ArticleMolecular systems biology2021
Metabolic response to point mutations reveals principles of modulation of in vivo enzyme activity and phenotype.
Article in Molecular systems biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
6 citing papers in PubMed, 15 citations in OpenAlex.
- Conserved interfaces mediate multiple protein-protein interactions in a prokaryotic metabolon.Molecular systems biology · 2025Article
- Patient-derived cornea organoid model to study metabolomic characterization of rare disease: aniridia-associated keratopathy.BMC ophthalmology · 2025Article
- Combining systems and synthetic biology for in vivo enzymology.The EMBO journal · 2024Article
- Empowering drug off-target discovery with metabolic and structural analysis.Nature communications · 2023Article
- Development of antibacterial compounds that constrain evolutionary pathways to resistance.eLife · 2021Article
- Metabolic response to point mutations reveals principles of modulation of in vivo enzyme activity and phenotype.Molecular systems biology · 2021Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
The relationship between sequence variation and phenotype is poorly understood. Here, we use metabolomic analysis to elucidate the molecular mechanism underlying the filamentous phenotype of E. coli strains that carry destabilizing mutations in dihydrofolate reductase (DHFR). We find that partial loss of DHFR activity causes reversible filamentation despite SOS response indicative of DNA damage, in contrast to thymineless death (TLD) achieved by complete inhibition of DHFR activity by high concentrations of antibiotic trimethoprim. This phenotype is triggered by a disproportionate drop in intracellular dTTP, which could not be explained by drop in dTMP based on the Michaelis-Menten-like in vitro activity curve of thymidylate kinase (Tmk), a downstream enzyme that phosphorylates dTMP to dTDP. Instead, we show that a highly cooperative (Hill coefficient 2.5) in vivo activity of Tmk is the cause of suboptimal dTTP levels. dTMP supplementation rescues filamentation and restores in vivo Tmk kinetics to Michaelis-Menten. Overall, this study highlights the important role of cellular environment in sculpting enzymatic kinetics with system-level implications for bacterial phenotype.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.