1. Gluconeogenesis The de novo synthesis of glucose and its role in preventing hypoglycemia

2. Gluconeogenesis: Overview Figure 13-2

3. General Features zTissues: yliver (80%) ykidneys (20%) zSubcellular location of enzymes ypyruvate carboxylase: mitochondrial yglucose-6-phosphatase: ER yall other enzymes cytoplasmic

4. Malate Shuttle zOAA produced in mitochondria zmitochondrial membrane impermeable to OAA zmalate transporter in mito. Membrane zmalate dehydrogenase in both mito and cyto zNADH produced in cyto also used in gluconeogenesis.

5. Energetics of Gluconeogenesis figure 13-1 zPyruvate Carboxylase y2 ATPs zPEP Carboxykinase y2 GTPs z3-P-glycerate kinase y2 ATPs zGlyceraldehyde-3-P dehydrogenase y2NADH

6. Precursers for gluconeogenesis figure 13-2 zGlycerol yderived from adipocyte lipolysis yhepatic glycerol kinase

7. Precursers for gluconeogenesis Figure13-3 zLactate yRBC ymuscle ythe Cori Cycle

8. Precursers for gluconeogenesis figure 13-4 zAlanine and other amino acids ytransamination of pyruvate ypyruvate derived from glycolysis or from amino acid degradation yalanine cycle

9. Coordinated Regulation of Gluconeogenesis and Glycolysis zGluconeogenesis and Glycolysis are regulated by similar effector molecues but in the opposite direction yavoid futile cycles xPK vs PC&PEPCK xPFK-1 vs FDP’tase xGK vs G6P’tase

10. Coordinated Regulation of Gluconeogenesis and Glycolysis zRegulation of enzyme quantity zFasting: glucagon, cortisol yinduces gluconeogenic enzymes yrepresses glycolytic enzymes yliver making glucose zFeeding: insulin yinduces glycolytic enzymes yrepresses gluconeogenic enzymes yliver using glucose

11. Coordinated Regulation of Gluconeogenesis and Glycolysis zShort-term Hormonal Effects yGlucagon, Insulin xcAMP & F2,6P 2 zPFK-2 & FBPase-2 yA Bifunctional enzyme ycAMP xInactivates PFK-2 xActivates FBPase-2 xDecreases F2,6P 2 Reduces activation of PFK-1 Reduces inhibition of FBPase-1 zLow blood sugar results in yHi gluconeogenesis yLo glycolysis

12. Coordinated Regulation of Gluconeogenesis and Glycolysis zAllosteric Effects zPyruvate kinase vs Pyruvate carboxylase yPK - Inhibited by ATP and alanine yPC - Activated by acetyl CoA yFasting results in gluconeogenesis zPFK-1 vs FBPase-1 yFBPase-1 inhibited by AMP & F2,6P 2 yPFK-1 activated by AMP and & F2,6P 2 yFeeding results in glycolysis