Coordinated regulation of glycolysis/gluconeogenesis

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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. - PowerPoint PPT Presentation

Text of Coordinated regulation of glycolysis/gluconeogenesis

  • Coordinated regulation of glycolysis/gluconeogenesis

  • High blood glucoseSynthesis of hexokinase II, PFK-1, pyruvate kinaseMovement of GLUT4 to plasma membrane of myocyte Activation of insulin-sensitive protein kinase Activation of protein kinase B Insulin secretion

  • p.903

  • p.887

  • GlucosePancreatic b cellGLUT2GlucoseGlucoseGlycolysispyruvateCitric acid cycleNADH,FADH2ATPOxidative phosphorylationATP-gated K+ channelK+- - - - - - -- - - - - - -+ + + + + + ++ + + + + + +Membrane depolarizationclosedVoltage-dep. Ca2+ channelCa2+ OpenCa2+ Insulin secretionp.903

  • Movement of GLUT4 to plasma membrane of myocyteGlcGlcGlcGlcGlcp.396Insulin receptorGlcGlcGlcGlcGlcCytosol of myocyte

  • Activation of insulin-sensitive kinasep. 588Insulin receptorInsulinInsulin-sensitive kinaseInsulin-sensitive kinaseGMPP1PP1Glycogen synthase aPhosphorylase kinaseGlycogen phosphorylaseGlycogen synthesis Glycogen degradation

  • Activation of protein kinase B (PKB)Insulin receptorInsulinp.587IRS-1GSK-3PIP2PIP3PI3-KPDK-1PI3-KPDK-1GSK-3Glycogen synthase aGlycogen synthase aGlycogen synthesisPKBPKB

  • GSK3 inactivate glycogen synthase by phosphorylationPPPPp.587Phosphorylation by Casein kinase II

  • GSK3 can be inactivated by phosphorylationPKBPPp.587

  • High blood glucose affect hexokinase IV activityGlcRegulator proteinGLUT2Hexokinase IVnucleusHexokinase IVGlcGlcGlcGlcGlcGlcGlcGlcGlcHepatocytep.578

  • Insulin regulate PFK-1 activityInsulin receptorInsulinPhosphoprotein phosphatasePhosphoprotein phosphatasePFK-2FBPase-2PFK-2FBPase-2PFK-1PFK-1FBPase-1FBPase-1

  • Low blood glucoseInactivation of pyruvate kinase L (liver form)Activation of FBPase-2 and inactivation of PFK-2Inactivation of glycogen synthase Activation of glycogen phosphorylaseGlucagon secretion

  • p.436Glucagon receptorgbGlucagon receptorAdenylyl cyclaseAdenylyl cyclaseATPcAMPProtein kinase AProtein kinase ARegulation pathway initiated by glucagon secretionPFK-2FBPase-2Pyruvate kinase L

  • Regulation of PFK-1 by glucagonProtein kinase APFK-2FBPase-2Protein kinase APFK-1PFK-1FBPase-1FBPase-1

  • Regulation of glycogen synthesis and breakdown by glucagonp. 588PP1PP1Glycogen synthase aPhosphorylase kinaseGlycogen phosphorylaseGlycogen synthesis Glycogen degradation Protein kinase AProtein kinase A

  • HexokinaseThere 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.

  • HexokinaseHexokinase 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.

  • HexokinaseHexokinase 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.

  • Muscle hexokinaseBecause 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.

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

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

  • ATP regulate the affinity of PFK-1 towards its substrate F-6-PNot 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.

  • Molecules regulate PFK-1 and FBPase-1 activityADP 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.PFK-1PFK-1FBPase-1ATPcitrateADPAMPF2.6BPPFK-1

  • Regulation of gluconeogenesisPyruvate carboxylaseFBPase-1

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