ArticleThe Journal of biological chemistry2013
Allosteric activation of trypanosomatid deoxyhypusine synthase by a catalytically dead paralog.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 50 citations in OpenAlex.
- An experimental target-based platform in yeast for screening Plasmodium vivax deoxyhypusine synthase inhibitors.PLoS neglected tropical diseases · 2024Article
- 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
- An X-Domain Phosphoinositide Phospholipase C (PI-PLC-like) ofPathogens (Basel, Switzerland) · 2023Article
- Domain function and predicted structure of three heterodimeric endonuclease subunits of RNA editing catalytic complexes in Trypanosoma brucei.Nucleic acids research · 2022Article
- Metabolic Pathways ofPharmaceutics · 2022Review
- Polyamine Metabolism inMedical sciences (Basel, Switzerland) · 2022Review
- Article
- Development of an activity assay for characterizing deoxyhypusine synthase and its diverse reaction products.FEBS open bio · 2021Article
- Structural features and development of an assay platform of the parasite target deoxyhypusine synthase of Brugia malayi and Leishmania major.PLoS neglected tropical diseases · 2020Article
- Structural Basis of Protein Arginine Methyltransferase Activation by a Catalytically Dead Homolog (Prozyme).Journal of molecular biology · 2020Article
- Editosome RNase III domain interactions are essential for editing and differ between life cycle stages inRNA (New York, N.Y.) · 2019Article
- Multi-Substrate Specificity and the Evolutionary Basis for Interdependence in tRNA Editing and Methylation Enzymes.Frontiers in genetics · 2019Review
- Polyamines in protozoan pathogens.The Journal of biological chemistry · 2018Review
- Polyamine function in archaea and bacteria.The Journal of biological chemistry · 2018Review
- Trypanosomatid Deoxyhypusine Synthase Activity Is Dependent on Shared Active-Site Complementation between Pseudoenzyme Paralogs.Structure (London, England : 1993) · 2018Article
- 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
- The N-terminal methyltransferase homologs NRMT1 and NRMT2 exhibit novel regulation of activity through heterotrimer formation.Protein science : a publication of the Protein Society · 2018Article
- The essential functions of KREPB4 are developmentally distinct and required for endonuclease association with editosomes.RNA (New York, N.Y.) · 2017Article
- The roles of polyamines in microorganisms.World journal of microbiology & biotechnology · 2017Review
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Polyamine biosynthesis is a key drug target in African trypanosomes. The "resurrection drug" eflornithine (difluoromethylornithine), which is used clinically to treat human African trypanosomiasis, inhibits the first step in polyamine (spermidine) biosynthesis, a highly regulated pathway in most eukaryotic cells. Previously, we showed that activity of a key trypanosomatid spermidine biosynthetic enzyme, S-adenosylmethionine decarboxylase, is regulated by heterodimer formation with a catalytically dead paralog (a prozyme). Here, we describe an expansion of this prozyme paradigm to the enzyme deoxyhypusine synthase, which is required for spermidine-dependent hypusine modification of a lysine residue in the essential translation factor eIF5A. Trypanosoma brucei encodes two deoxyhypusine synthase paralogs, one that is catalytically functional but grossly impaired, and the other is inactive. Co-expression in Escherichia coli results in heterotetramer formation with a 3000-fold increase in enzyme activity. This functional complex is also present in T. brucei, and conditional knock-out studies indicate that both DHS genes are essential for in vitro growth and infectivity in mice. The recurrent evolution of paralogous, catalytically dead enzyme-based activating mechanisms may be a consequence of the unusual gene expression in the parasites, which lack transcriptional regulation. Our results suggest that this mechanism may be more widely used by trypanosomatids to control enzyme activity and ultimately influence pathogenesis than currently appreciated.
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