glycogen metabolism and storage disease type

Question 1

what enzyme is deficient in Von Gierke disease?

Answer 1

Glucose 6-phosphate ( bound in ER, Ia) or glucose 6-P translocase(Ib)

Question 2

what is the glycogen amount in the Von Gierke disease?

Answer 2

High glycogen amount in the liver and the kidney (Normal glycogen structure)

Question 3

What organs are affected in the Von Gierke disease?

Answer 3

Liver: severe hypoglycemia

Question 4

What symptoms arise from the Von Giereke disease?

Answer 4

Hepatomegaly, Kidney disease, Early death if untreated, treatable by uncooked corn starch meal at night or nocturnal gastric glucose infusion

Question 5

what enzyme is deficient in the Pompe disease?

Answer 5

lysosomal (acid) glucosidase (acid maltose)

Question 6

what is the glycogen amount in the pompe disease?

Answer 6

normal glycogen amount and normal glycogen structure in cytosol, high amount in lysosomes, lysosmes can rupture

Question 7

What are the organs are affected in the Pompe disease?

Answer 7

Hear, Liver, Muscle

Question 8

what symptoms arise from the Pompe disease?

Answer 8

massive cardiomegaly, treatable with enzyme infusion, normal blood glucose levels, infantile and late onset

Question 9

What enzyme is defiecent in the Cori disease?

Answer 9

Glycogen debranching enzyme

Question 10

What is the glycogen amount in the Cori disease?

Answer 10

high amount of glycogen in liver, heart, and muscle, abnormal glycogen structure with short branches, limit dextrinosis ( an intermediate structure accumulates)

Question 11

what organs are affected in the Cori cycle?

Answer 11

Liver: mild hypoglycemia

Muscle, heart: weakness, hypotonia, cardiomyopathy

Question 12

what symptoms come from the cori cycle?

Answer 12

cardiomyopathy, muscular dystrophy, hepatomegaly

Question 13

What enzyme s deficient in the Anderson disease?

Answer 13

Glycigen branching enzyme

Question 14

What is the glycogen amount in the Anderson disease?

Answer 14

Low amount of glycogen in liver and muscle, abnormal glycogen structure with long unbranched glucose chains (attack by immune system and scarring)

Question 15

what organs are affected by Anderson disease?

Answer 15

Liver: Infantile cirrhosis
Muscle: infantile hypotonia

Question 16

what symptoms arise from Anderson disease?

Answer 16

Hepatomegaly due to cirrhosis, early death

Question 17

what enzyme is deficient in McArdle syndrome?

Answer 17

Muscle glycogen phosphorylase

Question 18

what is the glycogen amount in the McArdle syndrome?

Answer 18

High amount of glycogen only in liver, normal glycogen structure

Question 19

what organs are affected in the McArdle syndrome?

Answer 19

Muscle: weakness and cramping

Question 20

what symptoms occur in the McArdle syndrome?

Answer 20

no increase of lactate in blood afte exercise, lack ATP, normal blood glucose levels

Question 21

What enzyme is deficient in the Hers disease?

Answer 21

Liver glycogen phosphorylase

Question 22

what is the glycogen amount in the Hers disease?

Answer 22

High amount of glycogen only in liver, normal glycogen structure

Question 23

what organs are affected in the Hers disease?

Answer 23

Liver: mild hypoglycemia

Question 24

what are the symptoms of Hers disease?

Answer 24

Hepatomegaly, growth retardation

Question 25

What enzyme is deficient in Tarui disease?

Answer 25

glycolysis: muscle PFK-1, RBC PFK-1(M isoform)

Question 26

what is the glycogen amount in Tarui disease?

Answer 26

high glycogen amount in muscle, normal glycogen structure, deficient glycolysis in muscle and RBC

Question 27

what organs are affected in Tarui disease?

Answer 27

Muscle: lack of ATP leads to muscle cramping, nor rise in lactate
RBC: lack of ATP leads to hemolysis, normal blood glucose levels

Question 28

What is the main purpose and regulation of glycogen degradation in the liver in comparison to the muscle?

Answer 28

In the liver: the main purpose of glycogen degradation is to release glucose into the blood at low blood glucose levels. This is under tight hormonal control and only happens after the action of glucagon or epinephrine on the hepatocyte which leads to activation of glycogen degradation by phosphorylations.

In the skeletal muscle, the main purpose of glycogen degradation is to provide glucose 6-P for glycolysis in order to generate ATP for muscle contraction.
This process can be performed without regulation by hormones, it is connected to muscle contraction. The released calcium ions allosterically activate glycogen phosphorylase kinase and high AMP levels allosterically activate glycogen phosphorylase in muscle.
In addition, during fight and flight situations, epinephrine activates protein kinase A which phosphorylates and covalently activates glycogen phosphorylase kinase. This leads to the most effective glycogen degradation in skeletal muscle.

Question 29

Which pathway follows glycogen degradation in the muscle? Explain. Which pathway is inactive during glycogen degradation in the hepatocytes? Explain.

Answer 29

In the muscle, glycolysis follows glycogen degradation, both pathways happen at the same time. Glycogen degradation leads eventually to glucose 6-P which is used in glycolysis for ATP formation.

[aerobic glycolysis is linked to PDH and TCA cycle. Calcium ions released during muscle contraction activate glycogenolysis, PDH and TCA cycle.]

In hepatocytes, glycolysis is inactive during glycogen degradation.

The purpose of glycogen degradation in the liver is to release free glucose into the blood and the eventually formed glucose 6-P is cleaved by glucose 6-phosphatase.

Skeletal muscle Liver

Glycogen degradation Glycogen degradation///////
/// Release of glucose
Glycolysis Gluconeogenesis ///////

Question 30

Which pathway is active during glycogen degradation in the liver?

Answer 30

Gluconeogenesis and glycogen degradation are both activated by glucagon which signals low blood glucose levels.

Question 31

Which liver enzyme is used to cleave glucose 6-P formed by glycogen degradation and by gluconeogenesis?

Answer 31

Glucose 6-phosphatase is needed for the release of glucose into the blood as last step of both pathways in the hepatocyte.

Question 32

What is the advantage of the branched structure of glycogen? Discuss glycogen degradation and glycogen synthesis.

Answer 32

The branched structure allows several glycogen phosphorylase enzymes to simultaneously generate many glucose 1-phosphates during glycogen degradation.

On the other hand, after a meal, glycogen synthesis is rapidly performed by action of several glycogen synthase enzymes acting at the same time. In both, liver and skeletal muscle, glycogen synthesis is activated at high insulin/glucagon ratio.

Question 33

Are the reducing ends or are the non-reducing ends used for glycogen synthesis and glycogen degradation?

Answer 33

The nonreducing ends are used for glycogen synthase or for glycogen phosphorylase. The reducing end of glycogen is bound to glycogenin.

Question 34

What is glycogenin, what is its purpose and where is it found?

Answer 34

Glycogen is normally not totally degraded as some branches are wanted as primer for glycogen synthase. In case that all is degraded, “genesis” of glycogen has to happen, which is performed by the protein glycogenin. It can act as an enzyme and it uses UDP-glucose and links glucose to its own tyrosine residue.

[this is very unusual for O-glycosylation, most O-glycosylations add sugars to serine or threonine residues and not to a tyrosine residue]

After elongation to a short 1-4)-glycosidic chain, glycogenin action storps and the enzyme glycogen synthase has now a primer and can act and elongate further on.

Glycogenin is found in the core of the cytosolic glycogen granule.

Question 35

Where in the human body do you find the largest amount of glycogen, where do you find the highest concentration?

Answer 35

The largest amount is found in skeletal muscle,

and the highest concentration is found in the liver.

Question 36

Glycogen stores are used in liver to provide glucose during fasting. After these stores are depleted, can you use the glycogen stores in muscle for release of glucose into the blood during severe starvation? Explain.

Answer 36

The glycogen stores in the muscle can never be used for release of glucose into the blood, as muscle does not contain the enzyme glucose 6-phosphatase.

Question 37

Describe the action of glycogen synthase, what is special, what does it use, what does it form?

Answer 37

Glycogen synthase is a special enzyme that needs a primer, it cannot link UDP-glucose to a “free” glucose molecule.

It elongates glycogen at the non-reducing ends using UDP-glucose, which is the activated form of glucose. Glycogen synthase forms only 1-4)- glycosidic bonds

Question 38

Describe the action of the glycogen branching enzyme. Which glycogen storage disease is due to deficiency of this enzyme?

Answer 38

The glycogen branching enzyme is needed to make a branched structure from the long chains with linear 1-4) glycosidic bonds. It contains two enzyme activities that work together.

The glycogen branching enzymes cleaves an 1-4) bond found about 6-8 residues from the nonreducing end and transfers this glucose chain to a non-terminal glucosyl residue.

It forms with its second enzyme activity an 1-6) glycosidic linkage.

These newly formed branch points allow glycogen synthase to form again new 1-4) linkages.

The deficiency of the branching enzyme is a rare disease. It is found in patients with Andersen disease. Hepatomegaly due to infantile cirrhosis.

Question 39

Is glycogen synthase or is the glycogen branching enzyme the regulated enzyme of glycogen synthesis? How is the enzyme regulated?

Answer 39

The regulated enzyme of glycogen synthesis is glycogen synthase.

        Glycogen synthase is active in its dephosphorylated form at high insulin/glucagon   
         ratio (high blood glucose)    
         and glycogen synthase is inactive in its phosphorylated form at low 
         insulin/glucagon ratio (low blood glucose) and presence of epinephrine in blood.

Question 40

How is glycogen synthesis regulated? Why do you find glycogen accumulation in liver and kidney in the Von Gierke disease?

Answer 40

Glycogen synthesis is favored at high insulin/glucagon ratio which leads to the dephosphorylated glycogen synthase.

In addition, allosteric activation of glycogen synthase is found at high levels of glucose 6-P.

[Glucose 6-phosphatase is deficient in the Von Gierke disease in both liver and kidney. During fasting, glucose 6-P accumulates from glycogen degradation and from gluconeogenesis and allosterically activates glycogen synthase and allosterically inhibits glycogen phosphorylase. In these patients, glycogen synthesis takes place in spite of the severely hypoglycemic patients and leads to hepatomegaly!]

Question 41

Describe the reaction performed by glycogen phosphorylase. What is special, what is formed, what is limit dextrin?

Answer 41

Glycogen phosphorylase is a special enzyme that cleaves the 1-4) glycosidic linkage using inorganic phosphate (phosphorolytic cleavage) instead of water.

This generates glucose 1-P from the nonreducing end of glycogen without input of ATP.

Glycogen phosphorylase cleaves the 1-4) bonds until it come to about 6 residues to a branch point.

There the enzyme has found its limit, and the glycogen structure with these short branches is named limit dextrin. It is an intermediate glycogen structure during glycogen degradation.

Question 42

Describe the action of the glycogen debranching enzyme. Which glycogen storage disease has a deficiency of this enzyme?

Answer 42

The glycogen debranching enzymes contains two enzyme activities that work together.

The glycogen debranching enzyme cleaves the 1-4) linkage of short branches of limit dextrin closest to the branch point and links this glucose chain to a nonreducing end of glycogen.

With its second enzyme activity it cleaves the 1-6 ) linkage of the branch point and releases free glucose.

[in the liver this formed free glucose can be released into the blood, in the skeletal muscle this free glucose is phorphorylated to glucose 6-P by hexokinase]

Now limit dextrin is changed to normal glycogen and glycogen phosphorylase can act again until it comes close to the next branch point.

The debranching enzyme is deficient in Cori disease which is also known as limit dextrinosis,

Question 43

How is glycogen phosphorylase activated in the liver? How is it activated in the muscle?

Answer 43

Glycogen phosphorylase can be activated in both liver and muscle by glycogen phosphorylase kinase, an enzyme which covalently activates and phosphorylates glycogen phosphorylase.

Special for the muscle: allosteric activation of glycogen phosphorylase is found at high AMP levels that can result from anaerobic exercise or severe anoxia.

Question 44

What is the function of hepatic glycogen phosphorylase kinase? How is this enzyme activated?

Answer 44

The enzyme will phosphorylate and activate glycogen phosphorylase.

Glycogen phosphorylase kinase activity is under hormonal control and can be activated by phosphorylation by protein kinase A.

[Liver glycogen phosphorylase kinase can also be activated by high calcium ions in cytosol generated in the phosphoinositide messenger pathway. In this case glycogen phosphorylase kinase binds calcium with its own calmodulin subunits, makes a conformational change, and is active without being phosphorylated.]

Question 45

What is the function of glycogen phosphorylase kinase in the skeletal muscle? How is this enzyme activated?

Answer 45

The enzyme will phosphorylate and activate glycogen phosphorylase.

In the skeletal muscle it is special that the calcium ions generated by muscle contraction, link muscle contraction to allosteric activation of glycogen phosphorylase kinase without the actions of hormones or phosphorylations.

After allosteric activation, glycogen phosphorylase kinase is active in its dephosphorylated form.

In addition, glycogen phosphorylase kinase itself can be phosphorylated by protein kinase A (as in the liver) in the cAMP messenger system following epinephrine and is then also active in its phosphorylated form.

Question 46

Which enzyme contains 4 calmodulin subunits, glycogen phosphorylase kinase or is it glycogen phosphorylase?

Answer 46

Glycogen phosphorylase kinase contains 4 calmodulin subunits and is very responsive to allosteric activation by calcium and makes a conformational shift.

Question 47

Summarize the allosteric regulation of glycogen degradation and discuss it related to the liver or skeletal muscle or both.

Answer 47

Glycogen degradation is allosterically inhibited by ATP and glucose 6-P in liver and muscle.

In the liver, free glucose allosterically inhibits glycogen degradation.

In the muscle, glycogen degradation is allosterically activated during muscle contraction by calcium ions (glycogen phosphorylase kinase) and by AMP (glycogen phosphorylase).

Question 48

Which enzyme is for glycogen degradation other than in the cytosol? What is the name of the genetic defect of this enzyme and what is special?

Answer 48

Lysosomal acid glucosidase is needed in lysosomes. Some glycogen is taken up into lysosomes and needs to be degraded. The formed glucose is then released into the cytosol.

[This additional degradation other than in the cytosol was discovered in patients with Pompe disease. Pompe disease is grouped as Type II GSD, but it is also grouped as lysosomal storage disease (LSD) or muscular disease.]

Patients with Pompe disease show lysosomal glycogen accumulation in heart, muscle and liver with massive cardiomegaly, myopathy, hypotonia and hepatomegaly. Lysosomes can swell and rupture.

The glycogen structure in the cytosol is normal,
Pompe disease in the infantile form can lead to early death due to heart failure.

Question 49

When would you expect an abnormal structure of glycogen?

Answer 49

Abnormal glycogen structure is expected in patients with deficient glycogen branching enzyme (Andersen disease) or with deficient glycogen debranching enzyme (Cori disease).

Question 50

Describe the glycogen structure in patients with Cori disease.

Answer 50

Patients with Cori disease have a defect in glycogen degradation. They have a deficiency of the glycogen debranching enzyme.
The glycogen has short outer branches (limit dextrin)

[limit dextrin is a normal intermediate of glycogen degradation. In Cori disease, however, it is the main structure and leads to abnormal structure of glycogen (limit dextrinosis)]

Question 51

Describe the glycogen structure in patients with Andersen disease.

Answer 51

Patients with Andersen disease have a defect in the synthesis of glycogen.
They have a deficiency of the glycogen branching enzyme. The glycogen structure has long unbranched glucose chains with maltose-like structure. The abnormal structure is less soluble, can be attacked by the immune system and can lead to infantile cirrhosis and eventually death in infancy.

Question 52

Why do we find severe fasting hypoglycemia in patients with Von Gierke disease and milder hypoglycemia in patients with Cori disease or with Hers disease?

Answer 52

Patients with Von Gierke disease have a deficiency of glucose 6-phosphatase.

This enzyme generates free glucose not only from hepatic glycogen degradation, but also from gluconeogenesis. Deficiency results in severe fasting hypoglycemia.

[Patients with Cori disease (deficiency of the glycogen debranching enzyme) or Hers disease (deficiency of liver glycogen phosphorylase) have a hereditary defect in glycogen degradation, but they can still perform gluconeogenesis and release this glucose into the blood.]

Question 53

Strenuous exercise raises blood lactate. In which patients do you not find the increase in blood lactate? Is it also used as test for this disease?

Answer 53

In patients with McArdle syndrome, we find no raise in lactate due to deficiency of muscle glycogen phosphorylase which normally provides substrates for anaerobic glycolysis and generates lactate.

[liver glycogen phosphorylase is normal in these patients]

In the rare Tarui disease, PFK-1 is deficient and we do not find lactate increase after strenuous exercise due to deficient glycolysis. In addition we find mild hemolysis as the enzyme in RBC’s is also affected.

[note: muscle weakness is also found as result of defects in the carnitine shuttle and fatty acid degradation in muscle. In these patients, a normal increase of blood lactate after exercise is found as they can access glycogen stores in muscle]

Question 54

Name the glycogen storage diseases (GSD) that all lead to hepatomegaly.

Answer 54

Type I (von Gierke), Type II (Pompe), Type III (Cori) , Type IV (Andersen) and Type VI (Hers)

Question 55

What is characteristic for Type IV GSD (Andersen disease)?

Answer 55

Infantile liver cirrhosis (genetic) is characteristic for Andersen disease.
[This is due to deficiency of the glycogen branching enzyme leading to abnormal glycogen structure with long unbranched glucose chains that is attacked by the immune system. Early death by 5 years of age can occur.]

Question 56

What is characteristic for Type V GSD (McArdle syndrome)?

Answer 56

Muscle weakness and cramping after exercise. No raise of blood lactate.
Serum CK-MM is elevated. Rhabdomyolysis after exercise possible.

Question 57

What is characteristic for Type VII GSD (Tarui disease)?

Answer 57

Similar to McArdle but in addition mild hemolysis can occur.
The glycolytic enzyme PFK-1 is deficient in muscle and RBC. Very rare disease.