A Two-Enzyme Adaptive Unit within Bacterial Folate Metabolism.

TitleA Two-Enzyme Adaptive Unit within Bacterial Folate Metabolism.
Publication TypeJournal Article
Year of Publication2019
AuthorsSchober, AF, Mathis, AD, Ingle, C, Park, JO, Chen, L, Rabinowitz, JD, Junier, I, Rivoire, O, Reynolds, KA
JournalCell Rep
Volume27
Issue11
Pagination3359-3370.e7
Date Published2019 Jun 11
ISSN2211-1247
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.

DOI10.1016/j.celrep.2019.05.030
Alternate JournalCell Rep
PubMed ID31189117