Glycogen Metabolism And Glycogen Storage Diseases

Question 1

Where in the human body is glycogen mainly found?

Answer 1

The largest amount of glycogen is found in skeletal muscle

The highest concentration of glycogen is found in liver

The branched structure of glycogen allows rapid synthesis after a meal or rapid degradation when needed at the nonreducing ends.
Branches are formed by a-1,6 glycosidic bonds.

Question 2

In which cellukar compartment is glycogen found and metabolized?

Answer 2

Glycogen is stored in cytosolic glycogen granules mostly in the liver and muscle.

The enzymes for both, glycogen synthesis and for glycogen degradation are in the cytosol close to the glycogen granules and are tightly controlled in their activities.

A small amount of glycogen is degraded in lysosomes.

This was discovered in patients with Pompe Disease where lysosomal
degradation is deficient and glycogen accumulates in lysosomes

Question 3

What is the purpose of glycogen synthesis?

Answer 3

Purpose is the same for liver and muscle

The purpose is the storage of glucose in form of glycogen when blood glucose is abundant

Question 4

What is the purlose of glycogen degradation?

Answer 4

Purposes are different for liver and muscle.

The purpose in liver is the release of glucose into the blood, in muscle it is to generate energy (lactate is released into blood).

Question 5

What is the regulated enzyme of glycogen synthesis?

Answer 5

Glycogen synthesis in both, liver and muscle is activated by insulin

Glycogen synthase is the regulated enzyme.

Insulin leads to dephosphorylation and activation of the enzyme at high blood glucose.

Phosphorylation by PKA leads to inactivation

The enzyme is also allosterically activated by high glucose 6-P

Question 6

What is the purpose of glycogen synthesis?

Answer 6

Glycogen synthase a(1–> 4) bonds (regulated enzyme)

Branching enzyme a(1–> 6) bonds after 8-10 glycosyl residues

Question 7

How is glycogen synthesuzed?

Answer 7

1. Glucose needs to be activated to UDP-glucose. Glucose 6-P is changed to glucose 1-P which reacts with UTP. In this process, PPi is formed and the UMP is linked to glucose 1-P. Renaming of the molecule leads to UDP- glucose.
2. Glycogenin is a protein, enzyme that is able to autoglusosylate at its own tyrosine residues. It will be found in the core of the glycogen granule.
3. Glycogen synthase is the regulated enzyme and once it has a primer it will form alpha-1,4 linkages.
4. The elongation takes place at the nonreducing ends. The anomeric carbon is bound by a glycosidic bond to another glucose molecule.
5. In order to form the highly branched, tree-like structure of glycogen, we need the branching enzyme to form the alpha-1,6 linkages.
6. Then glycogen synthase elongates again, and the branching enzyme will make the respective branches until the glycogen store is filled

Question 8

How does glycogen synthase find a primer?

Answer 8

1. Glycogen synthase cannot link UDP-glucose to glucose molecules
   without a primer.
2. In most cases the primer is in the form of glycogen chains that have not been degraded.
3. Glycogenin is used the very first time in de-novo synthesis and forms
   a primer that is recognized by glycogen synthase.

Gycogenin is found inside of the glycogen granule

Question 9

Summarize glycogen synthesis

Answer 9

1. Glycogenin (genesis of glycogen) is a self-glucosylating enzyme that uses UDP-glucose and adds approximately 8 glucose units in tandem to its own tyrosine residue.
2. Glycogen synthase is the regulated enzyme and recognizes this primer and forms a(1 4) bonds at the nonreducing ends. In most cases glycogen is used as primer.
3. The branching enzyme (4:6 transferase) removes a chain of 6-8 glucosyl residues from the nonreducing end by cleavage of an a(1 —4) bond and attaches it to a
   non-terminal glucosyl residue by an a(1- -6) linkage

Question 10

How is glycogen degradation different in liver and muscle?

Answer 10

Liver glycogen degradation

Regulation: Glycogenolysis shall take place only at low blood glucose and is always under tight hormonal control by glucagon and epinephrine

Muscle glycogen degradation:

Regulation: Connection to muscle contraction and independent of the blood glucose level. It can be improved by epinephrine

Question 11

Summarize the concept of glycogen degradation

Answer 11

Glycogen converted to limit dextrin (has short branches 4-5 glucose residues)
By:

Glycogen phosphorylase acts on non-reducing ends
and forms glucose 1-P until the enzyme approaches a branch point and the temporary structure of limit dextrin is forme

The debranching enzyme has 2 enzyme activities
(4:4 transferase and 1:6 glucosidase) and forms again longer branches

Glycogen phosphorylase continues glycogen degradation until again limit dextrin is formed

Question 12

Explain the mechanism of action of glycogen phosphorylase

Answer 12

Glycogen phosphorylase forms glucose 1-P

1. Glycogen phosphorylase performs phosphorolytical cleavage of glycogen to glucose 1-P without the use of ATP.
2. Inorganic phosphate is used instead of water.
3. Pyridoxal phosphate is needed for this reaction. PLP is a coenzyme which is formed from vitamin B6.

Question 13

What is the significance of the debranching enzyme?

Answer 13

The debranching enzyme acts on limit dextrin and has 2 activities working together

1. The 4:4 transferase activity forms longer branches.
2. The 1:6 glucosidase activity cleaves the a(1 6) bond and forms
   free glucose.
3. Longer branches with only a(1 4) linkages are again available for glycogen phosphorylase

Question 14

Discuss Liver CHO metabolism after action of glucagon and epinephrine

Answer 14

Liver needs to switch from
glycogenesis and glycolysis to glycogenolysis and gluconeogenesis

cAMP-dependent protein kinase A phosphorylates directly

• Glycogen synthase inhibited
• Pyruvate kinase /glycolysis inhibited)
• Glycogen phosphorylase kinsase activated(glycogen degradation activated)
• Glycogen phosphorykase (active, forms glucise-1-P)

Bifunctional enzyme (glycolysus and gluconeogenesis activated)

Question 15

How is hepatic metabolism regulated by glucagon and insulin ?

Answer 15

1. Insulin leads to dephosphorylated key enzymes
   ⚫ Glycogen synthase: activated glycogen synthesis.
   ⚫ Glycogen phosphorylase kinase: inhibited glycogen degradation.
   ⚫ Bifunctional enzyme: activated glycolysis and inhibited gluconeogenesis.
   ⚫ Pyruvate kinase: activated glycolysis.
2. Glucagon leads to phosphorylated key enzymes via PKA
   ⚫ Glycogen synthase-P: inhibited glycogen synthesis.
   ⚫ Glycogen phosphorylase kinase-P: activated glycogen degradation.
   ⚫ Bifunctional enzyme-P: activated gluconeogenesis and inhibited glycolysis.
   ⚫ Pyruvate kinase-P: inhibited glycolysis

Question 16

What happens at a fed state ?

Answer 16

Glycolysis and glycogenesis

At high blood glucose: usage of glucose 6-P

Glucose from blood—> glucokinase
—> glucose -6-p

Is ussed in glycogen syntgesis, glycolysus, PDH, TCA cycle

Question 17

What happens in a fasting state?

Answer 17

At low blood glucose: Release of glucose into blood

Gkycogen degradation and gluconeogenesis—> glucose 6-P

Glucose 6-P—> glucise in the blood

B-oxidation

Question 18

What enzyme deficuency indicates type 0 glycogen storage disease?

Answer 18

Glycogen synthase (rare, early death)

Question 19

What is the name of Type I glycogen storage disease? What enzyme is deficient?

Answer 19

Von Gierke Disease-Glucise 6-phosohate

Answer 20

Pompe dusease= lysosomal a-1,4-glucosidase

Question 21

What is the name and enzyme deficiency of GSD Type III?

Answer 21

Cori disease, Forbes= debranching enzyme

Question 22

What is the name of GSD type IV and what enzyme is deficient?

Answer 22

Andersen disease.

Enzyme deficiency= branching enzyme

Question 23

What is the name of GSD Type V and what enzyme is deficient?

Answer 23

McArdle disease

Enzyme deficiency- Myophosphorylase enzyme

Question 24

What is the name of GSD Type VI? What enzyme is deficient?

Answer 24

Hers disease

Hepatophosphorylase enzyme

Question 25

What is the name of GSD Type VII and what is the enzyme deficient?

Answer 25

Tarui disease-Phosphofructose kinase (muscle, RBC)

Question 26

What. Is von George (type 1)?

Answer 26

Von Gierke Disease (Type I GSD)
⚫ Dr. Edgar Von Gierke described this disease in 1929 after autopsy of two children (Type I). (Drs. Carl and Gerti Cori described the enzyme deficiency 1952.)

⚫ High glycogen amount in liver and kidney with normal structure.

⚫ Glucose 6-phosphatase is deficient in liver and kidney cortex

Question 27

What are the characteristics of von Gierke’s ?

Answer 27

Clinical features:
- Massive enlargement of liver and progressive renal disease.

• Very severe hypoglycemia between meals. No rise of blood glucose after administration of
  glucagon or epinephrine. Convulsions due to hypoglycemia.
• Lactic acidosis results because lactate from the blood cannot be used for gluconeogenesis.
  The release of free glucose into the blood is needed to switch from glycolysis to gluconeogenesis, deficiency of glucose 6-phosphatase.
• Hyperuricemia: high lactate competes with uric acid release in the kidney.
• Hyperlipidemia: increased VLDL release and less active lipoprotein lipase.
• Failure to thrive

Question 28

How do we treat von Gierke’s?

Answer 28

Treatment:
Fasting metabolism needs to be avoided in these patients.
At night: Every few hours oral intake of uncooked corn starch in water which is slowly
hydrolyzed to glucose. Another option is nocturnal nasogastric glucose infusions

Deficiency of glucose 6-P translocase is rare but can occur

Question 29

Describe pompe disease (type 2)

Answer 29

1. Deficiency of lysosomal a(1 4) glucosidase (acid maltase).
2. Massive lysosomal glycogen accumulation in heart, muscle and liver.
   In severe cases the lysosomes can rupture.

This disease is grouped as:

• Glycogen storage disease.
• Lysosomal storage disease.
• Muscular disease

Question 30

What are the clinical features of pompe disease?

Answer 30

Clinical features:
- Massive cardiomegaly and hepatomegaly.
- Myopathy, Hypotonia and weakness (“floppy”). - Progressive neuromuscular disorder.
- Elevated serum CK-MM.
⚫ Normal glycogen structure and normal blood glucose levels.
⚫ Infantile form: early death in first year due to heart failure.
⚫ Late-onset: often breathing problems, myopathy.
⚫ Enzyme replacement therapy by infusion.

Infantile. Is most severe

Question 31

Describe Cori disease (type 3

Answer 31

Forbes disease or limit dextrinosis

Drs. Carl and Gerty Cori received the Nobel Price 1947.
Deficiency of the debranching enzyme (4:4 transferase)

Deficiency leads to abnormal glycogen
structure with short outer branches

Question 32

What are the clinical features of Cori disease?

Answer 32

1. Clinical features:
   - Muscular weakness and hypotonia.
   - Cardiomyopathy and hepatomegaly.
   - Mild hypoglycemia.
   Cori disease characteristics
2. This disease is also considered as muscular dystrophy. Patients are supported by the muscular dystrophy society.

Patients with Cori disease may need a wheelchair by the age of 50-60 years

Question 33

Whaat is Anderson disease (type 4)

Answer 33

Described by Dr. Dorothy H. Andersen as familial cirrhosis.

Deficiency of the glycogen branching enzyme (4:6 transferase) in liver and muscle.

Characterized by abnormal glycogen structure
with long glucose chains and less branches

Question 34

What are the characteristics of Anderson disease ?

Answer 34

1. Clinical features have large variety and severity:
   - Enlarged liver, infantile cirrhosis and early death in childhood.
   Cori disease characteristics
   - Muscular weakness, hypotonia.
   - Cardiomyopathy, weakened heart and lungs.
2. The abnormal glycogen structure in Anderson disease leads to hepatic scarring by the attack of the body’s immune system.

Question 35

Describe McArdle disease. (Type V)

Answer 35

Deficiency of muscle phosphorylase leads to high levels of muscle glycogen with normal structure.

The hepatic isozyme is normal.
This disease is often not diagnosed
as the child appears to be just tired and unmotivated
to do physical activity.

Patients can show rhabdomyolysis after forced exercise
due to lack of ATP. Serum CK-MM is increased

Question 36

Whaat are the characteristics of McArdle disease?

Answer 36

Clinical features
- Temporary weakness and muscle cramping after exercise. - Myoglobinemia and myoglobinuria.

Cori disease characteristics
Muscle weakness test measures blood lactate for diagnosis.

Under strenuous exercise lactate increases in the blood.
This is not seen in patients with McArdle Disease because the muscle glycogen
degradation is reduced and less lactate is formed in anaerobic glycolysis.

Question 37

Describe hers disease (type 6)

Answer 37

Deficiency of hepatic phosphorylase leads to high levels of liver glycogen with normal structure.
The muscle isozyme is normal.

Clinical features

• Hepatomegaly
• Growth retardation
• Mild fasting hypoglycemia

Question 38

Describe Tarui disease (Type VII GSD)

Answer 38

Reduced activity of the M-subunit of phosphofructokinase-1

⚫ Deficiency of PFK-1 in muscle (MM - type) and RBC (ML- type).
⚫ The liver isozyme (LL-Type) is normal.

Clinically similar to McArdle disease leading to muscle cramping due to lack of ATP.
Different: Hemolysis occurs in this disease due to 50% PFK-1 deficiency in RBC