Archive ouverte HAL - A Two-Enzyme Adaptive Unit within Bacterial Folate Metabolism

A Two-Enzyme Adaptive Unit within Bacterial Folate Metabolism

Abstract : Enzyme function and evolution are influenced by the larger context of a metabolic pathway. Deleterious mutations or perturbations in one enzyme can often be compensated by mutations to others. We used comparative genomics and experiments to examine evolutionary interactions with the essential metabolic enzyme dihydrofolate reductase (DHFR). Analyses of synteny and co-occurrence across bacterial species indicate that DHFR is coupled to thymidylate synthase (TYMS) but relatively independent from the rest of folate metabolism. Using quantitative growth rate measurements and forward evolution in Escherichia coli, we demonstrate that the two enzymes adapt as a relatively independent unit in response to antibiotic stress. Metabolomic profiling revealed that TYMS activity must not exceed DHFR activity to prevent the depletion of reduced folates and the accumulation of the intermediate dihydrofolate. Comparative genomics analyses identified >200 gene pairs with similar statistical signatures of modular co-evolution, suggesting that cellular pathways may be decomposable into small adaptive units.
Type de document :
Article dans une revue
Liste complète des métadonnées

https://hal.archives-ouvertes.fr/hal-02283154
Contributeur : Catherine Zoppis <>
Soumis le : mardi 10 septembre 2019 - 15:12:15
Dernière modification le : mardi 24 septembre 2019 - 16:22:05

Lien texte intégral

Identifiants

Collections

Citation

A.F. Schober, A.D. Mathis, C. Ingle, J.O. Park, Lin Chen, et al.. A Two-Enzyme Adaptive Unit within Bacterial Folate Metabolism. Cell Reports , Elsevier Inc, 2019, 27 (11), pp.3359-3370.e7. ⟨10.1016/j.celrep.2019.05.030⟩. ⟨hal-02283154⟩

Partager

Métriques

Consultations de la notice

16