ArticleMolecular microbiology2015
GMP synthase is essential for viability and infectivity of Trypanosoma brucei despite a redundant purine salvage pathway.
Article in Molecular microbiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 33 citations in OpenAlex.
- De novo or Salvage? Nucleotide Availability as a Driver of Bacterial Adaptation and Virulence.MicrobiologyOpen · 2026Review
- ExploringAntimicrobial agents and chemotherapy · 2026Article
- Energy metabolism inmBio · 2025Review
- GMP Synthetase: Allostery, Structure, and Function.Biomolecules · 2023Review
- Kinetic and Structural Characterization ofBiochemistry · 2023Article
- Tertiary and Quaternary Structure Organization in GMP Synthetases: Implications for Catalysis.Biomolecules · 2022Article
- Inosine triphosphate pyrophosphatase from Trypanosoma brucei cleanses cytosolic pools from deaminated nucleotides.Scientific reports · 2022Article
- Discovery of Novel GMPS Inhibitors ofBiology · 2021Article
- Acyclic nucleoside phosphonates with adenine nucleobase inhibit Trypanosoma brucei adenine phosphoribosyltransferase in vitro.Scientific reports · 2021Article
- Glutamine Analogues Impair Cell Proliferation, the Intracellular Cycle and Metacyclogenesis inMolecules (Basel, Switzerland) · 2020Article
- Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness.Nature communications · 2019Article
- Transcriptional responses of Leishmania (Leishmania) amazonensis in the presence of trivalent sodium stibogluconate.Parasites & vectors · 2019Article
- Mapping the metabolism of five amino acids in bloodstream formBioscience reports · 2019Article
- Search of Allosteric Inhibitors and Associated Proteins of an AKT-International journal of molecular sciences · 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
- Comparative proteomic analysis reveals the regulatory network of theBioscience reports · 2018Article
- The Uptake and Metabolism of Amino Acids, and Their Unique Role in the Biology of Pathogenic Trypanosomatids.Pathogens (Basel, Switzerland) · 2018Review
- Evaluation of the Trypanosoma brucei 6-oxopurine salvage pathway as a potential target for drug discovery.PLoS neglected tropical diseases · 2018Article
- Synthesis and evaluation of analogs of 5'-(((Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (MDL 73811, or AbeAdo) - An inhibitor of S-adenosylmethionine decarboxylase with antitrypanosomal activity.Bioorganic & medicinal chemistry · 2017Article
- Identification of Trypanosoma brucei AdoMetDC Inhibitors Using a High-Throughput Mass Spectrometry-Based Assay.ACS infectious diseases · 2017Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
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Abstract
The causative agent of human African trypanosomiasis, Trypanosoma brucei, lacks de novo purine biosynthesis and depends on purine salvage from the host. The purine salvage pathway is redundant and contains two routes to guanosine-5'-monophosphate (GMP) formation: conversion from xanthosine-5'-monophosphate (XMP) by GMP synthase (GMPS) or direct salvage of guanine by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). We show recombinant T. brucei GMPS efficiently catalyzes GMP formation. Genetic knockout of GMPS in bloodstream parasites led to depletion of guanine nucleotide pools and was lethal. Growth of gmps null cells was only rescued by supraphysiological guanine concentrations (100 μM) or by expression of an extrachromosomal copy of GMPS. Hypoxanthine was a competitive inhibitor of guanine rescue, consistent with a common uptake/metabolic conversion mechanism. In mice, gmps null parasites were unable to establish an infection demonstrating that GMPS is essential for virulence and that plasma guanine is insufficient to support parasite purine requirements. These data validate GMPS as a potential therapeutic target for treatment of human African trypanosomiasis. The ability to strategically inhibit key metabolic enzymes in the purine pathway unexpectedly bypasses its functional redundancy by exploiting both the nature of pathway flux and the limited nutrient environment of the parasite's extracellular niche.
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