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.