Regulation of Glycolysis and Gluconeogenesis Flashcards Preview

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Flashcards in Regulation of Glycolysis and Gluconeogenesis Deck (18)
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describe the irreversible steps of glycolysis and gluconeogenesis


describe how glycolysis in skeletal muscle is coupled to glycogen degradation

  • glycolysis starting with glucose from the blood needs hexokinase and ATP to form G6P
  • glycolysis can follow glycogen degradation and use the generated glucose 1-P to form G6P without usage of ATP
  • starting with G6P saves 1 ATP in the glycolysis investment phase and the overall gain of 3 ATP for anaerobic glycolysis is achieved


describe the regulation of glycolysis in skeletal muscle

  • the first regulated enzyme is hexokinase which is activated by glucose provided by GLUT-4 (insulin) and which is inhibited by its accumulating product G6P
  • the committed step of glycolysis is performed by PFK-1 which is inhibited by ATP
    • the inhibition of PFK-1 is overcome by AMP and F2,6-BP formed by PFK-2 activity of the bifunctional enzyme
  • pyruvate kinase is always highly active and does not need feed-forward activation by the committed step of glycolysis


contrast hexokinase and glucokinase

  • hexokinase has a high affinity for glucose
    • very efficient for small amounts of glucose that is saturated with glucose during hypoglycemia
  • glucokinase has a low affinity for glucose 
    • large Vmax which makes it very efficient to phosphorylate large amounts of glucose


how is insulin release regulated?

  • B-cells take up glucose (GLUT-2) and glucokinase forms G6P which is used in oxidative metabolism for ATP formation
    • glucokinase is not product inhibited 
  • Blood glucose levels >5 mM generate a high level of ATP which leads to the closing of ATP-sensitive K channels, which leads to membrane depolarization, calcium influx and triggers insulin release


describe glucokinase deficiency in B-cells of pancreas

  • Genetic deficiency of glucokinase can lead to maturity onset diabetes of the young type 2 (MODY-2) which is characterized by impaired insulin secretion from B-cells
  • results in chronic mild hyperglycemia
  • in MODY-2 patients, a higher blood glucose level (7-8 mM) is needed for insulin release


how is hepatic glucokinase regulated?

  • the hepatic glucokinase regulatory protein (GKRP) transports glucokinase into the nucleus at high levels of F6P and back into the cytosol at high free glucose levels 
  • glucokinase is induced by insulin and is not inhibited by its product G6P


how is PFK-1 regulated

  • PFK-1 catalyzes the committed step of glycolysis and is allosterically inhibited at normal physiological ATP levels in all cells
    • in many cells, ATP is end goal of glycolysis so if ATP levels achieved, it inhibits glycolysis
  • glycolysis provides 1,3-BPG and PEP for SLP and is essential for ATP formation during anoxia or for cells without mt


how is it possible to perform glycolysis in hepatocytes at normal ATP levels

  • the liver has to perform glycolysis after a meal in order to reduce high blood glucose level
  • insulin stimulates glycolysis as it leads to the dephosphorylation of the hepatic bifunctional enzyme
  • PFK-2 is active and forms F2,6-BP that overcomes the inhibition of PFK-1 by ATP


the allosteric inhibition of PFK-1 by ATP is overcome by 1) _____ and 2) ______

  1. AMP
    • formed in skeletal muscle during exercise 
      • glycolysis + glycogenolysis are activated
    • is formed in hepatocytes when ATP declines
      • glycolysis is activated and gluconeogenesis inhibited
  2. Fructose 2,6-BP (only the liver)
    • formed by the bifunctional enzyme in skeletal muscle, heart and liver


describe the feed-forward activation of pyruvate kinase during glycolysis

  • PFK-1 forms F1,6 BP which is a feed-forward activator for pyruvate kinase 
  • F1,6-BP continues in glycolysis but some molecules will allosterically bind to pyruvate kinase
  • pyruvate kinase is normally allosterically inhibited by ATP but F1,6-BP overcomes this inhibition


describe hepatic pyruvate kinase inactivation during gluconeogenesis

  • hepatic pyruvate kinase is inhibited by phosphorylation during gluconeogenesis
    • glucagon -> cAMP -> PKA -> phosphorylates pyruvate kinase leading to inhibition (you want gluconeogenesis, therefore turn off glycolysis enzymes)
  • the inhibition now saves PEP for gluconeogenesis


how is gluconeogenesis regulated?

  • gluconeogenesis is regulated by the availability of energy for the pathway which is mostly provided by degradation of fatty acids
    • B-oxidation provides NADH and acetyl CoA for regulations to inhibit PDH and TCA cycle and stimulate gluconeogenesis 
      • does not provide carbons for glucose formation


describe the substrates for gluconeogenesis

  • glycerol
  • lactate 
  • alanine
  • glutamine


describe insulin vs glucagon regulation of the bifunctional enzyme


name the enzymes that insulin induces the synthesis of

  • the irreversible steps:
    • glucokinase
    • PFK-1
    • pyruvate kinase


name the enzymes that glucagon induces the synthesis of

  • PEP carboxykinase 
  • Fructose 1,6 -bisphosphatase 
  • glucose 6 phosphatase


  • pyruvate carboxylase is needed for gluconeogenesis but is NOT INDUCED by glucagon


give a summary of allosteric effectors of glycolysis and gluconeogenesis