Regulation of glycolytic flux and overflow metabolism depending on the source of energy generation for energy demand.

Overflow metabolism is a common phenomenon observed at higher glycolytic flux in many bacteria, yeast (known as Crabtree effect), and mammalian cells including cancer cells (known as Warburg effect). This phenomenon has recently been characterized as the trade-offs between protein costs and enzyme efficiencies based on coarse-graining approaches. Moreover, it has been recognized that the glycolytic flux increases as the source of energy generation changes from energetically efficient respiration to inefficient respiro-fermentative or fermentative metabolism causing overflow metabolism. It is highly desired to clarify the metabolic regulation mechanisms behind such phenomena. Metabolic fluxes are located on top of the hierarchical regulation systems, and represent the outcome of the integrated response of all levels of cellular regulation systems. In the present article, we discuss about the different levels of regulation systems for the modulation of fluxes depending on the growth rate, growth condition such as oxygen limitation that alters the metabolism towards fermentation, and genetic perturbation affecting the source of energy generation from respiration to respiro-fermentative metabolism in relation to overflow metabolism. The intracellular metabolite of the upper glycolysis such as fructose 1,6-bisphosphate (FBP) plays an important role not only for flux sensing, but also for the regulation of the respiratory activity either directly or indirectly (via transcription factors) at higher growth rate. The glycolytic flux regulation is backed up (enhanced) by unphosphorylated EIIA and HPr of the phosphotransferase system (PTS) components, together with the sugar-phosphate stress regulation, where the transcriptional regulation is further modulated by post-transcriptional regulation via the degradation of mRNA (stability of mRNA) in Escherichia coli. Moreover, the channeling may also play some role in modulating the glycolytic cascade reactions.