1. Metabolism of glycogen

2. Regulation of glycogen metabolism Regulating site for glycogen synthesis Glycogen synthase Regulating site for glycogen catabolism Glycogen phosphorylase

3. Glycogen Phosphorylase  AMP activates Phosphorylase  ATP & glucose-6-phosphate inhibit Phosphorylase  Thus glycogen breakdown is inhibited when ATP and glucose- 6-phosphate are plentiful. Glycogen Synthase  Activated by glucose-6-P (opposite of effect on Phosphorylase). Thus Glycogen Synthase is active when high blood glucose leads to elevated intracellular glucose-6-P.

4. Regulation by hormones Glucagon and epinephrine: Inhibit glycogen synthase Activate glycogen phosphorylase Increase glycogen catabolism and increase blood glucose Insulin: Inhibit glycogen phosphorylase Activate glycogen synthase Increase glycogen synthesis and decrease blood glucose

6. Regulation of Glycogen Phosphorylase by Hormones

7. Regulation of Glycogen Synthase by Hormones

8. Glycogen Function In liver – The synthesis and breakdown of glycogen is regulated to maintain blood glucose levels. In muscle - The synthesis and breakdown of glycogen is regulated to meet the energy requirements of the muscle cells.

9. Gluconeogenesis A metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates. It is one of the two main mechanisms the body uses to keep blood glucose levels from dropping too low. In animals, gluconeogenesis takes place mainly in the liver. This process occurs during periods of fasting, starvation, or intense exercise.

10. Basically, gluconeogenesis pathway is a reverse of glycolysis but has three bypass.

11. Irreversible glycolytic steps bypassed 1.Hexokinase 2.Phosphofructokinase-1 3.Pyruvate kinase (PyrK) by Glucose-6-phosphatase by Fructose 1,6-bisphosphatase by Pyruvate Carboxylase and Phosphoenolpyruvate carboxykinase Glycolysis Gluconeogenesis

12. Glucose-6-Phosphatase catalyzes: glucose-6-phosphate + H 2 O  glucose + P i This is primarily a function of the liver to buffer blood glucose levels Glucose-6-Phosphatase is NOT present in brain and muscle! Bypass 1:

13. Fructose-1,6-bisphosphatase catalyzes: fructose-1,6-bisP + H 2 O  fructose-6-P + P i Bypass 2:

14. Bypass 3: Pyrovate carboxylase and PEP carboxykinase catalyze: Pyruvate + ATP+ GTP  PEP + ADP + GDP + Pi + CO2

15. Gluconeogenesis as it takes place in the mammalian liver.

16. PEP carboxykinase locates in both cytosol and mitochondral. So there are two ways to transfer pyruvate to PEP. Lactate feed into gluconeogenesis through pyruvate. Lactate dehydrogenase

17. Intermediates in citric acid cycle can be used for gluconeogenesis through oxaloacetate PEP

18. All amino acids can feed into gluconeogenesis except leucine and lysine.

19. Pyruvate can go “up” or “down” depending upon energy needs

20. Liver is the major source of blood glucose from gluconeogenesis Is the primary gluconeogenic organ Produces glucose for export to brain, muscle, RBC’s Uses many small metabolites and amino acids to feed gluconeogenesis Liver function is highly sensitive to insulin & glucagon

21. Cori CF Lactate and glucose shuttle between active muscle/RBC and liver Liver gluconeogenesis supplies the blood glucose for use by muscle, RBC’s and brain (120 g/day) Note: the brain fully oxidizes glucose, so it does not funnel back lactate

22. The liver can also use the amino acid Alanine similarly to Lactate Following transamination to pyruvate, gluconeogenesis allows the liver to convert it to glucose for secretion into the blood

23. Regulation of gluconeogenesis To prevent the waste of a futile cycle, Glycolysis & Gluconeogenesis are reciprocally regulated. F-1,6-Bisphosphatase is the most important control site in Gluconeogenesis.

24. Reciprocal regulation by ATP/AMP  AMP inhibits Fructose-1,6-bisphosphatase but activates Phosphofructokinase  ATP inhibits Phosphofructokinase but activate Fructose-1,6- bisphosphatase In high ATP/AMP ratio: stimulate gluconeogenesis In low ATP/AMP ratio: stimulate glycolysis

25. Reciprocal regulation by fructose-2,6-bisphosphate:  Fructose-2,6-bisphosphate stimulates Glycolysis. Fructose-2,6-bisphosphate activates Phosphofructokinase-1. Fructose-2,6-bisphosphate inhibits Fructose-1,6-bisphosphatase.

26. Reciprocal regulation by hormones Phosphofructokinase-1 (PFK-1) Induced in feeding by insulin Repressed in starvation by glucagon Fructose-1,6-bisphosphase Repressed in feeding by insulin Induced in starvation by glucagon So: Insulin activates glycolysis but inhibits gluconeogenesis; Glucagon activates gluconeogenesis but inhibits glycolysis.

27. Metabolism of fructose Fructose is metabolized in the liver

28. Metabolism of galactose

29. The first enzyme to act on galactose is galactokinase. This converts galactose into galactose-1-phosphate.

30. Galactose-1-phosphate uridyl transferase produces UDP- galactose and Glucose-1-Phosphate from galactose-1- phosphate and UDP-glucose. UDP-Galactose

31. UDP-galactose-4-epimerase produces UDP-glucose.

32. Phosphoglucomutase catalyzes the reversible reaction: glucose-1-phosphate  glucose-6-phosphate

33. The Entry of galactose into glycolysis and glyconeogenesis Fructose is metabolized in the liver.

34. You should know: 1.Chemical steps of gluconeogenesis; associate enzymes 2.Precursors that can enter gluconeogenesis; 3.Relationship of glycolysis to gluconeogenesis; shared enzymes, irreversible steps 4.Liver as the primary gluconeogenesis organ; Cori Cycle, Alanine Cycle.