1. Regulation of Metabolism Pratt and Cornely Chapter 19

2. Regulation by Compartmentalization Form of reciprocal regulation Degradation vs biosynthesis Requires transporters

3. Specialization of organs

4. Fuel Storage Total amounts Availability at time of need

5. Liver: Tissue Specific Gluconeogenesis ketogenesis Urea production Lactate recycling Alanine recycling

6. Liver: Fed state Glucose uptake Glycogen synthesis Convert excess sugar, amino acids to fatty acid Make, transport TAG

7. Liver: Fast state Glycogen breakdown Maintain blood sugar level Catabolize glucogenic amino acids to maintain glucose and citric acid cycle Catabolize fats and ketogenic amino acids for ketone body

8. Muscle Glucose trapped as glycogen (no blood sugar regulation) Source of energy in starvation

9. Muscle: Active State Immediate ATP/creatine Anaerobic muscle glycogen Aerobic muscle glycogen Aerobic liver glycogen Adipose fatty acids

10. Adipose Fed state: uptake of fats AND glucose (why?) Fast state: release of fats by hormone sensitive lipase (HSL)

11. Kidney Elimination of waste Maintenance of pH With liver, carries out gluconeogenesis

12. Cori Cycle

13. Alanine-Glucose Cycle

14. Chemical Regulation Local allosteric regulation Hormone mediated allosteric regulation Covalent modification

15. Major points of Regulation Urea:

16. Local Regulation Role of citrate in multiple pathways Regulation by energy charge (ATP, AMP ratio) – [ATP] does not change much AMP-dependent protein Kinase (AMPK) acts as energy sensor – High [AMP] activates kinase to switch off anabolism and switch on catabolism

17. Hormone Regulation: Insulin Small protein hormome Released at high [glucose] Pancreatic  cells Release probably triggered by glucose metabolism, not cell surface glucose receptor – May be mitochondrial difference, explaining why diabetes changes with age – May be difference between hexokinase and glucokinase isozyme in pancreas

18. Hexokinase Most tissues except pancreas and liver First irreversible reaction Linked to glucose uptake – Locks glucose in cell Many isozymes – Most inhibited by glucose- 6-phosphate – Product inhibition

19. Glucokinase Isozyme in liver and pancreas Higher K m – Hexokinase always saturated, but glucokinase sensitive to [glucose] Not inhibited by glucose-6-P – Why? Liver serves to modulate blood sugar

20. Isozyme kinetics Looks allosteric, but this is monomeric enzyme May be due to conformational change upon product release— stays in active state at high concentration of glucose

21. Insulin Signal Transduction

22. Glucose Entry into Cells Tissues have unique function Isozymes of glucose transporter, GLUT – Insulin dependent in muscle – Higher [glucose] required for liver uptake

23. Covalent modification Signal transdution leads to phosphatase and/or kinase activity Covalent modification Glycogen phosphorylase – Phosphatase inactivates (b form) – Kinase activates (a form)

24. Insulin Regulation of Glycogen Insulin

25. Glucagon and Epinephrine Glucagon released with low blood sugar (pancreas  cells) Epinephrine released by adrenal glands Oppose insulin – Activates glycogen breakdown – Activates gluconeogenesis – Activates hormone sensitive lipase

26. Glucagon Regulation of Glycogen Glucagon

27. Obesity Hereditary, age, and environmental Set-point Leptin – Appetite suppressant – Made in adipose Brown fat

28. Diabetes Type 1 (Juvenile onset) – Insulin dependent Type 2 – Insulin resistance Body feels like a fast – Gluconeogenesis increase – Lower fat storage – Increase in fat utilization ketogenesis

29. Hyperglycemia Non-enzymatic glycosylation Sorbitol production leads to tissue damage Drugs aimed at undoing metabolic problems Metformin – Activates AMPK » Suppress gluconeogenesis – Actuvates glucose and fatty acid uptake in muscle

30. Review Central molecules – Relate to reactions Enzyme classes Cofactors Basic reactions – Redox – Decarboxylation – energetics Reaction motifs

31. Central Molecules

33. Enzyme classes Problem 6.14. Propose a name for the enzyme, and indicate metabolic purpose of reaciton.

34. Cofactors

35. Problem 12.26-27 Identify the metabolic pathway. Indicate which redox cofactor is necessary.

36. Problem 33: Identify the necessary cofactors

37. Reaction Motifs