Cure of murine Trypanosoma brucei rhodesiense infections with an S-adenosylmethionine decarboxylase inhibitor

Bacchi, Cyrus J.; Nathan, Henry C.; Yarlett, Nigel; Goldberg, Burt; McCann, Peter P.; Bitonti, Alan J.; Sjoerdsma, Albert

doi:10.1128/aac.36.12.2736

Cited by 78 publications

(70 citation statements)

References 19 publications

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“…Gene knockout or RNA interference (RNAi) studies in T. brucei have shown that the polyamine and trypanothione biosynthetic enzymes are required for parasite growth (1,19,23,24,35,40). In addition to DFMO, inhibitors of AdoMetDC have also been reported to have antitrypanosomal activity (3,5,7), further demonstrating that polyamine metabolism is of clear medical and pharmacological importance in these parasites. DFMO treatment depletes the cells of putrescine and trypanothione, while leading to a partial depletion of spermidine (11).…”

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confidence: 99%

RNA Interference-Mediated Silencing of Ornithine Decarboxylase and Spermidine Synthase Genes in Trypanosoma brucei Provides Insight into Regulation of Polyamine Biosynthesis

2009

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Polyamine biosynthesis is a drug target for the treatment of African sleeping sickness; however, mechanisms regulating the pathway in Trypanosoma brucei are not well understood. Recently, we showed that RNA interference (RNAi)-mediated gene silencing or the inhibition of S-adenosylmethionine decarboxylase (AdoMetDC) led to the upregulation of the AdoMetDC activator, prozyme, and ornithine decarboxylase (ODC) proteins. To determine if this regulatory response is specific to AdoMetDC, we studied the effects of the RNAi-induced silencing of the spermidine synthase (SpdSyn) and ODC genes in bloodstream form T. brucei. The knockdown of either gene product led to the depletion of the polyamine and trypanothione pools and to cell death. Decarboxylated AdoMet levels were elevated, while AdoMet was not affected. There was no significant effect on the protein levels of other polyamine pathway enzymes. The treatment of parasites with the ODC inhibitor ␣-difluoromethylornithine gave similar results to those observed for ODC knockdown. Thus, the cellular response to the loss of AdoMetDC activity is distinctive, suggesting that AdoMetDC activity controls the expression levels of the other spermidine biosynthetic enzymes. RNAi-mediated cell death occurred more rapidly for ODC than for SpdSyn. Further, the ODC RNAi cells were rescued by putrescine, but not spermidine, suggesting that the depletion of both putrescine and spermidine is more detrimental than the depletion of spermidine alone. This finding may contribute to the effectiveness of ODC as a target for the treatment of African sleeping sickness, thus providing important insight into the mechanism of action of a key antitrypanosomal agent.

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RNA Interference-Mediated Silencing of Ornithine Decarboxylase and Spermidine Synthase Genes in Trypanosoma brucei Provides Insight into Regulation of Polyamine Biosynthesis

2009

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“…Knockout of the AdoMetDC gene in the trypanosomatid Leishmania donovani led to spermidine auxotropy (11). The suicide inhibitor of AdoMetDC, MDL73811, has demonstrated efficacy in animal models of both T. brucei (12) and a related parasite Trypanosoma cruzi (13), which is the causative agent of Chagas disease. Thus, AdoMetDC is considered a promising, but as yet unexploited target for the development of new anti-trypanosomal drugs.…”

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Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog

Willert

Fitzpatrick²,

Phillips

2007

Proc. Natl. Acad. Sci. U.S.A.

117

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African sleeping sickness is a fatal disease that is caused by the protozoan parasite Trypanosoma brucei. Polyamine biosynthesis is an essential pathway in the parasite and is a validated drug target for treatment of the disease. S-adenosylmethionine decarboxylase (AdoMetDC) catalyzes a key step in polyamine biosynthesis. Here, we show that trypanosomatids uniquely contain both a functional AdoMetDC and a paralog designated prozyme that has lost catalytic activity. The T. brucei prozyme forms a high-affinity heterodimer with AdoMetDC that stimulates its activity by 1,200-fold. Both genes are expressed in T. brucei, and analysis of AdoMetDC activity in T. brucei extracts supports the finding that the heterodimer is the functional enzyme in vivo. Thus, prozyme has evolved to be a catalytically dead but allosterically active subunit of AdoMetDC, providing an example of how regulators of multimeric enzymes can evolve through gene duplication and mutational drift. These data identify a distinct mechanism for regulating AdoMetDC in the parasite that suggests new strategies for the development of parasite-specific inhibitors of the polyamine biosynthetic pathway.gene duplication ͉ S-adenyosylmethionine decarboxylase ͉ prozyme ͉ Trypanosoma brucei

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“…This drug is also effective at killing other genera of protozoan parasites in vitro (1,9,27,49), including Leishmania promastigotes (35,37,41,49,55), and markedly ameliorates but does not eliminate short-term L. donovani infections in mice (30,37,45) and hamsters (42). In addition, inhibitors of a second enzyme in the polyamine pathway, Sadenosylmethionine decarboxylase (ADOMETDC), the enzyme that produces the decarboxylated S-adenosylmethionine substrate for the spermidine synthase (SPDSYN) reaction, are also effectual antitrypanosomal agents (2,3,6,8,9,16,18,58).…”

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Spermidine Synthase Is Required for Virulence of Leishmania donovani

et al. 2011

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Genetic lesions in the polyamine biosynthetic pathway of Leishmania donovani, the causal agent of visceral leishmaniasis, are conditionally lethal mutations that render the insect vector form of the parasite auxotrophic for polyamines. Recently, we have demonstrated that a ⌬odc L. donovani null mutant lacking ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, was profoundly compromised in its ability to infect mice, indicating that ODC is essential for the infectious mammalian stage of the parasite and further validating the enzyme as a possible drug target. To assess whether other components of the polyamine biosynthetic pathway were also essential for parasite virulence, a cell line deficient in spermidine synthase (SPDSYN), the enzyme that converts putrescine to spermidine, was created by double-targeted gene replacement within a virulent L. donovani background. This ⌬spdsyn strain was auxotrophic for polyamines, required spermidine for growth in its insect vector form, and was adversely impacted in its ability to infect mice. These findings establish that SPDSYN, like ODC, is essential for maintaining a robust infection in mammals and indicate that pharmacologic inhibition of SPDSYN, and perhaps all components of the polyamine biosynthetic pathway, is a valid therapeutic strategy for the treatment of visceral and, potentially, other forms of leishmaniasis.

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Cure of murine Trypanosoma brucei rhodesiense infections with an S-adenosylmethionine decarboxylase inhibitor

Cited by 78 publications

References 19 publications

RNA Interference-Mediated Silencing of Ornithine Decarboxylase and Spermidine Synthase Genes in Trypanosoma brucei Provides Insight into Regulation of Polyamine Biosynthesis

RNA Interference-Mediated Silencing of Ornithine Decarboxylase and Spermidine Synthase Genes in Trypanosoma brucei Provides Insight into Regulation of Polyamine Biosynthesis

Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog

Spermidine Synthase Is Required for Virulence of Leishmania donovani

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