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Glycogen Metabolism

Q: What are the steps of glycogen degradation?

1. Release of glucose 1-phosphate from glycogen 2. Remodeling of the glycogen substrate to permit further degradation 3. Conversion of glucose 1-phosphate into glucose 6-phosphate for further metabolism

Q: For what can the produced glucose 6-phosphate be used?

1. It can be metabolized by glycolysis 2. It can be converted into free glucose for release into the bloodstream (liver) 3. It can be processed by the pentose phosphate pathway to yield NADPH and ribose derivates * Conversion of glycogen into free glucose occurs mainly in the liver

Q: How is glycogen broken down?

1. Cleavage by phosphorylase from non-reducing end (creates glucose 1-phosphate). 2. Transferase shifts a block of 3 glucosyl residues from one outer branch to another. 3. Alpha-1,6-Glucosidase cleaves the last glucose residue

Q: What is the default state of liver phosphorylase?

Phosphorylase a . Glucose is being generated unless the enzyme is signaled otherwise. The binding of glucose to the active site shifts the a form from the active R state to the less-active T state.

Q: What is the default state of muscle phosphorylase?

Phsphorylase b . For muscle, phosphorylase must be active primarily during muscle contraction. It is activated by the presence of high concentrations of AMP . ATP acts as a negative allosteric. If ATP is unavailable, glucose 6-phosphate may bind to the ATP-binding site. In resting muscle, phosphorylase b is inactive because of the inhibitory effects of ATP and glucose 6-phosphate.

36 important questions on Glycogen Metabolism

Why can glucose not be stored?

High concentrations of glucose disrupt the osmotic balance of the cell, which would cause cell damage or death.

Why is glucose stored as glycogen?

Glycogen is a readily mobilized form of glucose. The controlled release of glucose from glycogen maintains blood-glucose concentration between meals. And, unlike fatty acids, the released glucose can be metabolized in the absence of oxygen and can thus supply energy for anaerobic activity.

What are the steps of glycogen degradation?

1. Release of glucose 1-phosphate from glycogen
2. Remodeling of the glycogen substrate to permit further degradation
3. Conversion of glucose 1-phosphate into glucose 6-phosphate for further metabolism

For what can the produced glucose 6-phosphate be used?

1. It can be metabolized by glycolysis
2. It can be converted into free glucose for release into the bloodstream (liver)
3. It can be processed by the pentose phosphate pathway to yield NADPH and ribose derivates

* Conversion of glycogen into free glucose occurs mainly in the liver

What does glycogen phosphorylase?

It cleaves glycogen by the addition of orthophosphate to yield glucose 1-phosphate.

Glycogen + Pi --> glucose 1-phosphate + glycogen (n - 1 residues)

* The phosphorolytic cleavage of glycogen is energetically advantageous because the released sugar (glucose 1-phosphate) is already phosphorylated.

How does glycogen phosphorylase prevents the occurrence of hydrolysis?

Water needs to be prevented from entering the active site.
The substrates bind synergistically, causing the crevice to narrow, thereby excluding water.

How is glycogen broken down?

1. Cleavage by phosphorylase from non-reducing end (creates glucose 1-phosphate).
2. Transferase shifts a block of 3 glucosyl residues from one outer branch to another.
3. Alpha-1,6-Glucosidase cleaves the last glucose residue

What does glucose 6-phosphatase do?

This enzyme is only present in the liver and resides on the lumenal side of the smooth ER. It converts glucose 6-phosphate to glucose, which can leave the liver and enter the bloodstream.

Glucose 6-phosphate + H20 --> Glucose + Pi

What is the default state of liver phosphorylase?

Phosphorylase a. Glucose is being generated unless the enzyme is signaled otherwise.

The binding of glucose to the active site shifts the a form from the active R state to the less-active T state.

What is the default state of muscle phosphorylase?

Phsphorylase b. For muscle, phosphorylase must be active primarily during muscle contraction. It is activated by the presence of high concentrations of AMP.
ATP acts as a negative allosteric. If ATP is unavailable, glucose 6-phosphate may bind to the ATP-binding site.

In resting muscle, phosphorylase b is inactive because of the inhibitory effects of ATP and glucose 6-phosphate.

How does phosphorylase b get converted into phosphorylase a?

By phosphorylase kinase.

The rise in glucagon concentration result in phosphorylation of the enzyme, converting it to the phosphorylase a form in the liver.

Epinephrine binds to receptors in the muscle (and liver), inducing the phosphorylation of phosphorylase b to phosphorylase a.

How does phosphorylase kinase get activated?

By the binding of Ca2+.

This mode of activation of the kinase is especially noteworthy in muscle, where contraction is triggered by the release of Ca2+ from the sarcoplasmic reticulum.

How does epinephrine or glucagon activate phosphorylase b?

1. Epinephrine or glucagon bind to a 7TM receptor
2. G-protein exchanges GDP for GTP
3. Beta and Gamma subunits dissociate, alpha subunit activates Adenylate cyclase
4. Adenylate cyclase activates ATP conversion into cAMP
5. CAMP activates protein kinase A
6. Protein kinase A activates phosphorylase kinase
7. Phosphorylase kinase activates phosphorylase b.

How is glycogen synthesized?

1. Glycogenin forms the primer, this enzyme can glycolyse itself.
2. Glycogen synthase adds glucosyl residues to a chain already containing at least 4 residues.
3. Branching enzyme forms aplha-1,6 linkages

* Every glycogen molecule has a glycogenin molecule at its core
* Glycogen synthase only catalyzes the synthesis of alpha-1,4 linkages --> branching enzyme

How many glucose residues does the branching enzyme require before it can work?

The branching enzyme requires that the block of 7 or so residues must include the nonreducing terminus, and must come from a chain of at least 11 residues long. The new branch point must be at least 4 residues away from the preexisting one.

By which kinases is the glycogen synthase phosphorylated?

- Glycogen synthase kinase (GSK), which is under control of insulin.
- Protein kinase A

How are glycogen breakdown and synthesis reciprocally regulated?

The same glucagon- and epinephrine-triggered cAMP cascades that initiate glycogen breakdown in the liver and muscle, also shut off glycogen synthesis. Glucagon and epinephrine control both glycogen breakdown and glycogen synthesis through protein kinase A.

Protein Kinase A phosphorylates phosphorylase kinase, activating the enzyme and initiating glycogen breakdown. Glycogen synthase kinase and protein kinase A phosphorylate glycogen synthase, inactivating it and therefore inhibiting synthesis.

How does protein phosphatase I (PP1) works?

It is active when organism is at rest of after a meal.
- It inhibits the glycogen breakdown by inactivating phosphorylase kinase and phosphorylase a by dephosphorylasing them.
- It stimulates glycogen synthesis by activating glycogen synthase b by dephosphorylating it.

How does protein kinase A reduce the activity of PP1?

When epinephrine or glucagon activate protein kinase A, it phosphorylates the glycogen-binding region making it dissociate from the PP1 and making PP1 less active. It also phosphorylates inhibitors which make PP1 inactive.

How does insulin stimulate glycogen synthesis?

When blood-glucose concentration is high, insulin stimulates the synthesis of glycogen by inactivating glycogen synthase kinase.

* Insulin increases the amount of glucose in the cell by increasing the number of glucose transporters in the membrane. The net effect of insulin is thus the replenishment of glycogen stores.

What prevents the degradation and synthesis from operating simultaneously?

The activity of glycogen synthase begins to increase only after most of phosphorylase a is converted into b. The lag between the decrease in glycogen degradation and the increase in glycogen synthesis prevents the 2 pathways from operating simultaneously.

How does glucose regulate the liver-glycogen metabolism?

When glucose binds to the glycogen phosphorylase a the complex dissociates leaving a glycogen phosphorylase a (T state) and PP1 coupled to G_L. PP1 dephosphorylates the glycogen phosphorylase a (T state) making it glycogen phosphorylase b (T state). It also dephosphorylates glycogen synthase b making it glycogen synthase a.

What is the Von Gierke disease?

It is a glycogen-storage disease. Glucose 6-phosphatase is missing from the liver. This causes hypoglycemia because glucose cannot be formed from glucose 6-phosphate. This phosphorylated sugar does not leave the liver, because it cannot cross the plasma membrane. The presence of excess glucose 6-phosphate triggers an increase in glycolysis in the liver, leading to high concentrations of lactate and pyruvate in the blood.

* Patients who have von Gierke disease also have an increased dependence on fat metabolism.
* It can also be caused by a defect in the glucose 6-phosphate transporter.

Why is glucose a reducing sugar?

It has a reactive group: the aldehyde group. It can reduce substrates. The aldehyde group is then oxidized into a carboxyl group. (gluconic acid)

Where does Glycation take place and how?

Glycation takes place in vivo between glucose and amino groups of proteins (albumin, hemoglobin).
1. Formation reversible Schiff base
2. Conversion to a stable ketoamine (Hemoglobin A). This is irreversible.

This is a spontaneous reaction.

What is the Amadori rearrangement?

This is the glycation of hemoglobin.
Glucose --> Schiff base ---> Hemoglobin A1CThe erythrocytes (with this Hemoglobin A_1C) live for about 4 months. There is no enzyme in erythrocytes which can remove the bond.
You can see the average blood-glucose level someone consumed during those 4 months.

How does the glycogen synthesis begin?

With glycogenin. Glycogenin is a homodimer, and each monomer glycosylates a Tyr residue. The Auto-glycosylation continues until maximally 8 glucose residues are added. Then they dissociate.

How does the reciprocal regulation of GP (glycogen phosphorylase) and GS (glycogen synthase) go?

- Phosphorylated Glycogen phosphorylase is active
- Phosphorylated Glycogen synthase is inactive

How is PP1 (Protein Phosphatase 1) regulated in muscle?

- PP1 is active while bound to the regulatory subunit G_muscle
- PKA phosphorylates G_muscle such PP1 gets released and becomes less active
- PKA also phosphorylates and activates an inhibitor of PP1
- GP becomes active, GS inactive.

How is PP1 (Protein Phosphatase 1) regulated in the liver?

-PP1 is bound to the regulatory subunit Gliver
- Glucose brings GP in the T state, allowing PP1 to dephosphorylate and inactive GP
- Free PP1 inactivates GP but activates GS

How does insulin result in the activation of GS?

- Binding of insulin activates intracellular protein kinase
- The kinases phosphorylate glycogen synthase kinase, inactivating it.
- Glycogen synthase kinase can no longer phosphorylate and inactive Glycogen Synthase.
- PP1 can now dephosphorylate and activate glycogen synthase.

How does Caffeine enhance the effect of glucagon on the blood-glucose concentration?

Caffeine inhibits the effect of PDE (Phosphodiesterase). The cyclic AMP can circulate a lot longer as it will not be broken down by PDE anymore. You will be in an energized state. Effects of cAMP are prolonged.

Which cell types are sensitive to insulin for glucose uptake?

Skeletal tissue, adipose tissue and liver cells.
- Liver cells always take up glucose, but this way they convert it into glycogen.
- Skeletal muscle cells and adipose tissue result in more glucose uptake.

Why do we store glucose in the form of glycogen and not as disaccharides?

Glycogen does not affect the osmotic pressure because it is bound together as one molecule. If you would make disacharides from them you’ll have a lot more molecules --> osmotic pressure --> cell won’t be able to survive.Plants can withstand that trugor pressure because of the cell wall.

What is the Andersen disease?

It is aglycogen storage disease with a defect in the branching enzyme.
Glycogen will get longer and longer --> there is no granule (only a linear molecule) --> anderson patient has just one non-reducing end --> difficult to remove glucose (little glucose avaiable) --> bloodglucose level change because the liver can’t deliver the energy --> no energy in the muscles --> muscles can’t move (stuck in the cycle).

What is Pompe disease?

Pompe disease is a glycogen storage disease caused by a lack of lysosomal a-1,4-glucosidase.

The autofage fuses together with the lysosmes. Those have a lot of hydrolases to break down everything and the pH is rather low.
The 1,4-glucosidase is not present anymore in the lysosome--> can’t break down the glucose --> accumulation in lysosome.

The question on the page originate from the summary of the following study material:

Medical Biochemistry and Pathophysiology

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