1. Regulation of Metabolism
Pratt and Cornely Chapter 19

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

4. Specialization of organs

5. Fuel Storage Fuel Usage: About 7000 kJ/day minimum
Storage: About 700,000 kJ
Fats and muscle protein: 1-3 months
Glucose: 7000 kJ (1 day)
Glucose is essential for brain

6. Liver: Tissue Specific Functions
Gluconeogenesis
Ketogenesis
Urea production
Lactate recycling
Alanine recycling

7. Liver in the Fed State Glucose uptake Glycogen synthesis
Convert excess sugar, amino acids to fatty acid
Make, transport TAG

8. Liver in the 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

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

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

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

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

13. Cori Cycle

14. Alanine-Glucose Cycle

15. Metabolic Issues Starvation Alcoholism Metabolic Syndrome Obesity
Diabetes

16. Starvation
Early starvation: convert protein to glucose (cannot convert fat to glucose)
Later starvation
Preserve muscle
Muscle uses fat as fuel; buildup of acetyl CoA shuts down pyruvate acetyl CoA
Low [OAA] means acetyl CoA buildup
Ketone bodies produced
Brain uses KB, glucose is conserved

17. Metabolism of Ethanol Liver damage Too much NADH and acetyl CoA
Shuts down citric acid cycle
Fatty acid synthesis upregulated
“fatty liver”
Ketone bodies form
acidosis

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

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

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

21. Review of Chemical Regulation
Local vs hormone-level regulation
Signal transduction pathways
Allosteric effectors
Covalent modification
Product inhibition, feedback inhibition, feed forward activation
Energy charge
Reciprocal Regulation
Isozymes
Logic of regulation
Know all purposes of pathway
Know differences in tissue physiology

22. Hormone Regulation: Insulin
Small protein hormome
Released at high [glucose]
Pancreatic b 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

23. 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

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

25. 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

26. Insulin Signal Transduction

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

28. Hormone Summary
“Insulin signals fuel abundance. It decreases the metabolism of stored fuel while promoting fuel storage.”
“Glucagon stimulates the liver to generate glucose by glycogenolysis and gluconeogenesis, and it stimulates lipolysis in adipose tissue.”

29. Some Major Points of Regulation
Entry of glucose into cell
Glycolysis/gluconeogenesis
Fatty acid synthesis/breakdown
Glycogen synthesis/breakdown
Urea:

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

31. Glycolysis/Gluconeogenesis
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
Boosts production of F-2,6-bP

32. Hormone Regulation of Glycolysis/Gluconeogenesis
and AMPK activates phosphoprotein phosphatase

33. Glycogen Metabolism

34. Glycogen Phosphorylase
Dimeric
Allosteric control
Hormone level control
Tissue isozymes
Muscle: Purpose it to release fuel for itself
Liver: Purpose is to release fuel for whole organism

35. Covalent Modification
Phosphorylase a
Phosphorylated
“usually active”
Default liver isozyme
Phosphorylase b
Dephosphorylated
“usually inactive”
Default muscle enzyme

36. Liver Activity Physiological purpose: release of glucose
Default setting
High glucose concentration favors T state in Phosphorylase a
Turns off active glycogen degradation

37. Muscle Activity
Physiological purpose: conserve glycogen until a burst is needed
Detection of energy charge
AMP shifts equilibrium to relaxed state

38. Glucagon/Epinephrine Regulation through Phosphorylase Kinase
Activation of cascade leads to active degradation of glycogen
Epinephrine affects liver through IP3 pathway

39. Regulating regulators
Influx of calcium in active muscle partially activates kinase
Hormone response fully activates

40. Reciprocal Regulation
Glucagon

41. Protein Phosphatase 1 Opposite of PKA
Deactivates phosphorylase
Activates glycogen synthase
Active in cell unless epinephrine signals PKA
PKA activates its inhibitors

42. Insulin stimulates glycogen synthesis
Insulin blocks the “turn off” switch for glycogen synthase
Allows PP1 to “turn on” glycogen synthase

43. Fatty Acid Regulation Carnitine Transporter Acetyl CoA carboxylase
Matrix malonyl CoA
Error in this picture
Actually produced by acetyl CoA carboxylase isozyme in matrix
Acetyl CoA carboxylase
Local
AMP level
Citrate and Fatty Acids
Hormones

44. AMP level AMP-activated protein kinase Fuel sensor
Inactivates acetyl CoA carboxylase under low energy conditions in cell

45. Citrate and Fatty Acids
[Citrate] high in well fed state
Lots of OAA and acetyl CoA
Carboxylase forms active filaments
If [fatty acids] is high, no need to synthesize
Fatty acids break down filaments

46. Hormone-level control
Glucagon and epinephrine
Suppress acetyl CoA carboxylase by keeping it phosphorylated
Insulin—activates storage
Leads to dephosphorylation of carboxylase

47. Review Principles of Metabolism Central molecules Enzyme classes
Relate to reactions
Enzyme classes
Cofactors
Basic reactions
Redox
Decarboxylation
energetics
Reaction motifs

48. Central Molecules

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

51. Cofactors

52. Problem
Identify the metabolic pathway. Indicate which redox cofactor is necessary.

53. Problem 33:
Identify the necessary cofactors

54. Reaction Motifs