Coordinated Regulation of Glycolysis and Gluconeogenesis

• Simultaneous operation of glycolysis and gluconeogenesis at each of the three bypass points would consume ATP without accomplishing chemical or biological work.
• Regulation of glycolysis and gluconeogenesis prevents wasteful operation of both pathways at the same time
• Which of these pairings is an example of a futile cycle?

  • Oxidative and nonoxidative pentose phosphate pathway
  • Phosphorylation and pyrophosphorylation
  • Oxidation and reduction
  • Glycolysis and gluconeogenesis
  • Glycolysis and glycogenolysis

  Glycolysis and gluconeogenesis. No biological work is done when both glycolysis and gluconeogenesis are active simultaneously. In general, if a molecule is oxidized in a reaction, another molecule in the same reaction is reduced.
• Hexokinases I, II, and III are all inhibited by their product glucose 6-phosphate.
• Hexokinase IV (glucokinase) in the liver is not inhibited by glucose 6-phosphate.
• Glucokinase in the liver has kinetic properties related to its role in maintaining glucose homeostasis.

  • Km is higher than the usual glucose concentration.
• The regulatory protein anchors glucokinase inside the nucleus, where it is segregated from the other glycolytic enzymes.

  • Fructose 6-phosphate is an allosteric effector
  • Glucose causes dissociation of the regulatory protein.
• Hexokinase IV (glucokinase):

  • Is found in muscle and is important for partitioning glucose between glycolysis and gluconeogenesis
  • is inhibited by glucose 6-phosphate
  • is more active when blood glucose concentrations are high
  • has a lower Km for glucose than do other kinases

  is more active when blood glucose concentrations are high. Hexokinase IV has kinetic properties related to is special role in the liver: releasing glucose to the blood when blood glucose is low.
• Which statement comparing hexokinase IV of the liver with hexokinases I, II, and III of muscle is false?

  • Hexokinase IV has a higher Km for glucose
  • Hexokinase IV is not inhibited by glucose 6-phosphate
  • Hexokinase IV is subject to inhibition by the reversible binding of a regulatory protein specific to the liver.
  • Hexokinase is activated by fructose 6-phosphate

  Hexokinase is activated by fructose 6-phosphate. Glucokinase's inhibitor binds much more tightly in the presence of fructose 6-phosphate. Glucose competes with fructose 6-phosphate and causes dissociation of the regulatory protein.
• ATP inhibits phosphofructokinase-1 (PFK-1) by binding to an allosteric site. ADP and AMP allosterically relieve this inhibition by ATP.
• Citrate is a key intermediate in the aerobic oxidation of pyruvate, fatty acids, and amino acids.
• Citrate allosterically regulates PFK-1

  • High concentration increase the inhibitory effect of ATP
  • Serves as an intracellular signal that the cell is meeting its current needs for energy yielding metabolism by the oxidation of fats and proteins.
• High concentrations of AMP, which corresponds to low ATP, inhibits FBPase and slows glucose synthesis.
• High concentrations of ATP slows glycolysis and speeds gluconeogenesis.
• Glucagon is the hormone that signals the liver to produce and release more glucose and to stop consuming it. It is released when blood glucose level decreases.
• Insulin is the hormone that signals the liver to use glucose as a fuel and as a precursor for the storage of glycogen and triacylglycerol. It is released when blood glucose levels increase.
• Phosphofructokinase-1 (PFK-1):

  • converts fructose 6-phosphate to fructose 2,6-bisphosphate
  • is allosterically inhibited by citrate
  • is part of the same polypeptide chain as FBPase-1
  • is indirectly stimulated by glucagon in the liver

  is allosterically inhibited by citrate. High citrate concentration increases the inhibitory effect of ATP, further reducing the flow of glucose through glycolysis.
• Fructose 2,6-bisphosphate mediates the rapid hormonal regulation of glycolysis and gluconeogenesis.

  • Binds to PFK-1 and increases it affinity for fructose 6-phosphate
  • Binds to FBPase-1 and reduces its affinity for its substrate.
• Phosphofructokinase-2 (PFK-2) catalyzes the formation of fructose 2,6-bisphosphate.
• Fructose 2,6-bisphosphate (FBPase-2) catalyzes the breakdown of fructose 2,6-bisphosphate
• It is uncommon for one molecule to acts as both an activator and an inhibitor in metabolism. Which molecules both activates glycolysis and inhibits gluconeogenesis?

  • NAD+
  • ADP
  • Pyruvate
  • Fructose 2,6-bisphosphate
  • Glucose 6-phosphate

  Fructose 2,6-bisphosphate (F26BP) activates PFK-1, stimulating glycolysis. At the same time, F26BP inactivates FBPase-1, inhibiting gluconeogenesis.
• Glucagon, through phosphorylation by cAMP dependent protein kinase, lowers the concentration of fructose 2,6-bisphosphate. This inhibits glycolysis and stimulates gluconeogenesis.
• Insulin, through the removal of the phosphoryl group, increases the concentration of fructose 2,6-bisphosphate. This stimulates glycolysis and inhibits gluconeogenesis.
• Xylulose 5-phosphate is an intermediate of the pentose phosphate pathway that activates phosphoprotein phosphatase 2A.
• Phosphoprotein phosphatase 2A dephosphorylates the bifunctional PFK-2/FBPase-2 enzyme. This causes an increase in fructose 2,6-biphosphate.
• Which statement correctly describes the regulatory role of xylulose 5-phosphate in glucose metabolism?

  • It stimulates glycolysis and inhibits gluconeogenesis
  • It inhibits both glycolysis and gluconeogenesis
  • It stimulates gluconeogenesis and inhibits glycolysis
  • It stimulates both glycolysis and gluconeogenesis

  It stimulates glycolysis and inhibits gluconeogenesis. Xylulose 5-phosphate activates PP2A, which dephosphorylates PFK-2/FBPase-2, thereby increasing F26BP.
• The glycolytic enzyme pyruvate kinase is allosterically inhibited by ATP.
• Conversion of pyruvate to phosphoenolpyruvate is stimulated when fatty acids are available.
• Acetyl CoA signals that further glucose oxidation is not needed.

  • It allosterically stimulates pyruvate carboxylase
  • It allosterically inhibits pyruvate dehydrogenase.
• Insulin transcriptionally regulates more than 150 genes.
• Which statement regarding the transcriptional regulation of PEP carboxykinase is false?

  • Transcription and degradation are the primary means of regulating PEP carboxykinase in mammals
  • A sterol regulatory binding element decreases expression of the PEP carboxykinase gene
  • The promotor region of the PEP carboxykinase gene has binding sites for more than a dozen transcription factors
  • Insulin decreases expression of the PEP carboxykinase gene.


  Insulin decreases the expression of the PEP carboxykinase gene. Insulin transcriptionally decreases expression of PEP carboxykinase.
• Carbohydrate response element binding protein (ChREBP) is a transcription factor expressed in the liver, adipose tissue, and kidney.
• ChREBP acts in the nucleus to regulate gene expression for genes coding for enzymes needed for carbohydrate and fat synthesis.
• Which statement about ChREBP is false?

  • It is primarily expressed in the liver, kidney, and adipose tissue.
  • Removal of a phosphoryl group by cytosolic protein phosphatase PP2A allows it to enter the nucleus.
  • Binding to a promotor inhibits the transcription of pyruvate kinase and fatty acid synthease.
  • Removal of a phosphoryl group by nuclear protein phosphatase PP2A allows it to join with the Mlx protein.

  Binding to a promotor inhibits the transcription of pyruvate kinase and fatty acid synthase.
• Which strategy is not actually applied in the coordinated regulation of carbohydrate metabolism?

  • A change in the expression of metabolic enzymes
  • An allosteric change in the activity of metabolic enzymes
  • A change in the cellular location of existing metabolic enzymes
  • Phosphorylation or dephosphorylation of an enzyme in a metabolic pathway
  • All of these strategies function in cells to regulate carbohydrate metabolism.

  All of these strategies function in cells to regulate carbohydrate metabolism.