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Questions and Answers
Which of the following statements about the regulation of glycolysis is TRUE?
Which of the following statements about the regulation of glycolysis is TRUE?
The presence of both regulatory Loop 1 and Loop 2 in the glycolysis pathway ensures a low glycolytic flux state under physiological glucose concentrations.
The presence of both regulatory Loop 1 and Loop 2 in the glycolysis pathway ensures a low glycolytic flux state under physiological glucose concentrations.
False
What is the function of the ordinary differential equation (ODE) model described?
What is the function of the ordinary differential equation (ODE) model described?
What was the purpose of maintaining the flasks for an additional 12 hours?
What was the purpose of maintaining the flasks for an additional 12 hours?
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What is included in the ODE model to facilitate the analysis of glucose metabolism?
What is included in the ODE model to facilitate the analysis of glucose metabolism?
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How were the supernatants assessed after the collection of samples?
How were the supernatants assessed after the collection of samples?
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What is observed when the [NAD]/[NADH] ratios are very low?
What is observed when the [NAD]/[NADH] ratios are very low?
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What was the concentration of cells inoculated into the wells for the experiment?
What was the concentration of cells inoculated into the wells for the experiment?
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What effect do Loop 1 and Loop 2 have on glycolytic flux states?
What effect do Loop 1 and Loop 2 have on glycolytic flux states?
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What type of model derived from the ODE model helps evaluate steady states?
What type of model derived from the ODE model helps evaluate steady states?
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When the concentration of lactate is varied, what is the effect on the steady state flux profile?
When the concentration of lactate is varied, what is the effect on the steady state flux profile?
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Why were the levels of each enzyme included in the ODE model?
Why were the levels of each enzyme included in the ODE model?
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How does varying alanine concentrations affect the flux state?
How does varying alanine concentrations affect the flux state?
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What analysis method was used to calculate specific rates from the measurement data?
What analysis method was used to calculate specific rates from the measurement data?
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At what glucose concentration does the flux switch to a high state when starting from a low state?
At what glucose concentration does the flux switch to a high state when starting from a low state?
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What happens to the multiplicity of steady states when the physiological range of glucose concentration is present?
What happens to the multiplicity of steady states when the physiological range of glucose concentration is present?
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What is the maximum flux observed under the influence of both Loop 1 and Loop 2?
What is the maximum flux observed under the influence of both Loop 1 and Loop 2?
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What effect does a decrease in glucose concentration have on a high flux state?
What effect does a decrease in glucose concentration have on a high flux state?
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What type of kinetics did the steady state flux of the system follow?
What type of kinetics did the steady state flux of the system follow?
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What was the range of K/P ratios used in the simulations?
What was the range of K/P ratios used in the simulations?
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What analysis technique was used to assess the stability of the steady state solutions?
What analysis technique was used to assess the stability of the steady state solutions?
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How were the initial guesses for the numerical solver generated?
How were the initial guesses for the numerical solver generated?
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Which PFK isozyme was used exclusively in the simulations?
Which PFK isozyme was used exclusively in the simulations?
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What characteristic behavior was observed regarding steady state flux in one set of simulations?
What characteristic behavior was observed regarding steady state flux in one set of simulations?
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What type of data was presented in Figure S7?
What type of data was presented in Figure S7?
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What did the steady state analysis reveal about states in the range of K/P ratios from 5 to 100?
What did the steady state analysis reveal about states in the range of K/P ratios from 5 to 100?
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What role does lactate play in the regulation of glycolytic enzymes?
What role does lactate play in the regulation of glycolytic enzymes?
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Which compound specifically activates phosphofructokinase according to the studies?
Which compound specifically activates phosphofructokinase according to the studies?
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What effect does phosphoenolpyruvate have on ascites tumor phosphofructokinase?
What effect does phosphoenolpyruvate have on ascites tumor phosphofructokinase?
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What is the primary function of phosphofructokinase-2/fructose-2,6-bisphosphatase in cancer metabolism?
What is the primary function of phosphofructokinase-2/fructose-2,6-bisphosphatase in cancer metabolism?
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Which molecule is known to inhibit the kinase activity of human brain 6-phosphofructo-2-kinase?
Which molecule is known to inhibit the kinase activity of human brain 6-phosphofructo-2-kinase?
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Which of these is a focus of the model concerning 2,3-bisphosphoglycerate metabolism?
Which of these is a focus of the model concerning 2,3-bisphosphoglycerate metabolism?
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What type of regulatory mechanism is associated with the enzymatic control of glycolysis?
What type of regulatory mechanism is associated with the enzymatic control of glycolysis?
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What is one function of the TIGAR protein in cellular metabolism?
What is one function of the TIGAR protein in cellular metabolism?
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Which cellular location is primarily associated with the function of mammalian hexokinase isozymes?
Which cellular location is primarily associated with the function of mammalian hexokinase isozymes?
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Which variable is associated with the regulation of 6-phosphofructo-2-kinase activity?
Which variable is associated with the regulation of 6-phosphofructo-2-kinase activity?
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What impact does the K/P ratio of PFKFB have on glycolytic flux?
What impact does the K/P ratio of PFKFB have on glycolytic flux?
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How does fructose diphosphate affect phosphofructokinase from skeletal muscle?
How does fructose diphosphate affect phosphofructokinase from skeletal muscle?
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What is a significant impact of the small-molecule inhibition of 6-phosphofructo-2-kinase on cellular processes?
What is a significant impact of the small-molecule inhibition of 6-phosphofructo-2-kinase on cellular processes?
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Which of the following is a characteristic of the Warburg effect?
Which of the following is a characteristic of the Warburg effect?
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What is the main function of fructose-2,6-bisphosphate in glucose metabolism?
What is the main function of fructose-2,6-bisphosphate in glucose metabolism?
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What role does the M2 splice isoform of pyruvate kinase play in cancer?
What role does the M2 splice isoform of pyruvate kinase play in cancer?
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Which statement correctly describes the role of phosphofructokinase in glycolysis?
Which statement correctly describes the role of phosphofructokinase in glycolysis?
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Which process is tyrosine phosphorylation associated with in relation to PKM2?
Which process is tyrosine phosphorylation associated with in relation to PKM2?
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What is one function of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in cancer cells?
What is one function of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in cancer cells?
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What is the mechanism of action for Akt/PKB in early apoptotic events?
What is the mechanism of action for Akt/PKB in early apoptotic events?
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What does the positive-feedback-based bistable 'memory module' govern in cellular biology?
What does the positive-feedback-based bistable 'memory module' govern in cellular biology?
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What is the impact of glucagon on pyruvate kinase in hepatocytes?
What is the impact of glucagon on pyruvate kinase in hepatocytes?
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Which factor induces over-expression of specific glycolytic isoforms in cancer cells?
Which factor induces over-expression of specific glycolytic isoforms in cancer cells?
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What is a key feature of the glycolytic isoform switch in cancer metabolism?
What is a key feature of the glycolytic isoform switch in cancer metabolism?
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Study Notes
Bistability in Glycolysis Pathway
- Glycolysis is tightly regulated by feedback and feed-forward allosteric mechanisms to maintain glucose homeostasis and respond to cellular needs.
- Mathematical modeling shows glycolysis can exist in multiple steady states (high and low flux).
- Two regulatory loops (phosphofructokinase and pyruvate kinase) create this bistability and control flux.
- Cells switch between flux states with external stimuli (hormones, signals, oncogenic cues).
- Different cell types express unique combinations of glycolytic isozymes, influencing their response to energy and biosynthetic needs.
- Metabolic intervention, targeting glycolysis, may treat metabolic disorders and cancer.
Introduction
- Glycolysis is a central glucose metabolism pathway for energy production and biosynthesis.
- Cancer cells have high glycolytic flux and high lactate production (Warburg effect).
- Highly proliferative tissues (fetal/stem) also exhibit high glycolytic rates.
- Quiescent cells have low glucose uptake and catabolize glucose to CO2.
- Allosteric regulation by metabolites (fructose-1,6-bisphosphate (F16BP), fructose-2,6-bisphosphate (F26BP), and phosphoenolpyruvate (PEP)) on enzymes (phosphofructokinase (PFK), pyruvate kinase (PK), phosphofructokinase/fructose-2,6-bisphosphatase (PFKFB)) are crucial.
- Multiple isozymes of these enzymes exist, allowing for diverse regulatory behavior in different cell types.
Results
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Bistability in the F6P-node:
- Phosphofructokinase (PFK) isozymes (muscle, liver, platelet) have varying F16BP feedback activation sensitivities.
- Without F16BP activation, PFK kinetics resembles Michaelis-Menten.
- With F16BP activation (e.g., PFKL/M), bistable PFK flux behavior occurs (low and high flux states).
- Stable PFK flux shifts sharply between states as glucose concentrations change.
- F6P concentration ranges cause bistable behavior.
- The K/P ratio (kinase/bisphosphatase activity) of PFKFB modulates bistability span, affecting the switch-up/switch-down F6P concentrations.
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Bistable Behavior in Glycolysis:
- Two regulatory loops (Loop 1 and Loop 2) from PFK, PFKFB and PK determine flux through the whole glycolysis pathway.
- Without either regulatory loop, glycolysis flux exhibits Michaelis-Menten kinetics or no real bistability.
- With only Loop 1, glycolysis flux increases.
- By varying the K/P ratio, steady state fluxes shift and show bistability.
- Cell isozyme expression and combination determine glycolysis response.
Bistability in Cultured Cells
- HeLa cells exhibit bistable glucose metabolism.
- Glucose consumption rate shifts between high and low when exposed to different glucose concentrations.
- Lactate production rate mirrors this pattern.
- The initial metabolic state (e.g., high or low glucose conditions) of the cells determines the response to subsequent glucose changes.
PFKFB Modulates Metabolic Switch
- Four PFKFB isoforms with different K/P ratios influence response time.
- Isozyme expression levels do not affect steady-state fluxes directly.
- Changes in K/P ratio influence the flux state switching, allowing quick adjustments to energetic demands.
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Description
Explore the complex regulation of glycolysis through feedback and feed-forward mechanisms, vital for glucose homeostasis. This quiz delves into the mathematical modeling of bistability and its implications for different cell types and potential metabolic interventions.
