PT  - JOURNAL ARTICLE
AU  - Severin Schink
AU  - Dimitris Christodoulou
AU  - Avik Mukherjee
AU  - Edward Athaide
AU  - Uwe Sauer
AU  - Markus Basan
TI  - Trade-offs in adaptation to glycolysis and gluconeogenesis result in a preferential flux direction in central metabolism
AID  - 10.1101/2021.05.07.443112
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.05.07.443112
4099  - http://biorxiv.org/content/early/2021/05/08/2021.05.07.443112.short
4100  - http://biorxiv.org/content/early/2021/05/08/2021.05.07.443112.full
AB  - Microbes exhibit an astounding phenotypic diversity, including large variations in growth rates and their ability to adapt to sudden changes in conditions. Understanding such fundamental traits based on molecular mechanisms has largely remained elusive due to the complexity of the underlying metabolic and regulatory network. Here, we study the two major opposing flux configurations of central carbon metabolism, glycolysis and gluconeogenesis using a coarse-grained kinetic model. Our model captures a remarkable self-organization of metabolism in response to nutrient availability: key regulatory metabolites respond to the directionality of flux and adjust activity and expression levels of metabolic enzymes to efficiently guide flux through the metabolic network. The model recapitulates experimentally observed temporal dynamics of metabolite concentrations, enzyme abundances and growth rates during metabolic shifts. In addition, it reveals a fundamental limitation of flux based sensing: after nutrient shifts, metabolite levels collapse and the cell becomes ‘blind’ to direction of flux. The cell can partially overcome this limitation at the cost of three trade-offs between lag times, growth rates and metabolic futile cycling that constrain the efficiency of self-organization after nutrient shifts. We show that these trade-offs impose a preferential flux direction and can explain the glycolysis preference observed for Escherichia coli, Saccharomyces cerevisiae and Bacillus subtilis, which only shift fast to glycolysis, but slow to gluconeogenisis Remarkably, as predicted from the model, we experimentally confirmed this preference could also be reversed in different species. Indeed, P. aeruginosa shows precisely the opposite phenotypic patterns, switching very quickly to gluconeogenesis, but showing multi-hour lag times that sharply increase with pre-shift growth rate in shifts to glycolysis. These trade-offs between opposing flux directions can explain specialization of microorganisms for either glycolytic or gluconeogenic substrates and can help elucidate the complex phenotypic patterns exhibited by different microbial species.Competing Interest StatementThe authors have declared no competing interest.