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Science 17 October 1980:
Vol. 210. no. 4467, pp. 332 - 334
DOI: 10.1126/science.6775372
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Articles

Science, Vol 210, Issue 4467, 332-334
Copyright © 1980 by American Association for the Advancement of Science

articles

Polyamine metabolism: a potential therapeutic target in trypanosomes

CJ Bacchi, HC Nathan, SH Hutner, PP McCann, and A Sjoerdsma

alpha-Difluoromethylornithine (RMI 71,782), a specific irreversible inhibitor of the first step in polyamine biosynthesis, that is, the formation of putrescine from ornithine by ornithine decarboxylase, cures mice infected with a virulent, rodent-passaged strain of Trypanosoma brucei brucei. This parasite is closely related to the trypanosomes that cause human sleeping sickness. The drug, which is remarkably nontoxic, was effective when administered in drinking water or by intubation. The ability of the compound to inhibit ornithine decarboxylase in vitro was demonstrated by the reduced amounts of putrescine synthesized from tritiated ornithine in Trypanosoma brucei suspensions. These observations direct attention to polyamine metabolism as a target for chemotherapy of parasitic diseases.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Novel S-Adenosylmethionine Decarboxylase Inhibitors for the Treatment of Human African Trypanosomiasis.
R. H. Barker Jr., H. Liu, B. Hirth, C. A. Celatka, R. Fitzpatrick, Y. Xiang, E. K. Willert, M. A. Phillips, M. Kaiser, C. J. Bacchi, et al. (2009)
Antimicrob. Agents Chemother. 53, 2052-2058
   Abstract »    Full Text »    PDF »
RNA Interference-Mediated Silencing of Ornithine Decarboxylase and Spermidine Synthase Genes in Trypanosoma brucei Provides Insight into Regulation of Polyamine Biosynthesis.
Y. Xiao, D. E. McCloskey, and M. A. Phillips (2009)
Eukaryot. Cell 8, 747-755
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Enantioselective and Nonlinear Intestinal Absorption of Eflornithine in the Rat.
R. Jansson, M. Malm, C. Roth, and M. Ashton (2008)
Antimicrob. Agents Chemother. 52, 2842-2848
   Abstract »    Full Text »    PDF »
Safety and effectiveness of first line eflornithine for Trypanosoma brucei gambiense sleeping sickness in Sudan: cohort study.
G. Priotto, L. Pinoges, I. B. Fursa, B. Burke, N. Nicolay, G. Grillet, C. Hewison, and M. Balasegaram (2008)
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Phylogenetic Diversity and the Structural Basis of Substrate Specificity in the beta/{alpha}-Barrel Fold Basic Amino Acid Decarboxylases.
J. Lee, A. J. Michael, D. Martynowski, E. J. Goldsmith, and M. A. Phillips (2007)
J. Biol. Chem. 282, 27115-27125
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Arginase Plays a Pivotal Role in Polyamine Precursor Metabolism in Leishmania: CHARACTERIZATION OF GENE DELETION MUTANTS.
S. C. Roberts, M. J. Tancer, M. R. Polinsky, K. M. Gibson, O. Heby, and B. Ullman (2004)
J. Biol. Chem. 279, 23668-23678
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Antiplasmodial activity of a series of 1,3,5-triazine-substituted polyamines.
B. Klenke, M. P. Barrett, R. Brun, and I. H. Gilbert (2003)
J. Antimicrob. Chemother. 52, 290-293
   Abstract »    Full Text »    PDF »
X-ray Structure Determination of Trypanosoma brucei Ornithine Decarboxylase Bound to D-Ornithine and to G418: INSIGHTS INTO SUBSTRATE BINDING AND ODC CONFORMATIONAL FLEXIBILITY.
L. K. Jackson, E. J. Goldsmith, and M. A. Phillips (2003)
J. Biol. Chem. 278, 22037-22043
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S-Adenosylmethionine Decarboxylase from Leishmania donovani. MOLECULAR, GENETIC, AND BIOCHEMICAL CHARACTERIZATION OF NULL MUTANTS AND OVERPRODUCERS.
S. C. Roberts, J. Scott, J. E. Gasteier, Y. Jiang, B. Brooks, A. Jardim, N. S. Carter, O. Heby, and B. Ullman (2002)
J. Biol. Chem. 277, 5902-5909
   Abstract »    Full Text »    PDF »
Development of Difluoromethylornithine (DFMO) as a Chemoprevention Agent.
F. L. Meyskens Jr. and E. W. Gerner (1999)
Clin. Cancer Res. 5, 945-951
   Abstract »    Full Text »    PDF »
More surprises from Kinetoplastida.
J. E. Donelson, M. J. Gardner, and N. M. El-Sayed (1999)
PNAS 96, 2579-2581
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Rat Antizyme Inhibits the Activity but Does Not Promote the Degradation of Mouse Ornithine Decarboxylase in Trypanosoma brucei.
S.-b. Hua, X. Li, P. Coffino, and C. C. Wang (1995)
J. Biol. Chem. 270, 10264-10271
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