Glycogen

Question 1

General facts about glycogen

Answer 1

1. Glycogen is a highly branched polymer (dendrimer) of glucose, containing many thousands of such monomers; the presence of the branches provides more opportunities for rapid degradation and synthesis
2. Amount of glycogen in healthy man, weighting 70 kg, after carbohydrate meal:
   
   1. Liver (1.5 kg) glycogen… 100 grams = 400 kcal
   2. Muscle (35 kg) glycogen… 400 grams = 1600 kcal
   3. Compare to blood glucose amounts… 7 grams = 28 kcal; adipose reserves… 14 kg = 126,000 kcal
3. Amount of liver glycogen (0.1% of wet weight after 24 hour fast to 10% if on a special diet) fluctuates much more than amount of muscle glycogen (0.7% of wet weight to rarely more than 2 %)

Question 2

Function of glycogenesis and glycogenolysis

Answer 2

1. The function of glycogenesis and glycogenolysis in the liver is the amintenance of blood glucose levels during early portions of fast, and during exercise
2. The function of muscle glycogenesis and glycogenolysis is the provision of a fuel to be used by the muscle during exercise (selfish)

Question 3

Glycogen

Answer 3

1. Every 8 to 10 glucosyl residues, there is a branch which contains alpha (1→6) linkage
2. Glycogen is sotred in both muscle and liver in granules; the enzymes associated with its synthesis and degradation are localized inside these granules
3. Note: glycogenolysis stands in contrast to the fate of extra-cellular (dietary) glycogen, which is degraded by amylase into maltose and dextrins.
4. Muscle and liver serve different purposes in terms of glycogenlysis; one is blood glucose modulation and the other is energy source.

Question 4

Glycogenesis

Answer 4

1. Glucose 6-phosphate is “activated” by phosphoglucomutase and become Glucose 1-phosphate. It involves Glucose 1,6-P as a transient intermediate. This reaction takes place in cytosol.
2. Uracil Triphosphate (UTP) combines with G 1-P to becomes UDP-glucose, which is an active form of glucosyl molecule, carried out by UDP-glucose pyrophosphorylase.
3. The hydrolysis of pyrophosphate (PPi) ensures that UDP-glucose pyrophosphorylase reaction proceeds in the direction of UDP-glucose production.
4. Glycogenin, with its tyrosine residue, serves as a primer and become the starting molecule where active form of glucose can bind to. This is because UDP-glucose can only elongate already existing chains of glucose. Since the reaction is catalyzed by glycogenin itself, it is considered both a protein and an enzyme. Glycogenin stays associated.
5. Elongation of linear chain involves addition UDP-glucose molecules and glycogen synthase to form alpha (1→4) bonds.
6. In every 8-10 glucosyl residues, branching enzyme called 4:6 transferase breaks alpha (1→4) bond and transfers a portion of the chain and create new alpha (1→6) bond thusly making branches in glycogen.
7. The elongation and branching repeats via glycogen synthase and 4:6 transferase (branching enzyme).

Question 5

Glycogenolysis

Answer 5

1. Glycogen chain is broken down via phophorolysis carried out by Glycogen phosphorylase, yielding Glucose 1-P.
2. This is the rate-limiting step for digestion/glycogenolysis where some hormones may promote the process.
3. Epinephrine will induce glycogenolysis; “adrenalin rush” = energy rush; spurt of energy
4. Insulin and epinephrine are antagonistic to each other
5. Glycogen phosphorylase requires as a coenzyme pyridoxal phosphate, which is a forom of vitamin B6
6. The rate-limiting step in glycogenolysis is the reaction catalyzed by glycogen phosphorylase.
   7.

Question 6

Glycogen metabolism

Answer 6

1. Epinephrine and norepinephrine stimulate the synthesis of cAMP and the elevation of intracellular calcium levels by binding to alpha- and beta- adrenergic receptors. The cAMP functions in a synergistic manner with the calcium to regulate glycogen metabolism.
2. The binding of hormones, such as glucagon or epinephrine, to plasma membrane G protein-coupled receptors (GPCR) signals the need for glycogen to be degraded - either to elevate blood glucose levels or to provide energy for exercising muscle.
3. Binding of glucagon or epinephrine to GPCR results in G protein-mediate activation of adenylyl cyclase.
4. cAMP is synthesized activating protein kinase A, where its catalytic subunit (C) phosphorylates several enzymes of glycogen metabolism
5. Phosphorylase kinase is activated which subsequently activates glycogen phosphorylase, ultimately leading to glycogen degradation resulting in G 6-P.
6. During muscle contraction, Ca2+ is released from the sarcoplasmic reticulum. Ca2+ binds to the calmodulin subunit of phosphorylase kinase, activiating it without phosphorylation. Phosphorylase kinase can then activate glycogen phosphorylase, causing glycogen degradation.
7. Epinephrine is catabolic (involved in break down of glycogen)
8. Thus Glucagon and Epinephrine have parallel agenda
9. Ca+ is an activator –> glycogen in muscle is broken down for energy use as a result
10. Insulin can inactivate glycogen phosphorylase and thus inhibit glycogen degradation
11. Glucose 6-phosphate is more useful since it can be either diverted to be used for glycolysis to generate energy OR dephosphorylated by glucose 6-phosphatase.

Question 7

Effect of AMP levels

Answer 7

1. High AMP → inhibit gluconeogenesis since there is not enough ATP in the system; AMP is inversely related to gluconeogenesis.
2. Low AMP → more glycogen in the liver and more glycogenesis since there is already enough ATP in the system.
3. Low AMP (muscle) → maximum capacity of glycogen stored in reserve; low glycolysis/hiatus.

Question 8

Inactivation of glycogen synthase

Answer 8

1. Binding of glucagon or epinephrine further ensures glycogenolysis to proceed by inactivating glycogen synthase, thusly preventing the process from becoming what is called a “futile” reaction.
2. Insulin, on the other hand, can activate the glycogen synthase and reverse the process, which with its presence inhibited glycogen phosphorylase and prevent glycogenolysis from taking place.

Question 9

Summary of Inhibition and Activation of glycogen metabolism

Answer 9

Question 10

Calmodulin

Answer 10

1. Calmodulin is involved in many functions indcluding: nerve growth, muscle contraction, inflammation, apoptosis, intracellular movement, and immune processes. It functions inside of different organelles, including the plasma membrane.
2. Ca²⁺ is a critical messenger; generally at a low level so any small change will bring about dramatic change.
3. Calcium modulating (CalModulin) protein is not limited to just one place or one function.
4. Phosphorylase kinase, which is usually activated by PKA can be activated by the Ca²⁺-calmodulin complex without the help of the kinase.

Question 11

Good summary

Answer 11