Lecture 32 - Glycogen Metabolism And Glycogen Storage Disease

Front 1

How does glycogen degradation differ in liver and muscle?

Back 1

In the liver, glycogen is regulated by hormones. Takes place during fasting at low insulin/glucagon ratio.
RELEASE glucose into blood.
In muscle, glycogen degradation is linked to muscle contraction, independent of hormones. Glucose 6-P is used in glycolysis (MUSCLE KEEPS IT FOR OWN METABOLISM).

Front 2

What is the affect of epinephrine on glycogenolysis?

Back 2

Hormone stimulates glycohenlysis in both muscle and liver.

Front 3

When does glycogen degradation, glycolysis and gluconeogenesis take place in liver and muscle?

Back 3

In liver, glycogen degradation and gluconeogenesis take place at the same time at low insulin/glucagon. The liver glycogen is depleted after about one day.

In muscle, glycogen degradation and glycolysis taken place at the same time during muscle contraction. Muscle glycogen store is not depleted during fasting but during extensive extensive muscle exercise.

Front 4

Where in the human body is glycogen mainly found?

Back 4

Overall largest amount is in skeletal muscle.
Highest concentration is in liver (10%).

Front 5

What is the purpose of glycogen metabolism?

Back 5

- It is synthesized when glucose 6-P is abundant (high blood insulin levels).
- It is degraded when when glucose 6-P is needed (low insulin/glucagon ratio in liver/muscle contraction).

Front 6

In which cellular compartment is glycogen found and metabolized?

Back 6

Glycogen and its enzymes for degradation and synthesis are both in cytosol.
Exception - also found in lysosomes

Front 7

What is the basic structure of glycogen?

Back 7

It is a storage polysaccharide made up of glucose units that are linked by α1→4 glycosidic linkages and branch at α1→6 linkages.

Front 8

How is UDP-glucose synthesized and what is it used for?

Back 8

Glucose 6-P is converted to Glucose 1-P by enzyme phosphoglucomutase. UDP-glucose + PPi are then synthesized from Glucose 1-P by UDP-glucose pyrophosphorylase. UDP-glucose is a highly activated form of glucose for synthesis of glycogen.

Front 9

What is the function of glycogen synthase and what is glycogenin?

Back 9

It is a self-glycosylating enzyme
It is responsible for making the α1→4 linkages in glycogen. It cannot synthesize free glucose but can only elongate existing chains of glucose.
- A fragment of glycogen whose store are not totally depleted serves as a primer. In absence of this, a protein glycogenic can serve as acceptor for UDP-glucose and hydroxyl unit of a specific tyrosine serves as initial site where glycogenic catalyzes transfer of a few molecules of glucose to produce a short α1→4 chain (8 linkages)
-This will serve as a primer for glycogen synthase.

Front 10

What is the function of 4:6 transferase?

Back 10

It is the branching enzyme that further elongates glycogen during synthesis.
It removes a chain of 6-8 glycosyl residues from the non-reducing end by cleavage of α1→4 bonds and attaches non-terminal glycosyl residues by a α1→6 linkage.

Front 11

Explain the hormonal regulation of glycogen synthase?

Back 11

Glucagon and epinephrine bind to specific G-protein coupled receptor which results in synthesis of cAMP which activates cAMP dependent PROTEIN KINASE A. Protein kinase A (PKA) phosphorylates glycogen synthase (B) rendering it inactive (glycogen synthesis is inhibited).
High Insulin levels activate protein phosphatase-1, which cleaves phosphate from glycogen synthase (A) making it active (glycogen synthesis is on)

Front 12

What is function of glycogen phosphorylase? and PLP

Back 12

It is cystolic enzyme that degrades glycogen by cleaving at α1→4 bonds and produces Glucose 1-P. Pyridoxal phosphate (PLP) is a coenzyme require by glycogen phosphorylase.
PLP is formed from Vitamin B6.

Front 13

What is the advantage of glycogenolysis in anerobic glycolysis?

Back 13

Usage of glycogenolysis as a results of glucose phosphorylase results in phosphorylated glucose. This saves one ATP that would be required during glycolysis (hexokinase). This results in net gain of 3-ATP compared to 2 ATP.

Front 14

What is the allosteric regulation of glycogen synthesis and degradation in muscle and liver?

Back 14

In both liver and muscle:
--Glucose synthase is (+) activated by Glucose 6-P
--Glucose phoshporylase is (-) by Glucose 6-P and ATP

In Liver:
Glucose inhibits glycogen phosphorylase

In Muscle:
AMP stimulates glucose phosphorylase

Front 15

What is a limit dextrin during glycogenolysis?

Back 15

Glycogen phosphorylase cleaves glucosyl residues from glycogen until four glucosyl residues remain on each chain before a branch point. The resulting structure is called a limit dextrin.

Front 16

What is the debranching enzyme?

Back 16

It is a bifunctional enzyme that removes branches during glycogenolysis.
The first activity is of 4:4 transferase removes the outer 3 out of the 4 residues on limit dextrin and transfers to non-reducing end of another chain.
The remaining single residue linkage is cleaved by 1:6 glycosidase activity, releasing one free glucose.

Front 17

How is activation of glycogen done by cAMP-directed pathway?

Back 17

Glycogen phosphorylase exists in two forms (a) - active and (b)- inactive form. Active PKA (cAMP dependent - activated by epinephrine or glucagon) phosphorylates the inactive (b) form to the (a) of glycogen phosphorylase kinase. This phosphate can be removed by insulin which produce protein-phosphatase -1.
Glycogen phoshprylase kinase (a) phosphorylates glycogen phosphorylase (b) to its active form. When active it will degrade glycogen. Insulin can cleave the phosphate via protein-phosphatases-1 to (b) form.

Front 18

How does calcium activate glycogen degradation?

Back 18

Ca+ is released into the cytoplasm by muscle during contraction or in liver by epinephrine. Ca binds to calmodulin, which allows 4 Ca2+ ions to bind. This triggers a conformation change to activate Ca2+-calmodulin.
Calmodulin can then activate various proteins such as glycogen phoshorylase kinase (b) to its active form with PKA. This can then activate glycogen phosphorylase which leads to glycogen degradation.

Front 19

How does AMP activate glycogen synthesis?

Back 19

Muscle during extreme conditions, AMP increases which binds and allosterically activates glycogen phosphorylase b, without it being phosphorylated.
Remember that AMP also activates PFK-1 so that glycolysis can begin.

Front 20

What is Von Gierke Disease (Type 1 GSD)? How common is it, and what is affected?

Back 20

25% - affects liver and kidney
1a: deficiency of glucose 6-phosphatase in the ER membrane
1b: deficiency of glucose 6-P translocase
Both glycogen degradation and gluconeogenesis is impaired - results in severe hypoglycemia
- Hepatonephromegaly - high glycogen content in liver + kidney
-Severe fasting hypoglycemia (low blood glucose
-Lactic Acidemia
-Hyperuricemia
-Hyperlipidemia
-Progressive Renal failure

Front 21

What is Pompe Disease (Type II GSD)?

Back 21

15% - Heart, liver muscle
Defective glycogen degradation in lysosomes by acid maltase (α1→4 glucosidase)
- Results in lysosomal glycogen accumulation - which can rupture.
-Blood glucose is normal and normal glycogen
Affects:
Massive cardiomegaly, myopathy, hypotonia, hepatomegaly
Early death in first year - infantile
Treatable by enzyme infusion

Front 22

What is Cori Disease (Type III GSD)

Back 22

24% - Heart, Muscle nad Liver
Deficiency in the debranching enzyme (Forbes disease or limit dextrinosis)
Results in high amount of glycogen in liver, heart and muscle --> results in abnormal glycogen structure with short branches - accumulation of limit dextrinios (usually an intermediate)
Affects:
Muscle weakness, hypotonia
cardiomyopathy
Muscle - muscular dystrophy
Liver - mild hypoglycemia
Hepatomegaly

Front 23

What is Anderson Disease (Type IV GSD)

Back 23

3%
Deficiency of glycogen branching enzyme during synthesis .
Results in abnormal glycogen structure with long glucose chains with less branches.
- low amount of glycogen in liver and muscle
Affects:
Liver: infantile cirrhosis
Muscle: infantile hypotonia
Early death - by 5 years

Front 24

What is McArdle Syndrome (Type V GSD)?

Back 24

2%
-Caused by deficiency of muscle phoshporylase - reduced and abnormal glycogen degradation in muscle
- Will have normal blood glucose because liver - isozyme is normal
Results in high amount of glycogen in muscle
Causes:
Muscle weakness and cramping
Rhabdomyolysis - due to lack of ATP - serum CK-MM increase
- test for no increase of lactate after exercise

Front 25

What is Hers disease (Type VI GSD)?

Back 25

30%
Deficiency of hepatophosphorylase, muscle isozyme is normal - results in abnormal glycogen degradation in the liver.
Will have high amount of glycogen only in muscle.
Results in mild-fasting hypoglycemia
Liver only : mild hypoglycemia

Front 26

What is Tarui Disease (VII GSD)?

Back 26

0.2% - very rare
Is the deficiency of PFK-1 - reduced activity - in muscle (MM) and RBC.
Results in muscle cramping due to lack of ATP.
Have high glycogen amount in muscle.
HEMOLYSIS in RBC - lack of ATP
Normal blood glucose