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bioRxiv · 10.1101/2021.05.07.443112

Trade-offs in adaptation to glycolysis and gluconeogenesis result in a preferential flux direction in central metabolism

Schink, S. J.·Christodoulou, D.·Mukherjee, A.·Athaide, E.·Sauer, U.·Basan, M.
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Abstract

Central carbon metabolism is highly conserved across microbial species, but can catalyze very different pathways depending on the organism and their ecological niche. Here, we study the dynamic re-organization of central metabolism after switches between the two major opposing pathway configurations of central carbon metabolism, glycolysis and gluconeogenesis in Escherichia coli, Pseudomonas aeruginosa and Pseudomonas putida. We combined growth dynamics and dynamic changes of intracellular metabolite levels with a coarse-grained model that integrates fluxes, regulation, protein synthesis and growth and uncovered fundamental limitations of the regulatory network: after nutrient shifts, metabolite concentrations collapse to their equilibrium, rendering the cell unable to sense which direction the flux is supposed to flow through the metabolic network. The cell can partially alleviate this by picking a preferred direction of regulation at the expense of increasing lag times in the opposite direction. Moreover, decreasing both lag times simultaneously comes at the cost of reduced growth rate or higher futile cycling between metabolic enzymes. These three trade-offs can explain why microorganisms specialize for either glycolytic or gluconeogenic substrates and can help elucidate the complex growth patterns exhibited by different microbial species. Graphical synopsis O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY Standfirst textMicrobes face a series of fundamental trade-offs that limit their ability to optimize simultaneously for both glycolytic and gluconeogenic growth. Bullet pointsO_LILag times between glycolysis and gluconeogenesis show asymmetry in many microbes: A long lag in one direction, but a short lag in the other. C_LIO_LILong lag times are caused by an inability to sense fluxes after nutrient shifts. C_LIO_LIWith existing regulation, lag time asymmetry can only be overcome by reducing either growth rate or increasing futile cycling in metabolism. C_LI

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Schink, S. J., Christodoulou, D., Mukherjee, A., Athaide, E., Sauer, U., Basan, M.. 2021-05-08. Trade-offs in adaptation to glycolysis and gluconeogenesis result in a preferential flux direction in central metabolism. https://doi.org/10.1101/2021.05.07.443112

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