System-level analysis of flux regulation of yeast show that glycolytic flux is controlled by allosteric regulation and enzyme phosphorylation

Abstract

Energy metabolism is central for cellular function and has therefore evolved to be tightly regulated such that energy production can be balanced to energy demand. Energy is being produced in the central carbon metabolism (CCM) and even though there has been extensive studies on how fluxes through the different pathways in this part of metabolism are regulated. There is little understanding of how fluxes are affected by posttranslational modifications and by allosteric regulators. Here we integrated multi-omics data (intracellular metabolome, extracellular metabolome, proteome, phosphoproteome, and fluxome) under 9 different chemostat conditions for building a mathematical model that could map functional regulatory events (FREs) in the Saccharomyces cerevisiae. Using hierarchical analysis combined with the mathematical model, we observed pathway and metabolism-specific flux regulation mechanisms in the CCM. We also found that the glycolytic flux increased with specific growth rate, and this increase was accompanied by a decrease of both metabolites derived FREs and protein phosphorylation level.