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Science 22 March 1985:
Vol. 227. no. 4693, pp. 1485 - 1487
DOI: 10.1126/science.3883489
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Articles

Science, Vol 227, Issue 4693, 1485-1487
Copyright © 1985 by American Association for the Advancement of Science

articles

Trypanothione: a novel bis(glutathionyl)spermidine cofactor for glutathione reductase in trypanosomatids

AH Fairlamb, P Blackburn, P Ulrich, BT Chait, and A Cerami

Glutathione reductase from trypanosomes and leishmanias, unlike glutathione reductase from other organisms, requires an unusual low molecular weight cofactor for activity. The cofactor was purified from the insect trypanosomatid Crithidia fasciculata and identified as a novel glutathione-spermidine conjugate, N1,N8-bis(L-gamma-glutamyl-L-hemicystinyl-glycyl)spermidine, for which the trivial name trypanothione is proposed. This discovery may open a new chemotherapeutic approach to trypanosomiasis and leishmaniasis.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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G. A. Holloway, W. N. Charman, A. H. Fairlamb, R. Brun, M. Kaiser, E. Kostewicz, P. M. Novello, J. P. Parisot, J. Richardson, I. P. Street, et al. (2009)
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Enzymatic Mechanism Controls Redox-mediated Protein-DNA Interactions at the Replication Origin of Kinetoplast DNA Minicircles.
D. Sela, N. Yaffe, and J. Shlomai (2008)
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The Development of Drug Metabolism Research as Expressed in the Publications of ASPET: Part 1, 1909-1958.
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Drug Metab. Dispos. 36, 1-5
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Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog.
E. K. Willert, R. Fitzpatrick, and M. A. Phillips (2007)
PNAS 104, 8275-8280
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Trypanothione Synthesis in Crithidia Revisited.
M. Comini, U. Menge, J. Wissing, and L. Flohe (2005)
J. Biol. Chem. 280, 6850-6860
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Leishmania major Elongation Factor 1B Complex Has Trypanothione S-Transferase and Peroxidase Activity.
T. J. Vickers, S. Wyllie, and A. H. Fairlamb (2004)
J. Biol. Chem. 279, 49003-49009
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A trypanothione-dependent glyoxalase I with a prokaryotic ancestry in Leishmania major.
T. J. Vickers, N. Greig, and A. H. Fairlamb (2004)
PNAS 101, 13186-13191
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Two Interacting Binding Sites for Quinacrine Derivatives in the Active Site of Trypanothione Reductase: A TEMPLATE FOR DRUG DESIGN.
A. Saravanamuthu, T. J. Vickers, C. S. Bond, M. R. Peterson, W. N. Hunter, and A. H. Fairlamb (2004)
J. Biol. Chem. 279, 29493-29500
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Trypanothione S-Transferase Activity in a Trypanosomatid Ribosomal Elongation Factor 1B.
T. J. Vickers and A. H. Fairlamb (2004)
J. Biol. Chem. 279, 27246-27256
   Abstract »    Full Text »    PDF »
Redox Potential Regulates Binding of Universal Minicircle Sequence Binding Protein at the Kinetoplast DNA Replication Origin.
I. Onn, N. Milman-Shtepel, and J. Shlomai (2004)
Eukaryot. Cell 3, 277-287
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Apoptotic Death in Leishmania donovani Promastigotes in Response to Respiratory Chain Inhibition: COMPLEX II INHIBITION RESULTS IN INCREASED PENTAMIDINE CYTOTOXICITY.
A. Mehta and C. Shaha (2004)
J. Biol. Chem. 279, 11798-11813
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Gene Knockdown of {gamma}-Glutamylcysteine Synthetase by RNAi in the Parasitic Protozoa Trypanosoma brucei Demonstrates That It Is an Essential Enzyme.
T. T. Huynh, V. T. Huynh, M. A. Harmon, and M. A. Phillips (2003)
J. Biol. Chem. 278, 39794-39800
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RNA Interference Identifies Two Hydroperoxide Metabolizing Enzymes That Are Essential to the Bloodstream Form of the African Trypanosome.
S. R. Wilkinson, D. Horn, S. R. Prathalingam, and J. M. Kelly (2003)
J. Biol. Chem. 278, 31640-31646
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Bis(glutathionyl)spermine and Other Novel Trypanothione Analogues in Trypanosoma cruzi.
M. R. Ariyanayagam, S. L. Oza, A. Mehlert, and A. H. Fairlamb (2003)
J. Biol. Chem. 278, 27612-27619
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The In Vivo Susceptibility of Leishmania donovani to Sodium Stibogluconate Is Drug Specific and Can Be Reversed by Inhibiting Glutathione Biosynthesis.
K. C. Carter, S. Sundar, C. Spickett, O. C. Pereira, and A. B. Mullen (2003)
Antimicrob. Agents Chemother. 47, 1529-1535
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Proteome Mapping of the Protozoan Parasite Leishmania and Application to the Study of Drug Targets and Resistance Mechanisms.
J. Drummelsmith, V. Brochu, I. Girard, N. Messier, and M. Ouellette (2003)
Mol. Cell. Proteomics 2, 146-155
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A Second Class of Peroxidases Linked to the Trypanothione Metabolism.
H. Hillebrand, A. Schmidt, and R. L. Krauth-Siegel (2003)
J. Biol. Chem. 278, 6809-6815
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A Single Enzyme Catalyses Formation of Trypanothione from Glutathione and Spermidine in Trypanosoma cruzi.
S. L. Oza, E. Tetaud, M. R. Ariyanayagam, S. S. Warnon, and A. H. Fairlamb (2002)
J. Biol. Chem. 277, 35853-35861
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Oligopeptidase B from Trypanosoma brucei, a New Member of an Emerging Subgroup of Serine Oligopeptidases.
R. E. Morty, J. D. Lonsdale-Eccles, J. Morehead, E. V. Caler, R. Mentele, E. A. Auerswald, T. H. T. Coetzer, N. W. Andrews, and B. A. Burleigh (1999)
J. Biol. Chem. 274, 26149-26156
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Trypanosoma brucei gamma -Glutamylcysteine Synthetase. CHARACTERIZATION OF THE KINETIC MECHANISM AND THE ROLE OF CYS-319 IN CYSTAMINE INACTIVATION.
D. L. Brekken and M. A. Phillips (1998)
J. Biol. Chem. 273, 26317-26322
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Endogenous Glutathione Conjugates: Occurrence and Biological Functions.
W. Wang and N. Ballatori (1998)
Pharmacol. Rev. 50, 335-356
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Cloning and Characterization of the Two Enzymes Responsible for Trypanothione Biosynthesis in Crithidia fasciculata.
E. Tetaud, F. Manai, M. P. Barrett, K. Nadeau, C. T. Walsh, and A. H. Fairlamb (1998)
J. Biol. Chem. 273, 19383-19390
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Convenient Isolation and Kinetic Mechanism of Glutathionylspermidine Synthetase from Crithidia fasciculata.
K. Koenig, U. Menge, M. Kiess, V. Wray, and L. Flohe (1997)
J. Biol. Chem. 272, 11908-11915
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Dissection of Glutathionylspermidine Synthetase/Amidase from Escherichia coli into Autonomously Folding and Functional Synthetase and Amidase Domains.
D. S. Kwon, C.-H. Lin, S. Chen, J. K. Coward, C. T. Walsh, and J. M. Bollinger Jr. (1997)
J. Biol. Chem. 272, 2429-2436
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Characterization of Trypanosoma brucei gamma -Glutamylcysteine Synthetase, an Essential Enzyme in the Biosynthesis of Trypanothione (Diglutathionylspermidine).
D. V. Lueder and M. A. Phillips (1996)
J. Biol. Chem. 271, 17485-17490
   Abstract »    Full Text »    PDF »
Glutathionylspermidine Metabolism in Escherichia coli.
J. M. BollingerJr., D. S. Kwon, G. W. Huisman, R. Kolter, and C. T. Walsh (1995)
J. Biol. Chem. 270, 14031-14041
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