The trypanothione system and the opportunities it offers to create drugs for the neglected kinetoplast diseases

Biotechnology Advances

Volumn 30, Issue 1, 2012, Pages 294-301

  Flohé, Leopold ^a  

^a OTTO VON GUERICKE UNIVERSITY   (Germany)

Author keywords

Antioxidant defense; DNA synthesis; Drug target; Drugability; Leishmaniasis; Target validation; Trypanosomiasis; Trypanothione; Trypanothione synthetase; Tryparedoxin

Indexed keywords

ANTIOXIDANT DEFENSE; DNA SYNTHESIS; DRUG TARGETS; DRUGABILITY; LEISHMANIASIS; TRYPANOSOMIASIS; TRYPANOTHIONE; TRYPANOTHIONE SYNTHETASE; TRYPAREDOXIN;

GENETIC ENGINEERING;

POLYMERASE CHAIN REACTION;

AMIDE SYNTHASE; ANTITRYPANOSOMAL AGENT; DRUG DERIVATIVE; GLUTATHIONE; SPERMIDINE; THIOREDOXIN; TRYPANOTHIONE; TRYPANOTHIONE SYNTHETASE; TRYPAREDOXIN;

ANTIOXIDANT; CHAGAS DISEASE; COHORT ANALYSIS; CRYSTALLIZATION; DRUG; FLAGELLATE; GENE EXPRESSION; HEALTH RISK; INHIBITION; LEISHMANIASIS; MORBIDITY; PATHOGENICITY; PUBLIC HEALTH;

ANIMAL; CHEMISTRY; DRUG DELIVERY SYSTEM; DRUG DEVELOPMENT; HUMAN; KINETOPLASTIDA; LEISHMANIASIS; METABOLISM; METHODOLOGY; NEGLECTED DISEASE; PARASITOLOGY; REVIEW; TRYPANOSOMIASIS;

AMIDE SYNTHASES; ANIMALS; DRUG DELIVERY SYSTEMS; DRUG DISCOVERY; GLUTATHIONE; HUMANS; LEISHMANIASIS; NEGLECTED DISEASES; SPERMIDINE; THIOREDOXINS; TRYPANOCIDAL AGENTS; TRYPANOSOMATINA; TRYPANOSOMIASIS;

AFRICA;

CRITHIDIA FASCICULATA; HEXAPODA; KINETOPLASTIDA; TRYPANOSOMA BRUCEI; TRYPANOSOMATIDAE;

EID: 80755142192     PISSN: 07349750     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.biotechadv.2011.05.012     Document Type: Review

References (97)

1. Alphey M.S., Leonard G.A., Gourley D.G., Tetaud E., Fairlamb A.H., Hunter W.N. The high resolution crystal structure of recombinant Crithidia fasciculata tryparedoxin-I. J Biol Chem 1999, 274:25613-25622.
2. Alphey M.S., Bond C.S., Tetaud E., Fairlamb A.H., Hunter W.N. The structure of reduced tryparedoxin peroxidase reveals a decamer and insight into reactivity of 2Cys-peroxiredoxins. J Mol Biol 2000, 300:903-916.
3. Alphey M.S., Konig J., Fairlamb A.H. Structural and mechanistic insights into type II trypanosomatid tryparedoxin-dependent peroxidases. Biochem J 2008, 414:375-381.
4. Ariyanayagam M.R., Oza S.L., Guther M.L., Fairlamb A.H. Phenotypic analysis of trypanothione synthetase knockdown in the African trypanosome. Biochem J 2005, 391:425-432.
5. Barr S.D., Gedamu L. Role of peroxidoxins in Leishmania chagasi survival. Evidence of an enzymatic defense against nitrosative stress. J Biol Chem 2003, 278:10816-10823.
6. Boveris A., Sies H., Martino E.E., Docampo R., Turrens J.F., Stoppani A.O. Deficient metabolic utilization of hydrogen peroxide in Trypanosoma cruzi. Biochem J 1980, 188:643-648.
7. Brigelius-Flohé R., Flohé L. Basic principles and emerging concepts in the redox control of transcription factors. Antioxid Redox Signal 2011.
8. Carnieri E.G., Moreno S.N., Docampo R. Trypanothione-dependent peroxide metabolism in Trypanosoma cruzi different stages. Mol Biochem Parasitol 1993, 61:79-86.
9. Castro H., Tomas A.M. Peroxidases of trypanosomatids. Antioxid Redox Signal 2008, 10:1593-1606.
10. Castro H., Sousa C., Novais M., Santos M., Budde H., Cordeiro-da-Silva A., et al. Two linked genes of Leishmania infantum encode tryparedoxins localised to cytosol and mitochondrion. Mol Biochem Parasitol 2004, 136:137-147.
11. Castro H., Romao S., Carvalho S., Teixeira F., Sousa C., Tomas A.M. Mitochondrial redox metabolism in trypanosomatids is independent of tryparedoxin activity. PLoS One 2010, 5:e12607.
12. Comini M, Menge U, Flohé L. Additions and Corrections for König et al. (1997): J Biol Chem 272, 11908-11915. 2005a;280:7407-8.
13. Comini M., Menge U., Flohé L. Biosynthesis of trypanothione in Trypanosoma brucei brucei. Biol Chem Hoppe Seyler 2003, 384:653-656.
14. Comini M.A., Guerrero S.A., Haile S., Menge U., Lünsdorf H., Flohé L. Validation of Trypanosoma brucei trypanothione synthetase as drug target. Free Radic Biol Med 2004, 36:1289-1302.
15. Comini M., Menge U., Wissing J., Flohé L. Trypanothione synthesis in crithidia revisited. J Biol Chem 2005, 280:6850-6860.
16. Comini M.A., Krauth-Siegel R.L., Flohé L. Depletion of the thioredoxin homologue tryparedoxin impairs antioxidative defence in African trypanosomes. Biochem J 2007, 402:43-49.
17. Daunes S., D'Silva C., Kendrick H., Yardley V., Croft S.L. QSAR study on the contribution of log P and E(s) to the in vitro antiprotozoal activity of glutathione derivatives. J Med Chem 2001, 44:2976-2983.
18. Dormeyer M., Reckenfelderbäumer N., Lüdemann H., Krauth-Siegel R.L. Trypanothione-dependent synthesis of deoxyribonucleotides by Trypanosoma brucei ribonucleotide reductase. J Biol Chem 2001, 276:10602-10606.
19. El-Sayed N.M., Alarcon C.M., Beck J.C., Sheffield V.C., Donelson J.E. cDNA expressed sequence tags of Trypanosoma brucei rhodesiense provide new insights into the biology of the parasite. Mol Biochem Parasitol 1995, 73:75-90.
20. El-Sayed N.M., Myler P.J., Blandin G., Berriman M., Crabtree J., Aggarwal G., et al. Comparative genomics of trypanosomatid parasitic protozoa. Science 2005, 309:404-409.
21. Fairlamb A.H., Cerami A. Metabolism and functions of trypanothione in the Kinetoplastida. Annu Rev Microbiol 1992, 46:695-729.
22. Fairlamb A.H., Blackburn P., Ulrich P., Chait B.T., Cerami A. Trypanothione: a novel bis(glutathionyl)spermidine cofactor for glutathione reductase in trypanosomatids. Science 1985, 227:1485-1487.
23. Fairlamb A.H., Henderson G.B., Cerami A. The biosynthesis of trypanothione and N1-glutathionylspermidine in Crithidia fasciculata. Mol Biochem Parasitol 1986, 21:247-257.
24. Fairlamb A.H., Ridley R.G., Vial H.J. Drugs against parsitic diseases. R&D Methodologies and Issues 2003, WHO/TDR, Geneva.
25. Flohé L. The Achilles' heel of trypanosomatids: trypanothione-mediated hydroperoxide metabolism. Biofactors 1998, 8:87-91.
26. Flohé L. Changing paradigms in thiology from antioxidant defense toward redox regulation. Methods Enzymol 2010, 473:1-39.
27. Flohé L., Brigelius-Flohé R. Selenoproteins of the glutathione system. Selenium Its Molecular Biology and Role in Human Health 2006, 161-172. Springer, New York. 2nd ed. D.L. Hatfield, M.J. Berry, V.N. Gladyshev (Eds.).
28. Flohé L., Budde H., Bruns K., Castro H., Clos J., Hofmann B., et al. Tryparedoxin peroxidase of Leishmania donovani: molecular cloning, heterologous expression, specificity, and catalytic mechanism. Arch Biochem Biophys 2002, 397:324-335.
29. Flohé L., Castro H., Comini M.A., Heller K., Koch O., Schinzer D., et al. Paullones as drugs for trypanosomatids. Abstracts10th Drug Design and Development Seminar Abstracts 2009, IL33. University of Gießen, Gießen. K. Becker, P. Selzer (Eds.).
30. Fyfe P.K., Oza S.L., Fairlamb A.H., Hunter W.N. Leishmania trypanothione synthetase-amidase structure reveals a basis for regulation of conflicting synthetic and hydrolytic activities. J Biol Chem 2008, 283:17672-17680.
31. Gommel D.U., Nogoceke E., Morr M., Kiess M., Kalisz H.M., Flohé L. Catalytic characteristics of tryparedoxin. Eur J Biochem 1997, 248:913-918.
32. Guerrero S.A., Flohé L., Kalisz H.M., Montemartini M., Nogoceke E., Hecht H.J., et al. Sequence, heterologous expression and functional characterization of tryparedoxin1 from Crithidia fasciculata. Eur J Biochem 1999, 259:789-794.
33. Hillebrand H., Schmidt A., Krauth-Siegel R.L. A second class of peroxidases linked to the trypanothione metabolism. J Biol Chem 2003, 278:6809-6815.
34. Hofmann B., Budde H., Bruns K., Guerrero S.A., Kalisz H.M., Menge U., et al. Structures of tryparedoxins revealing interaction with trypanothione. Biol Chem Hoppe Seyler 2001, 382:459-471.
35. Hofmann B., Hecht H.J., Flohé L. Peroxiredoxins. Biol Chem Hoppe Seyler 2002, 383:347-364.
36. Holloway G.A., Charman W.N., Fairlamb A.H., Brun R., Kaiser M., Kostewicz E., et al. Trypanothione reductase high-throughput screening campaign identifies novel classes of inhibitors with antiparasitic activity. Antimicrob Agents Chemother 2009, 53:2824-2833.
37. Holmgren A. Thioredoxin. Annu Rev Biochem 1985, 54:237-271.
38. Inhoff O., Richards J.M., Briet J.W., Lowe G., Krauth-Siegel R.L. Coupling of a competitive and an irreversible ligand generates mixed type inhibitors of Trypanosoma cruzi trypanothione reductase. J Med Chem 2002, 45:4524-4530.
39. Irigoin F., Cibils L., Comini M.A., Wilkinson S.R., 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.
40. Irsch T., Krauth-Siegel R.L. Glyoxalase II of African trypanosomes is trypanothione-dependent. J Biol Chem 2004, 279:22209-22217.
41. Jackson A.P., Sanders M., Berry A., McQuillan J., Aslett M.A., Quail M.A., et al. The genome sequence of Trypanosoma brucei gambiense, causative agent of chronic human african trypanosomiasis. PLoS Negl Trop Dis 2010, 4:e658.
42. Jacoby E.M., Schlichting I., Lantwin C.B., Kabsch W., Krauth-Siegel R.L. Crystal structure of the Trypanosoma cruzi trypanothione reductase.mepacrine complex. Proteins 1996, 24:73-80.
43. Kissinger J.C. A tale of three genomes: the kinetoplastids have arrived. Trends Parasitol 2006, 22:240-243.
44. Klebanoff S.J. Myeloperoxidase: friend and foe. J Leukoc Biol 2005, 77:598-625.
45. Koch O., Jaeger T., Heller K., Stuhlmann F., Flohé L., Selzer P. What makes the difference? A computational approach to explain varying paullone inhibition activity on trypanothione synthetase from different species. Abstracts10th Drug Design and Development Seminar 2009, L34. University of Gießen, Gießen. K. Becker, P. Selzer (Eds.).
46. Koenig K., Menge U., Kiess M., Wray V., Flohé L. Convenient isolation and kinetic mechanism of glutathionylspermidine synthetase from Crithidia fasciculata. J Biol Chem 1997, 272:11908-11915.
47. Krauth-Siegel R.L., Comini M.A. Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism. Biochim Biophys Acta 2008, 1780:1236-1248.
48. Krauth-Siegel L.R., Comini M.A., Schlecker T. The trypanothione system. Subcell Biochem 2007, 44:231-251.
49. Krieger S., Schwarz W., Ariyanayagam M.R., Fairlamb A.H., Krauth-Siegel R.L., Clayton C. Trypanosomes lacking trypanothione reductase are avirulent and show increased sensitivity to oxidative stress. Mol Microbiol 2000, 35:542-552.
50. Krumme D., Budde H., Hecht H.J., Menge U., Ohlenschlager O., Ross A., et al. NMR studies of the interaction of tryparedoxin with redox-inactive substrate homologues. Biochemistry 2003, 42:14720-14728.
51. Kunick C. Fused azepinones with antitumor activity. Curr Pharm Des 1999, 5:181-194.
52. Kunick C., Lauenroth K., Leost M., Meijer L., Lemcke T. 1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-3 beta. Bioorg Med Chem Lett 2004, 14:413-416.
53. Lee B., Bauer H., Melchers J., Ruppert T., Rattray L., Yardley V., et al. Irreversible inactivation of trypanothione reductase by unsaturated Mannich bases: a divinyl ketone as key intermediate. J Med Chem 2005, 48:7400-7410.
54. Levick M.P., Tetaud E., Fairlamb A.H., Blackwell J.M. Identification and characterisation of a functional peroxidoxin from Leishmania major. Mol Biochem Parasitol 1998, 96:125-137.
55. Lopez J.A., Carvalho T.U., de Souza W., Flohé L., Guerrero S.A., Montemartini M., et al. Evidence for a trypanothione-dependent peroxidase system in Trypanosoma cruzi. Free Radic Biol Med 2000, 28:767-772.
56. Lüdemann H., Dormeyer M., Sticherling C., Stallmann D., Follmann H., Krauth-Siegel R.L. Trypanosoma brucei tryparedoxin, a thioredoxin-like protein in African trypanosomes. FEBS Lett 1998, 431:381-385.
57. McGrath C.F., Pattabiraman N., Kellogg G.E., Lemcke T., Kunick C., Sausville E.A., et al. Homology model of the CDK1/cyclin B complex. J Biomol Struct Dyn 2005, 22:493-502.
58. Meiering S., Inhoff O., Mies J., Vincek A., Garcia G., Kramer B., et al. Inhibitors of Trypanosoma cruzi trypanothione reductase revealed by virtual screening and parallel synthesis. J Med Chem 2005, 48:4793-4802.
59. Montemartini M., Kalisz H.M., Kiess M., Nogoceke E., Singh M., Steinert P., et al. Sequence, heterologous expression and functional characterization of a novel tryparedoxin from Crithidia fasciculata. Biol Chem Hoppe Seyler 1998, 379:1137-1142.
60. Montemartini M., Nogoceke E., Singh M., Steinert P., Flohé L., Kalisz H.M. Sequence analysis of the tryparedoxin peroxidase gene from Crithidia fasciculata and its functional expression in Escherichia coli. J Biol Chem 1998, 273:4864-4871.
61. Mukherjee A., Roy G., Guimond C., Ouellette M. The gamma-glutamylcysteine synthetase gene of Leishmania is essential and involved in response to oxidants. Mol Microbiol 2009, 74:914-927.
62. Myler P.J. Searching the Tritryp genomes for drug targets. Adv Exp Med Biol 2008, 625:133-140.
63. Myler J.P., Fasel N. Leishmania after the genome 2008, Caister Acad Press, Norfolk.
64. Nogoceke E., Gommel D.U., Kiess M., Kalisz H.M., Flohé L. A unique cascade of oxidoreductases catalyses trypanothione-mediated peroxide metabolism in Crithidia fasciculata. Biol Chem Hoppe Seyler 1997, 378:827-836.
65. Ondarza R.N., Iturbe A., Hurtado G., Tamayo E., Ondarza M., Hernandez E. Entamoeba histolytica: a eukaryote with trypanothione metabolism instead of glutathione metabolism. Biotechnol Appl Biochem 1999, 30(Pt 1):47-52.
66. Ondarza R.N., Hurtado G., Tamayo E., Iturbe A., Hernandez E. Naegleria fowleri: a free-living highly pathogenic amoeba contains trypanothione/trypanothione reductase and glutathione/glutathione reductase systems. Exp Parasitol 2006, 114:141-146.
67. Otero L., Vieites M., Boiani L., Denicola A., Rigol C., Opazo L., et al. Novel antitrypanosomal agents based on palladium nitrofurylthiosemicarbazone complexes: DNA and redox metabolism as potential therapeutic targets. J Med Chem 2006, 49:3322-3331.
68. Oza S.L., Tetaud E., Ariyanayagam M.R., Warnon S.S., Fairlamb A.H. A single enzyme catalyses formation of Trypanothione from glutathione and spermidine in Trypanosoma cruzi. J Biol Chem 2002, 277:35853-35861.
69. Padmanabhan P.K., Mukherjee A., Madhubala R. Characterization of the gene encoding glyoxalase II from Leishmania donovani: a potential target for anti-parasite drugs. Biochem J 2006, 393:227-234.
70. Piacenza L., Peluffo G., Alvarez M.N., Kelly J.M., Wilkinson S.R., Radi R. Peroxiredoxins play a major role in protecting Trypanosoma cruzi against macrophage- and endogenously-derived peroxynitrite. Biochem J 2008, 410:359-368.
71. Piattoni C.V., Blancato V.S., Miglietta H., Iglesias A.A., Guerrero S.A. On the occurrence of thioredoxin in Trypanosoma cruzi. Acta Trop 2006, 97:151-160.
72. Pineyro M.D., Pizarro J.C., Lema F., Pritsch O., Cayota A., Bentley G.A., et al. Crystal structure of the tryparedoxin peroxidase from the human parasite Trypanosoma cruzi. J Struct Biol 2005, 150:11-22.
73. Ravaschino E.L., Docampo R., Rodriguez J.B. Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis. J Med Chem 2006, 49:426-435.
74. Reckenfelderbäumer N., Ludemann H., Schmidt H., Steverding D., Krauth-Siegel R.L. Identification and functional characterization of thioredoxin from Trypanosoma brucei brucei. J Biol Chem 2000, 275:7547-7552.
75. Richardson J.L., Nett I.R., Jones D.C., Abdille M.H., Gilbert I.H., Fairlamb A.H. Improved tricyclic inhibitors of trypanothione reductase by screening and chemical synthesis. ChemMedChem 2009, 4:1333-1340.
76. Romao S., Castro H., Sousa C., Carvalho S., Tomas A.M. The cytosolic tryparedoxin of Leishmania infantum is essential for parasite survival. Int J Parasitol 2009, 39:703-711.
77. Salmon-Chemin L., Buisine E., Yardley V., Kohler S., Debreu M.A., Landry V., et al. 2- and 3-substituted 1,4-naphthoquinone derivatives as subversive substrates of trypanothione reductase and lipoamide dehydrogenase from Trypanosoma cruzi: synthesis and correlation between redox cycling activities and in vitro cytotoxicity. J Med Chem 2001, 44:548-565.
78. Schlecker T., Schmidt A., Dirdjaja N., Voncken F., Clayton C., Krauth-Siegel R.L. Substrate specificity, localization, and essential role of the glutathione peroxidase-type tryparedoxin peroxidases in Trypanosoma brucei. J Biol Chem 2005, 280:14385-14394.
79. Shames S.L., Fairlamb A.H., Cerami A., Walsh C.T. Purification and characterization of trypanothione reductase from Crithidia fasciculata, a newly discovered member of the family of disulfide-containing flavoprotein reductases. Biochemistry 1986, 25:3519-3526.
80. Shlomai J. Redox control of protein-DNA interactions: from molecular mechanisms to significance in signal transduction, gene expression, and DNA replication. Antioxid Redox Signal 2010, 13:1429-1476.
81. Spinks D., Shanks E.J., Cleghorn L.A., McElroy S., Jones D., James D., et al. Investigation of trypanothione reductase as a drug target in Trypanosoma brucei. ChemMedChem 2009, 4:2060-2069.
82. Stuhlmann F., Flohé L., Schinzer D., Jaeger T. N-substituted 2-(6-oxo-6,7-dihydro-5H-benzo[2,3]azepino[4,5-b]indol-5-yl)-acetamides for treating tropical diseases 2005, EP 05 018 385.4.
83. Stump B., Eberle C., Schweizer W.B., Kaiser M., Brun R., Krauth-Siegel R.L., et al. Pentafluorosulfanyl as a novel building block for enzyme inhibitors: trypanothione reductase inhibition and antiprotozoal activities of diarylamines. Chembiochem 2009, 10:79-83.
84. Tabor H., Tabor C.W. Glutathionylspermidine. Methods Enzymol 1983, 94:434-437.
85. TDR Innovation for health: research that makes a difference: TDR annual report 2009 2010, WHO/TDR, Geneva.
86. Torrie L.S., Wyllie S., Spinks D., Oza S.L., Thompson S., Harrison J.R., et al. Chemical validation of trypanothione synthetase: a potential drug target for human trypanosomiasis. J Biol Chem 2009, 284:36137-36145.
87. Tovar J., Wilkinson S., Mottram J.C., Fairlamb A.H. Evidence that trypanothione reductase is an essential enzyme in Leishmania by targeted replacement of the tryA gene locus. Mol Microbiol 1998, 29:653-660.
88. Trujillo M., Ferrer-Sueta G., Thomson L., Flohé L., Radi R. Kinetics of peroxiredoxins and their role in the decomposition of peroxynitrite. Subcell Biochem 2007, 44:83-113.
89. Vickers T.J., Fairlamb A.H. Trypanothione S-transferase activity in a trypanosomatid ribosomal elongation factor 1B. J Biol Chem 2004, 279:27246-27256.
90. Vickers T.J., Greig N., Fairlamb A.H. A trypanothione-dependent glyoxalase I with a prokaryotic ancestry in Leishmania major. Proc Natl Acad Sci USA 2004, 101:13186-13191.
91. Wendler A., Irsch T., Rabbani N., Thornalley P.J., Krauth-Siegel R.L. Glyoxalase II does not support methylglyoxal detoxification but serves as a general trypanothione thioesterase in African trypanosomes. Mol Biochem Parasitol 2009, 163:19-27.
92. Wilkinson S.R., Meyer D.J., Kelly J.M. Biochemical characterization of a trypanosome enzyme with glutathione-dependent peroxidase activity. Biochem J 2000, 352(Pt 3):755-761.
93. Wilkinson S.R., Temperton N.J., Mondragon A., Kelly J.M. Distinct mitochondrial and cytosolic enzymes mediate trypanothione-dependent peroxide metabolism in Trypanosoma cruzi. J Biol Chem 2000, 275:8220-8225.
94. Wilkinson S.R., Meyer D.J., Taylor M.C., Bromley E.V., Miles M.A., Kelly J.M. The Trypanosoma cruzi enzyme TcGPXI is a glycosomal peroxidase and can be linked to trypanothione reduction by glutathione or tryparedoxin. J Biol Chem 2002, 277:17062-17071.
95. Wilkinson S.R., Obado S.O., Mauricio I.L., Kelly J.M. Trypanosoma cruzi expresses a plant-like ascorbate-dependent hemoperoxidase localized to the endoplasmic reticulum. Proc Natl Acad Sci USA 2002, 99:13453-13458.
96. Wilkinson S.R., Horn D., Prathalingam S.R., Kelly J.M. RNA interference identifies two hydroperoxide metabolizing enzymes that are essential to the bloodstream form of the African trypanosome. J Biol Chem 2003, 278:31640-31646.
97. Zaharevitz D.W., Gussio R., Leost M., Senderowicz A.M., Lahusen T., Kunick C., et al. Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases. Cancer Res 1999, 59:2566-2569.