Evolutionary dynamics determines adaptation to inactivation of an essential gene

Rodrigues, João V.; Shakhnovich, E. I.

doi:10.1101/552240

Cited by 2 publications

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“…Kwon et al (Kwon et al, 2010) have shown that inhibition of intracellular DHFR with very high concentration of TMP (6μg/ml) incurs large metabolic changes in the cell, with drop in glycine, methionine, purines and thymine levels. Similar data have been reported for engineered E. coli cells containing inactive mutants of DHFR (Rodrigues and Shakhnovich, 2019). However, as discussed in the previous section ( Figure 2E), we found that cells treated with high concentrations of TMP were phenotypically (with regard to cell length) very different than those treated with sub lethal concentrations.…”

Section: Filamentous Strains Have Imbalance Between Dttp and Other Desupporting

confidence: 91%

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

Bhattacharyya

Bershtein

Adkar

et al. 2019

Preprint

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Understanding genotype-phenotype relationship is a central problem in modern biology. Here we report that several destabilizing mutations in E. coli Dihydrofolate Reductase (DHFR) enzyme result in pronounced yet reversible filamentation of bacterial cells. We find that drop in DHFR activity in the mutants results in massive metabolic shifts leading to significant excess of dUMP and dCTP in the pyrimidine biosynthesis pathway. Both deoxyribonucleotides inhibit downstream essential enzyme Thymidylate Kinase (Tmk) which phosphorylates dTMP, eventually leading to almost complete loss of the DNA building block dTTP. Severe imbalance in deoxyribonucleotide levels ultimately leads to DNA damage, SOS response and filamentation. Supplementation of dTMP in the medium competitively alleviates Tmk inhibition and rescues filamentation, thereby illustrating a classic case of enzyme inhibition by structural mimic of its cognate ligand. Overall, this study highlights the complex interconnected nature of the metabolic network, and the fundamental role of folate metabolism in shaping the cell.

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Section: Filamentous Strains Have Imbalance Between Dttp and Other Desupporting

confidence: 91%

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

Bhattacharyya

Bershtein

Adkar

et al. 2019

Preprint

Self Cite

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A two-enzyme adaptive unit within bacterial folate metabolism

Schober

Ingle

Park

et al. 2017

Preprint

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2The ability to predict cell behavior is complicated by an unknown pattern of functional interdependence among genes. Here, we use the conservation of gene proximity across species (synteny) to infer functional couplings between genes. For the folate metabolic pathway, we observe a sparse, modular architecture of interactions, with two small groups of genes coevolving in the midst of others that evolve independently. For one such module -dihydrofolate reductase and thymidylate synthase -we use epistasis measurements and forward evolution to demonstrate both internal functional coupling and independence from the remainder of the genome. Mechanistically, the coupling is driven by a constraint on their relative activities, which must be balanced to prevent accumulation of a metabolic intermediate. The results indicate an organization of cellular systems not apparent from inspection of biochemical pathways or physical complexes, and support the strategy of using evolutionary information to decompose cellular systems into functional units. Keywords:co-evolution, statistical genomics, folate metabolism, dihydrofolate reductase (DHFR), epistasis, experimental evolution . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/120006 doi: bioRxiv preprint first posted online Mar. 23, 2017; 3 IntroductionThe activity of one gene is often modified by the activity of other genes in the genome.This functional coupling between genes makes it difficult to predict cellular behavior as a whole from measurements of each gene (or protein) taken independently. As a consequence, our ability to rationally engineer new metabolic systems (Kim and Copley, 2012; Michener et al., 2014a; Michener et al., 2014b), and quantify the relationship between mutations and disease (Kondrashov et al., 2002; Zuk et al., 2012) is limited. Further, this interdependency amongst genes makes it non-trivial to understand how complex cellular systems are possible through an evolutionary process of stepwise variation with selection (Breen et al., 2012; Wagner and Altenberg, 1996; Weinreich et al., 2013). Thus, an ability to globally map functional couplings between genes and subsequently decompose cellular systems into quasi-independent moduleseach module consisting of several genes engaged in cooperative function -would help render biological systems tractable and predictable.However, it remains unclear if such a modular decomposition is possible, and if so, what the general strategy should be for finding it. A fundamental aspect of this problem is to distinguish functional couplings associated with core, conserved processes from those couplings that reflect species and/or environment specific adaptations. In this sense, we seek a general description of genetic interactions that can serve as a basis for guiding targeted experiments and modeling cellular systems. Here, we develop a map of pairwise gene interactions through ...

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Evolutionary dynamics determines adaptation to inactivation of an essential gene

Cited by 2 publications

References 40 publications

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

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

A two-enzyme adaptive unit within bacterial folate metabolism

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