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Coordinated regulation of glycolysis/gluconeogenesis

Coordinated regulation of glycolysis/gluconeogenesis. High blood glucose. Insulin secretion. Synthesis of hexokinase II, PFK-1, pyruvate kinase. Movement of GLUT4 to plasma membrane of myocyte. Activation of insulin-sensitive protein kinase. Activation of protein kinase B. p.903. p.887.

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Coordinated regulation of glycolysis/gluconeogenesis

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  1. Coordinated regulation of glycolysis/gluconeogenesis

  2. High blood glucose Insulin secretion Synthesis of hexokinase II, PFK-1, pyruvate kinase Movement of GLUT4 to plasma membrane of myocyte Activation of insulin-sensitive protein kinase Activation of protein kinase B

  3. p.903

  4. p.887

  5. Glucose p.903 Glucose GLUT2 Pancreatic b cell Glucose Glycolysis pyruvate Citric acid cycle NADH,FADH2 Oxidative phosphorylation ATP closed K+ Ca2+ ATP-gated K+ channel - - - - - - - Open + + + + + + + - - - - - - - Insulin secretion + + + + + + + Voltage-dep. Ca2+ channel Membrane depolarization Ca2+

  6. Insulin GLUT4 p.396 Movement of GLUT4 to plasma membrane of myocyte Glc Glc Glc Glc Glc Glc Glc Glc Glc Glc Insulin receptor Cytosol of myocyte

  7. p. 588 Glycogen phosphorylase GM Phosphorylase kinase Glycogen synthase b Activation of insulin-sensitive kinase Insulin Insulin receptor Insulin- sensitive kinase Insulin- sensitive kinase GM Glycogen synthase a Glycogen phosphorylase PP1 PP1 Phosphorylase kinase Glycogen synthesis  Glycogen degradation 

  8. p.587 IRS-1 GSK-3 Glycogen synthase b Activation of protein kinase B (PKB) Insulin Insulin receptor PIP2 PI3-K PI3-K PIP3 PDK-1 PDK-1 PKB PKB IRS-1 GSK-3 GSK-3 Glycogen synthase a Glycogen synthase a Glycogen synthesis

  9. GSK3 GSK3 p.587 GSK3 inactivate glycogen synthase by phosphorylation Phosphorylation by Casein kinase II P P P P

  10. p.587 GSK3 can be inactivated by phosphorylation PKB P P

  11. Hexokinase IV Regulator protein Glc Regulator protein Regulator protein Fru Fru Fru p.578 High blood glucose affect hexokinase IV activity Glc nucleus Glc Hexokinase IV Glc GLUT2 Hexokinase IV Regulator protein Glc Glc Glc Glc Glc Glc Glc Hepatocyte

  12. Fru Fru F6P F6P Fru Fru Fru F1,6BP F2,6BP F2,6BP PFK-2 FBPase-2 Insulin regulate PFK-1 activity Insulin Insulin receptor Phosphoprotein phosphatase Phosphoprotein phosphatase PFK-2 FBPase-2 FBPase-1 FBPase-1 PFK-1 PFK-1 PFK-2 FBPase-2

  13. Low blood glucose Glucagon secretion Inactivation of pyruvate kinase L (liver form) Activation of FBPase-2 and inactivation of PFK-2 Inactivation of glycogen synthase Activation of glycogen phosphorylase

  14. glucagon GDP a GTP a GM Pyruvate kinase L GM PFK-2 FBPase-2 p.436 Regulation pathway initiated by glucagon secretion Glucagon receptor Glucagon receptor Adenylyl cyclase Adenylyl cyclase b cAMP g ATP Protein kinase A Protein kinase A Pyruvate kinase L PFK-2 FBPase-2

  15. Fru Fru F6P F6P Fru Fru Fru F1,6BP F2,6BP F2,6BP PFK-2 FBPase-2 Regulation of PFK-1 by glucagon Protein kinase A Protein kinase A PFK-1 PFK-1 FBPase-1 FBPase-1 PFK-2 FBPase-2

  16. p. 588 Inhibitor-1 Glycogen phosphorylase GM Phosphorylase kinase GM Inhibitor-1 Glycogen synthase b Regulation of glycogen synthesis and breakdown by glucagon Protein kinase A Protein kinase A Glycogen synthase a Glycogen phosphorylase PP1 PP1 Phosphorylase kinase Glycogen synthesis  Glycogen degradation 

  17. Hexokinase • There are four isozymes (I, II, III and IV) of hexokinase encoded by four different genes. • Hexokinase I and II are allosterically inhibited by their product, glucose 6-phosphate. Hexokinase IV is not inhibited by G-6-P.

  18. Hexokinase • Hexokinase I and II are the predominant forms existing in muscle. Hexokinase IV is the predominant form in liver. • Hexokinase I and II will be half-saturated at about 0.1mM, but hexokinase IV will not be half-saturated until 10mM.

  19. Hexokinase • Hexokinase has different functions in liver and muscle. • Muscle consumes glucose, using it for energy production. • Liver maintains blood glucose homeostasis by removing or producing glucose.

  20. Muscle hexokinase • Because blood glucose concentration is about 4 to 5 mM, hexokinase in the muscle (which will be half saturated at 0.1mM) is always working at or near its maximal rate.

  21. Liver hexokinase • However, liver hexokinase (half-saturated at 10mM) will not ever reach its maximal rate even after meal.

  22. Phosphofructokinase-1 • PFK-1 catalyze the committing step of glycolysis. • This enzyme is regulated by ATP, AMP, ADP, citrate and fructose 2,6-bisphosphate.

  23. ATP regulate the affinity of PFK-1 towards its substrate F-6-P • Not only as a substrate, ATP is also one of the end product of the glycolytic pathway. • ATP inhibit PFK-1 by binding to an allosteric site and lowering the affinity of the enzyme for F-6-P.

  24. Molecules regulate PFK-1 and FBPase-1 activity ATP citrate PFK-1 PFK-1 PFK-1 FBPase-1 ADP AMP F2.6BP • ADP and AMP relieve the inhibition by ATP. • Citrate increases the inhibitory effect of ATP. • F-2,6-BP is the strongest activator of PFK-1.

  25. Regulation of gluconeogenesis Pyruvate carboxylase FBPase-1

  26. Pyruvate carboxylase • Pyruvate carboxylase is being positively regulated by acetyl-CoA. • The accumulation of acetyl-CoA signals that cell’s energy demands are met. • Acetyl-CoA also indirectly inhibit pyruvate dehydrogenase complex.

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