-8.
67. Adak S, Datta AK. Leishmania major encodes an unusual peroxidase that is a close homologue of plant ascorbate peroxidase: a novel role of the transmembrane domain. Biochem J 2005; 390: 465-74.
68. Moutiez M, Aumercier M, Schoneck R, et al. Purification and characterization of a trypanothione-glutathione thioltransferase from Trypanosoma cruzi. Biochem J 1995; 310 (Pt 2): 433-7.
69. Moutiez M, Quemeneur E, Sergheraert C, Lucas V, Tartar A, Davioud-Charvet E. Glutathione-dependent activities of Trypanosoma cruzi p52 makes it a new member of the thiol:disulphide oxidoreductase family. Biochem J 1997; 322 (Pt 1): 43-8.
70. Clark D, Albrecht M, Arevalo J. Ascorbate variations and dehydroascorbate reductase activity in Trypanosoma cruzi epimastigotes and trypomastigotes. Mol Biochem Parasitol 1994; 66: 143-5.
71. Vickers TJ, Fairlamb AH. Trypanothione S-transferase activity in a trypanosomatid ribosomal elongation factor 1B. J Biol Chem 2004; 279: 27246-56.
72. Vickers TJ, Wyllie S, Fairlamb AH. Leishmania major elongation factor 1B complex has trypanothione S-transferase and peroxidase activity. J Biol Chem 2004; 279: 49003-9.
73. Krauth-Siegel RL, Enders B, Henderson GB, Fairlamb AH, Schirmer RH. Trypanothione reductase from Trypanosoma cruzi. Purification and characterization of the crystalline enzyme. Eur J Biochem 1987; 164: 123-8.
74. Kelly JM, Taylor MC, Smith K, Hunter KJ, Fairlamb AH. Phenotype of recombinant Leishmania donovani and Trypanosoma cruzi which over-express trypanothione reductase. Sensitivity towards agents that are thought to induce oxidative stress. Eur J Biochem 1993; 218: 29-37.
75. Krieger S, Schwarz W, Ariyanayagam MR, Fairlamb AH, Krauth-Siegel RL, Clayton C. Trypanosomes lacking trypanothione reductase are avirulent and show increased sensitivity to oxidative stress. Mol Microbiol 2000; 35: 542-52.
76. Shames SL, Fairlamb AH, Cerami A, Walsh CT. Purification and characterization of trypanothione reductase from Crithidia fasciculata, a newly discovered member of the family of disulfidecontaining flavoprotein reductases. Biochemistry 1986; 25: 3519-26.
77. Jockers-Scherubl MC, Schirmer RH, Krauth-Siegel RL. Trypanothione reductase from Trypanosoma cruzi. Catalytic properties of the enzyme and inhibition studies with trypanocidal compounds. Eur J Biochem 1989; 180: 267-72.
78. Sullivan FX, Shames SL, Walsh CT. Expression of Trypanosoma congolense trypanothione reductase in Escherichia coli: overproduction, purification, and characterization. Biochemistry 1989; 28: 4986-92.
79. Cunningham ML, Fairlamb AH. Trypanothione reductase from Leishmania donovani. Purification, characterisation and inhibition by trivalent antimonials. Eur J Biochem 1995; 230: 460-8.
80. Borges A, Cunningham ML, Tovar J, Fairlamb AH. Site-directed mutagenesis of the redox-active cysteines of Trypanosoma cruzi trypanothione reductase. Eur J Biochem 1995; 228: 745-52.
81. Mittal MK, Misra S, Owais M, Goyal N. Expression, purification, and characterization of Leishmania donovani trypanothione reductase in Escherichia coli. Protein Expr Purif 2005; 40: 279-86.
82. Bailey S, Fairlamb AH, Hunter WN. Structure of trypanothione reductase from Crithidia fasciculata at 2.6 A resolution; enzyme-NADP interactions at 2.8 A resolution. Acta Crystallogr D Biol Crystallogr 1994; 50: 139-54.
83. Zhang Y, Bond CS, Bailey S, Cunningham ML, Fairlamb AH, Hunter WN. The crystal structure of trypanothione reductase from the human pathogen Trypanosoma cruzi at 2.3 A resolution. Protein Sci 1996; 5: 52-61.
84. Krauth-Siegel RL, Schoneck R. Flavoprotein structure and mechanism. 5. Trypanothione reductase and lipoamide dehydrogenase as targets for a structure-based drug design. FASEB J 1995; 9: 1138-46.
85. Bond CS, Zhang Y, Berriman M, Cunningham ML, Fairlamb AH, Hunter WN. Crystal structure of Trypanosoma cruzi trypanothione reductase in complex with trypanothione, and the structure-based discovery of new natural product inhibitors. Structure 1999; 7: 81-9.
86. Henderson GB, Murgolo NJ, Kuriyan J, et al. Engineering the substrate specificity of glutathione reductase toward that of trypanothione reduction. Proc Natl Acad Sci USA 1991; 88: 8769-73.
87. Sullivan FX, Sobolov SB, Bradley M, Walsh CT. Mutational analysis of parasite trypanothione reductase: acquisition of glutathione reductase activity in a triple mutant. Biochemistry 1991; 30: 2761-7.
88. Stoll VS, Simpson SJ, Krauth-Siegel RL, Walsh CT, Pai EF. Glutathione reductase turned into trypanothione reductase: structural analysis of an engineered change in substrate specificity. Biochemistry 1997; 36: 6437-47.
89. Hunter WN, Bailey S, Habash J, et al. Active site of trypanothione reductase. A target for rational drug design. J Mol Biol 1992; 227: 322-33.
90. Huynh TT, Huynh VT, Harmon MA, Phillips MA. Gene knockdown of gamma-glutamylcysteine synthetase by RNAi in the parasitic protozoa Trypanosoma brucei demonstrates that it is an essential enzyme. J Biol Chem 2003; 278: 39794-800.
91. Faundez M, Pino L, Letelier P, et al. Buthionine sulfoximine increases the toxicity of nifurtimox and benznidazole to Trypanosoma cruzi. Antimicrob Agents Chemother 2005; 49: 126-30.
92. Faundez M, Lopez-Munoz R, Torres G, et al. Buthionine sulfoximine has anti-Trypanosoma cruzi activity in a murine model of acute Chagas' disease and enhances the efficacy of nifurtimox. Antimicrob Agents Chemother 2008; 52: 1837-9.
93. Maeda H, Hori S, Ohizumi H, et al. Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine. Cell Death Differ 2004; 11: 737-46.
94. Fell D. In: Understanding the control of metabolism London, Portland Press 1997.
95. Moreno-Sanchez R, Saavedra E, Rodriguez-Enriquez S, Olin-Sandoval V. Metabolic control analysis: a tool for designing strategies to manipulate metabolic pathways. J Biomed Biotechnol 2008; 2008: 597913.
96. Mendoza-Cozatl DG, Moreno-Sanchez R. Control of glutathione and phytochelatin synthesis under cadmium stress. Pathway modeling for plants. J Theor Biol 2006; 238: 919-36.
97. Hofmeyr JS, Cornish-Bowden A. Regulating the cellular economy of supply and demand. FEBS Lett 2000; 476: 47-51.
98. Comini MA, Guerrero SA, Haile S, Menge U, Lunsdorf H, Flohe L. Validation of Trypanosoma brucei trypanothione synthetase as drug target. Free Radic Biol Med 2004; 36: 1289-302.
99. Dumas C, Ouellette M, Tovar J, et al. Disruption of the trypanothione reductase gene of Leishmania decreases its ability to survive oxidative stress in macrophages. EMBO J 1997; 16: 2590-8.
100. Tovar J, Wilkinson S, Mottram JC, Fairlamb AH. Evidence that trypanothione reductase is an essential enzyme in Leishmania by targeted replacement of the tryA gene locus. Mol Microbiol 1998; 29: 653-60.
101. Tovar J, Cunningham ML, Smith AC, Croft SL, Fairlamb AH. Down-regulation of Leishmania donovani trypanothione reductase by heterologous expression of a trans-dominant mutant homologue: effect on parasite intracellular survival. Proc Natl Acad Sci USA 1998; 95: 5311-6.
102. Spinks D, Shanks EJ, Cleghorn LA, et al. Investigation of trypanothione reductase as a drug target in Trypanosoma brucei. ChemMedChem 2009; 4: 2060-9.
103. Wilkinson SR, Horn D, Prathalingam SR, Kelly JM. RNA interference identifies two hydroperoxide metabolizing enzymes that are essential to the bloodstream form of the african trypanosome. J Biol Chem 2003; 278: 31640-6.
104. Comini MA, Krauth-Siegel RL, Flohe L. Depletion of the thioredoxin homologue tryparedoxin impairs antioxidative defence in African trypanosomes. Biochem J 2007; 402: 43-9.
105. Muller S, Coombs GH, Walter RD. Targeting polyamines of parasitic protozoa in chemotherapy. Trends Parasitol 2001; 17: 242-9.
106. Thomas T, Thomas TJ. Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications. Cell Mol Life Sci 2001; 58: 244-58.
107. Van Nieuwenhove S, Schechter PJ, Declercq J, Bone G, Burke J, Sjoerdsma A. Treatment of gambiense sleeping sickness in the Sudan with oral DFMO (DL-alpha-difluoromethylornithine), an inhibitor of ornithine decarboxylase; first field trial. Trans R Soc Trop Med Hyg 1985; 79: 692-8.
108. Heby O, Persson L, Rentala M. Targeting the polyamine biosynthetic enzymes: a promising approach to therapy of African sleeping sickness, Chagas' disease, and leishmaniasis. Amino Acids 2007; 33: 359-66.
109. Carrillo C, Cejas S, Cortes M, et al. Sensitivity of trypanosomatid protozoa to DFMO and metabolic turnover of ornithine decarboxylase. Biochem Biophys Res Commun 2000; 279: 663-8.
110. Jiang Y, Roberts SC, Jardim A, et al. Ornithine decarboxylase gene deletion mutants of Leishmania donovani. J Biol Chem 1999; 274: 3781-8.
111. Willert EK, Phillips MA. Regulated expression of an essential allosteric activator of polyamine biosynthesis in African trypanosomes. PLoS Pathog 2008; 4: e1000183.
112. Byers TL, Bush TL, McCann PP, Bitonti AJ. Antitrypanosomal effects of polyamine biosynthesis inhibitors correlate with increases in Trypanosoma brucei brucei S-adenosyl-L-methionine. Biochem J 1991; 274 (Pt 2): 527-33.
113. Hornberg JJ, Bruggeman FJ, Bakker BM, Westerhoff HV. Metabolic control analysis to identify optimal drug targets. Prog Drug Res 2007; 64: 171, 3-89.
114. Saavedra E, Marín-Hernández A, Encalada R, Olivos A, Mendoza-Hernández G, Moreno-Sánchez R. Kinetic modeling can describe in vivo glycolysis in Entamoeba histolytica. FEBS J 2007; 274: 4922-49.
115. Moreno-Sanchez R, Encalada R, Marin-Hernandez A, Saavedra E. Experimental validation of metabolic pathway modeling. An illustration with glycolytic segments from Entamoeba histolytica. FEBS J 2008; 275: 3454-69.
116. Hornberg JJ, Bruggeman FJ, Westerhoff HV, Lankelma J. Cancer: a Systems Biology disease. Biosystems 2006; 83: 81-90.
117. Moreno-Sánchez R, Saavedra E, Rodríguez-Enríquez S, Gallardo-Pérez JC, Quezada H, Westerhoff HV. Metabolic Control Analysis indicates a change of strategy in the treatment of cancer. Mitochondrion 2010. DOI: 10.1016/j.mito.2010.06.002
118. Mukherjee A, Roy G, Guimond C, Ouellette M. The γ-glutamylcysteine synthetase of Leishmania is essential and involved in response to oxidants. Mol Microbiol 2009; 74:914-927
119. Alphey MS, Bond CS, Tetaud E, Fairlamb AH, Hunter WN. The structure of reduced tryparedoxin peroxidase reveals a decamer and insight into reactivity of 2Cys-peroxiredoxins. J Mol Biol 2000; 300: 903-16.
120. Grishin NV, Osterman AL, Brooks HB, Phillips MA, Goldsmith EJ. X-ray structure of ornithine decarboxylase from Trypanosoma brucei: the native structure and the structure in complex with alphadifluoromethylornithine. Biochemistry 1999; 38: 15174-84.