ArticleEukaryotic cell2009
RNA interference-mediated silencing of ornithine decarboxylase and spermidine synthase genes in Trypanosoma brucei provides insight into regulation of polyamine biosynthesis.
Article in Eukaryotic cell, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 46 citations in OpenAlex.
- Polyamine Metabolism for Drug Intervention in Trypanosomatids.Pathogens (Basel, Switzerland) · 2024Review
- The Role of Spermidine and Its Key Metabolites in Important, Pathogenic Human Viruses and in Parasitic Infections Caused byBiomolecules · 2023Review
- Polyamine Metabolism inMedical sciences (Basel, Switzerland) · 2022Review
- A tryparedoxin-coupled biosensor reveals a mitochondrial trypanothione metabolism in trypanosomes.eLife · 2020Article
- Polyamines in protozoan pathogens.The Journal of biological chemistry · 2018Review
- A dual regulatory circuit consisting of S-adenosylmethionine decarboxylase protein and its reaction product controls expression of the paralogous activator prozyme in Trypanosoma brucei.PLoS pathogens · 2018Article
- Alpha-Difluoromethylornithine, an Irreversible Inhibitor of Polyamine Biosynthesis, as a Therapeutic Strategy against Hyperproliferative and Infectious Diseases.Medical sciences (Basel, Switzerland) · 2018Review
- Ornithine uptake and the modulation of drug sensitivity inFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
- Article
- Genetic validation of Trypanosoma brucei glutathione synthetase as an essential enzyme.Eukaryotic cell · 2014Article
- The silicon trypanosome: a test case of iterative model extension in systems biology.Advances in microbial physiology · 2014Review
- Product feedback regulation implicated in translational control of the Trypanosoma brucei S-adenosylmethionine decarboxylase regulatory subunit prozyme.Molecular microbiology · 2013Article
- Mathematical modelling of polyamine metabolism in bloodstream-form Trypanosoma brucei: an application to drug target identification.PloS one · 2013Article
- Untargeted metabolomics reveals a lack of synergy between nifurtimox and eflornithine against Trypanosoma brucei.PLoS neglected tropical diseases · 2012Article
- Polyamine homoeostasis as a drug target in pathogenic protozoa: peculiarities and possibilities.The Biochemical journal · 2011Review
- Spermidine synthase is required for virulence of Leishmania donovani.Infection and immunity · 2011Article
- State of the art in African trypanosome drug discovery.Current topics in medicinal chemistry · 2011Review
- A molecular mechanism for eflornithine resistance in African trypanosomes.PLoS pathogens · 2010Article
- Discovery of potent and selective inhibitors of Trypanosoma brucei ornithine decarboxylase.The Journal of biological chemistry · 2010Article
- A Gateway® compatible vector for gene silencing in bloodstream form Trypanosoma brucei.Molecular and biochemical parasitologyArticle
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
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 alpha-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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