Bistability in Glycolysis Pathway as a Physiological Switch in Energy Metabolism

Abstract

The flux of glycolysis is tightly controlled by feed-back and feed-forward allosteric regulations to maintain the body's glucose homeostasis and to respond to cell's growth and energetic needs. Using a mathematical model based on reported mechanisms for the allosteric regulations of the enzymes, we demonstrate that glycolysis exhibits multiple steady state behavior segregating glucose metabolism into high flux and low flux states. Two regulatory loops centering on phosphofructokinase and on pyruvate kinase each gives rise to the bistable behavior, and together impose more complex flux control. Steady state multiplicity endows glycolysis with a robust switch to transit between the two flux states. Under physiological glucose concentrations the glycolysis flux does not move between the states easily without an external stimulus such as hormonal, signaling or oncogenic cues. Distinct combination of isozymes in glycolysis gives different cell types the versatility in their response to different biosynthetic and energetic needs. Insights from the switch behavior of glycolysis may reveal new means of metabolic intervention in the treatment of cancer and other metabolic disorders through suppression of glycolysis.

Low glucose concentrations within typical industrial operating conditions have minimal effect on the transcriptome of recombinant CHO cells

“…Lactate is the principal waste metabolite that can cause growth inhibition and decrease recombinant protein productivity . It has been well‐documented that the metabolic states of CHO cells can be changed to a lower lactate producing state by controlling the glucose concentrations to a lower concentration . RNA‐Seq was used to characterize the impact of the glucose concentration on exponentially growing CHO cells, where the glucose concentration was the only major difference at the time of the comparison.…”

“…24,26,27 It has been well-documented that the metabolic states of CHO cells can be changed to a lower lactate producing state by controlling the glucose concentrations to a lower concentration. 25,[34][35][36]45,62 RNA-Seq was used to characterize the impact of the glucose concentration on exponentially growing CHO cells, where the glucose concentration was the only major difference at the time of the comparison. To achieve these conditions, rCHO DP-12 cells were seeded into a chemically defined medium with initial low (10 mM) and high (30 mM) glucose concentrations at a low cell concentrations to control the glucose depletion and minimize the lactate build-up.…”

“…Other researchers have focused directly on maintaining low glucose concentrations (∼5 mM) via controlled fed‐batch conditions interfaced with nonlinear models . Despite these improvements, there are still biphasic outcomes …”

“…31,33,[40][41][42][43][44] Despite these improvements, there are still biphasic outcomes. 25,35,36,45 In the early studies to control the glucose concentration in fed-batch cultures (pre-2000), high glucose concentrations in the batch phase were used, which resulted in high lactate (> 20 mM) at the end of the batch phase and glutamine build-up. 44 Later, glutamine-limited fed-batch cultures were used to limit lactate, where glucose was severely limited.…”

Heterogeneity of glycolysis in cancers and therapeutic opportunities

“…Better kinetic characterization of glycolytic enzymes especially when isoforms are expressed in parallel can be helpful to elucidate the dynamic behavior of glycolysis in various (tumor) cell types though mathematical modeling using techniques such as Metabolic Control Analysis (MCA)[132, 133] and can find use in in identifying better drug targets[134, 135]. …”