ArticleThe Biochemical journal2008
Validation of spermidine synthase as a drug target in African trypanosomes.
Article in The Biochemical journal, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 52 citations in OpenAlex.
- Polyamine Metabolism for Drug Intervention in Trypanosomatids.Pathogens (Basel, Switzerland) · 2024Review
- Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies.International journal of molecular sciences · 2023Review
- Discovery of a HiddenACS omega · 2023Article
- The Role of Spermidine and Its Key Metabolites in Important, Pathogenic Human Viruses and in Parasitic Infections Caused byBiomolecules · 2023Review
- Identification of small molecule enzyme inhibitors as broad-spectrum anthelmintics.Scientific reports · 2019Article
- Polyamines in protozoan pathogens.The Journal of biological chemistry · 2018Review
- Ornithine uptake and the modulation of drug sensitivity inFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
- In silico, in vitro, X-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for Chagas disease.Scientific reports · 2017Article
- Discovery of novel polyamine analogs with anti-protozoal activity by computer guided drug repositioning.Journal of computer-aided molecular design · 2016Article
- Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids.PLoS neglected tropical diseases · 2016Article
- Mathematical modelling of polyamine metabolism in bloodstream-form Trypanosoma brucei: an application to drug target identification.PloS one · 2013Article
- Polyamine homoeostasis as a drug target in pathogenic protozoa: peculiarities and possibilities.The Biochemical journal · 2011Review
- State of the art in African trypanosome drug discovery.Current topics in medicinal chemistry · 2011Review
- Target validation: linking target and chemical properties to desired product profile.Current topics in medicinal chemistry · 2011Review
- Cross-species activation of trypanosome S-adenosylmethionine decarboxylase by the regulatory subunit prozyme.Molecular and biochemical parasitology · 2009Article
- RNA interference-mediated silencing of ornithine decarboxylase and spermidine synthase genes in Trypanosoma brucei provides insight into regulation of polyamine biosynthesis.Eukaryotic cell · 2009Article
- Regulated expression of an essential allosteric activator of polyamine biosynthesis in African trypanosomes.PLoS pathogens · 2008Article
- In vitro antileishmanial, trypanocidal, and Mammalian cell activities of diverse n,n' -dihetaryl substituted diamines and related compounds.Scientia pharmaceuticaArticle
- In-silico gene co-expression network analysis in Paracoccidioides brasiliensis with reference to haloacid dehalogenase superfamily hydrolase gene.Journal of pharmacy & bioallied sciencesArticle
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
The trypanocidal activity of the ODC (ornithine decarboxylase) inhibitor DFMO (difluoromethylornithine) has validated polyamine biosynthesis as a target for chemotherapy. As DFMO is one of only two drugs used to treat patients with late-stage African trypanosomiasis, the requirement for additional drug targets is paramount. Here, we report the biochemical properties of TbSpSyn (Trypanosoma brucei spermidine synthase), the enzyme immediately downstream of ODC in this pathway. Recombinant TbSpSyn was purified and shown to catalyse the formation of spermidine from putrescine and dcSAM (decarboxylated S-adenosylmethionine). To determine the functional importance of TbSpSyn in BSF (bloodstream form) parasites, we used a tetracycline-inducible RNAi (RNA interference) system. Down-regulation of the corresponding mRNA correlated with a decrease in intracellular spermidine and cessation of growth. This phenotype could be complemented by expressing the SpSyn (spermidine synthase) gene from Leishmania major in cells undergoing RNAi, but could not be rescued by addition of spermidine to the medium due to the lack of a spermidine uptake capacity. These results therefore genetically validate TbSpSyn as a target for drug development and indicate that in the absence of a functional biosynthetic pathway, BSF T. brucei cannot scavenge sufficient spermidine from their environment to meet growth requirements.
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