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The relationship between sequence variation and phenotype is poorlyunderstood. Here we use metabolomic analysis to elucidate the molecularmechanism underlying the filamentous phenotype of E. coli strains that carrydestabilizing mutations in the Dihydrofolate Reductase (DHFR). We find thatpartial loss of DHFR activity causes SOS response indicative of DNA damage andcell filamentation. This phenotype is triggered by an imbalance in deoxynucleotide levels, most prominently a disproportionate drop in theintracellular dTTP. We show that a highly cooperative (Hill coefficient 2.5) invivo activity of Thymidylate Kinase (Tmk), a downstream enzyme thatphosphorylates dTMP to dTDP, is the cause of suboptimal dTTP levels. dTMPsupplementation in the media rescues filamentation and restores in vivo Tmkkinetics to almost perfect Michaelis-Menten, like its kinetics in vitro.Overall, this study highlights the important role of cellular environment insculpting enzymatic kinetics with system level implications for bacterialphenotype.

Metabolic response to point mutations reveals principles of modulation of in vivo enzyme activity and phenotype