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S 2007 BIOC 3406

S 2007 BIOC 3406. 02-13-07. Management of Inventories of Glucose and Glycogen. Coordinated regulation of Glycolysis and Gluconeogenesis Coordinated regulation of glycogen synthesis and breakdown. Coordinate Regulation of Glycolysis and Gluconeogenesis. Three control points

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S 2007 BIOC 3406

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  1. S 2007 BIOC 3406 02-13-07

  2. Management of Inventories of Glucose and Glycogen • Coordinated regulation of Glycolysis and Gluconeogenesis • Coordinated regulation of glycogen synthesis and breakdown

  3. Coordinate Regulation of Glycolysis and Gluconeogenesis • Three control points • Direction of flow through reactions coordinately turned one way or the other, as opposed to • Both on at the same time, controlling by turning one or the other up (futile or substrate cycling) ATP + F 6P  ADP + F 1,6BP F 1,6BP + H2O  F 6P + Pi ATP + H2O  ADP + Pi PFK-1 H neg FBPase-1 H neg work wasted H neg

  4. Glycolysis

  5. Hexokinase • Muscle (Hexokinases I-III) • Primary isozyme (II) has KM ~ 0.1 mM (cf normal blood glucose ~ 5 mM (90 mg/dl)) • Continuous push of glucose toward glycolysis, enzyme operating at top capacity • Inhibition by glucose 6-phosphate (end product inhibition)

  6. Hexokinase • Liver • Hexokinase IV has KM ~ 10 mM (cf normal blood glucose ~ 5 mM (90 mg/dl)) • Rapid equilibration with blood glucose (GLUT-2) • Blood glucose immediately and directly affects efficiency of enzyme • High BG glucose  G 6P • Low BG glucose  no reaction • When BG low, Hexokinase IV sequestered in nucleus and inhibited by protein • G 6P NOT inhibitory • F 6P role

  7. Phosphofructokinase-1 • Glucose “committed” to glycolysis at this step • ATP allosteric inhibitor (even though a substrate) • ADP, AMP promoters • Citrate (condensation product of acetyl CoA and OAA) increases action of ATP • Fructose 2,6-bisphosphate STRONG activator

  8. Pyruvate kinase • ATP, acetyl-CoA, long chain fatty acids, alanine, allosteric inhibitors • L form inactivated by phosphorylation (phosphorylation potentiated via cAMP-dependent protein kinase, or protein kinase A) • L form activated by dephosphorylation (protein phosphatase) • M form activated by cAMP • F 1,6BP activator

  9. Gluconeogenesis

  10. Pyruvate Carboxylase • PDH complex converts pyruvate to Acetyl-CoA (AcSCoA) • AcSCoA inhibits PDH (oxidative phosphorylation slows, NADH/NAD+ increases, CAC slows, AcSCoA builds up, stimulates kinase which deactivates PDH) • Pyruvate carboxylase converts pyruvate to oxaloacetate • AcSCoA allosterically activates pyruvate carboxylase

  11. Coordinate regulation of FBPase-1 and PFK-1 • ATP, ADP, AMP, citrate • F 2,6BP

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