1. CARBOHYDRATE METABOLISM

2. METABOLISM? WHY?  A 59-year-old man with a history of diabetes and alcohol abuse is brought to the emergency room in a semiconscious and minimally responsive state  How are glucose, triacylglycerols, and amino acids normally metabolized and what happens in diabetes?

3. Major Pathways 1. Glycolysis 2. Citric acid cycle 3. Gluconeogenesis 4. Glycogen metabolism (a) Glycogenesis (b) Glycogenolysis

4.  Glucose is the most important carbohydrate  Glucose is the major metabolic fuel of mammals.  Monosaccharide from diet : - Glucose - Fructose - Galactose  Fructose and Galactose glucose at the liver Glucose

5. Acetyl-CoALactate G6P Glucose Glycolysis Pyruvate Krebs cycle Electron Transport Chain Glycogen Glycogenolysis Fatty acids (TGA) β - Oxidation Ketone bodies Glycogenesis Gluconeogenesis Lipogenesis Amino acids (Protein) Lipolysis Glucose at the center of metabolism

6. Major organ of metabolism Glycogenesis Glycogenolysis Lipogenesis Lipolysis β -Oxidation Glycogenesis Glycogenolysis Gluconeogenesis Lipogenesis Lipolysis β -Oxidation Ketogenesis Glycogenesis Glycogenolysis Glycolysis β -Oxidation Glycogenesis Glycogenolysis Glycolysis β -Oxidation Blood Glucose Serum Triglycerides

7. The origine of glucose GLUCOSE Fats Amino acids monosaccharide Glycogen Exogenous

8. Glucose Homeostasis

9. The fate of glucose

10. Glycolysis

12. Krebs Cycle

13. Integration of metabolism  Common intermediates  Common organs

14. The metabolic intermediates. Metabolic integration

15. Major organ of metabolism, metabolic integration Glycogenesis Glycogenolysis Lipogenesis Lipolysis β -Oxidation Glycogenesis Glycogenolysis Gluconeogenesis Lipogenesis Lipolysis β -Oxidation Ketogenesis Glycogenesis Glycogenolysis Glycolysis β -Oxidation Glycogenesis Glycogenolysis Glycolysis β -Oxidation Blood Glucose Serum Triglycerides

16. Glucose, in between organ currency

17. Regulation of Blood Glucose: Insulin  Insulin  Produced by beta cells of the pancreas  Helps transport glucose from the blood into cells  Stimulates the liver to take up glucose and convert it to glycogen

18. Regulation of Blood Glucose: Insulin

19. Insulin

20.  Glucagon  Produced by alpha cells of the pancreas  Stimulates the breakdown of glycogen to glucose to make glucose available to cells of the body  Stimulates gluconeogenesis—the production of “new” glucose from amino acids Regulation of Blood Glucose: Glucagon

22. Glucangon

23. Insulin, Glucagon, and blood glucose

24.  High Blood glucose 1. Glycolysis 2. Glycogenesis 3. HMP Shunt 4. Oxidation of Pyruvate 5. Kreb’s Cycle 6. Change to lipids  Low blood glucose 1. Glycogenolysis 2. Gluconeogenesis Blood glocose

25. GLUCONEOGENESIS

26. Overview of Glucose Metabolism

27. gluco neo genesis sugar (re)new create glycolysis glucose pyruvate lactate gluconeogenesis

28. Topics: Gluconeogenesis 1. Principles, substrates & relationship to glycolysis 2. Bypass of irreversible steps in glycolysis 3. Link between liver gluconeogenesis and muscle/RBC/brain glycolysis; the Cori and Alanine cycles

29. Gluconeogenesis  Occurs in all animals, plants, fungi and microbes  Occurs largely in the liver; some in renal cortex  Of 10 enzymatic steps, 7 are reversals of glycolytic reactions

30. Metabolites feed into gluconeogenesis at various points main path

31. AA can feed into gluconeogenesis

32. TCA intermediates are gluconeogenic; funnel through oxaloacetate

33. Bypass of irreversible steps in glycolysis

34. Irreversible glycolytic steps bypassed 1.Hexokinase (hexK) 2.Phosphofructokinase-1 (PFK-1) 3.Pyruvate kinase (PyrK) by Glucose-6-phosphatase by Fructose 1,6-bisphosphatase (FBP-1) by Pyruvate Carboxylase & Phosphoenolpyruvate carboxykinase (PEPCK) These 3 key enzymes glycolysis gluconeogenesis

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

36. First bypass step is generation of PEP from pyruvate via oxaloacetate *Note: In order to cross the mito membrane, oxaloacetate must: 1.Be reduced to malate 2.Go through the malate shuttle 3.Be reoxidized to oxaloacetate

37. Addition of CO 2 to pyruvate to form oxaloacetate Hydrolysis of ATP

38. Decarboxylation and phosphorylation to PEP

39. 2 nd & 3 rd bypass steps are near the end of gluconeogenesis (“top” of glycolysis) Regulation of FBP-1 by AMP and F2,6P

40. Dephosphorylation of G6P, 3 rd bypass reaction

41. Glucose 6-phosphatase removes the phosphate to liberate free glucose This is primarily a function of the liver to buffer blood glucose levels G6Pase is NOT present in brain and muscle! (Gluconeogenesis does not occur in these tissues) glucose-6-P + H 2 O  glucose + P i G6Pase

42. Gluconeogenesis is energetically expensive to cells (hepatocytes) cost

43. Note that both Glycolysis and Gluconeogenesis are energetically favorable under physiological conditions and therefore both ~ irreversible processes Glycolysis  G [phys] = -63 kJ/mol Gluconeogenesis  G [phys] = -16 kJ/mol

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

45. The Cori Cycle 2 ATP 6 ATP 2 Lactate and glucose shuttle between active muscle/RBC and liver (glucagon/insulin reg.) Liver gluconeogenesis buffers 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 GN GL RBCs

46. The Alanine Cycle 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

47. REGULATION OF GLUCONEOGENESIS

49. First Coordinated Control Point (1) (2) (3) 1. high energy charge or abundance of biosynthetic intermediates turn off glycolysis.. Glycolytic pathway intermediate turns it on 2. when energy charge of the cell is low, the biosynthetic pathway is turned off. 3. when excess acetyl CoA builds up glucose formation is stimulated. When the energy charge in the cell is low, biosynthesis is turned off.

50. Second Coordinated Control Point Recall that F-2,6-BP is a signal molecule that is present at low concentration during starvation and high concentration in the fed state due to the antagonistic effects of glucagon and insulin on its production.

51. Glucagon

52. Fructose-2,6-bisphosphate is a powerful inhibitor of fructose-1,6-bisphosphatase Inhibition of fructose-1,6- bisphosphatase by fructose-2,6- bisphosphate.