2.4.3. Glycogen I and II

Question 1

How are chains of glycogens attached?

Answer 1

α-1,4-linked glucose residues

Question 2

How are branches attached to the glycogen chains?

Answer 2

α-1,6-linkages

Question 3

What stimulates glycogen breakdown in the liver?

Answer 3

Glucagon and epinephrine

Question 4

What stimulates glycogen breakdown in muscles?

Answer 4

Epinephrine (via cAMP)

Question 5

Describe glycogen

Answer 5

Large, branched polymer consisting of D-glucose residues

Branching is more frequent in the interior of the molecule and less frequent at the periphery (one α-1,6 branch every 8 to 10 residues)

One glucose unit, located at the reducing end of each glycogen molecule, is attached to the protein glycogenin

Question 6

Action of glycogen phosphorylase

Answer 6

1. The key regulatory enzyme for glycogen degradation, removes glucose residues, one at a time, from the nonreducing ends of glycogen molecules
2. Uses inorganic phosphate to cleave α-1,4 bonds, producing G1P
3. Can act only until it is four glucose units from a branch point

Question 7

Removal of branches

Answer 7

The four units remaining at a branch are removed by the “debranching enzyme,” which has both glucosyl 4:4 transferase and α-1,6-glucosidase activity

Question 8

4:4 transferase

Answer 8

Cleaves at the α-1,4 bond, forming a new α-1,4 bond

Result is the removal of 3 of the 4 glucose residues (trisaccharide) and their attachment to the nonreducing end of another chain

Question 9

α-1,6-glucosidase

Answer 9

Hydrolyzes the last glucose unit at the branch point, forming free glucose

Question 10

Degradation of glycogen chains

Answer 10

The phosphorylase/debranching process is repeated, generating G1P and free glucose in a 10:1 ratio that reflects the length of the chains in the outer region of the glycogen molecules

Question 11

Fates of glucosyl units in the liver

Answer 11

Glycogen is degraded to maintain blood glucose levels:

1. G1P is converted to G6P (phosphoglucomutase)
2. Pi is released from G6P, and free glucose enters the blood

Question 12

Fate of glucosyl units in muscle

Answer 12

Glycogen is degraded to provide energy for contraction

1. G1P is converted to G6P (phosphoglucomutase), which enters the pathway of glycolysis and is converted either to lactate or to CO2 and H2O generating ATP
2. Muscle does not contain glucose-6-phosphatase and, therefore, does not contribute to the maintenance of blood glucose levels

Question 13

Lysosomal degradation of glycogen

Answer 13

Glycogen is degraded by α-glucosidase (located in lysosomes)

Lysosomal degradation is not necessary for maintaining normal blood glucose levels, but a lack of this enzyme activity leads to a fatal glycogen storage disease (Pompe disease)

Question 14

Glycogen storage disease in the liver

Answer 14

Results in hepatomegaly and conditions ranging from mild hypoglycemia to liver failure

Because different forms of the enzymes (isozymes) that degrade glycogen or convert it to glucose exist in the muscle/liver, one tissue may be affected, but not the other

Question 15

Glycogen storage disease in the muscle

Answer 15

Causes problems ranging from difficulty in performing strenuous exercise to cardiorespiratory failure

Question 16

UDP-glucose

Answer 16

The precursor for glycogen synthesis

Question 17

Synthesis of UDP-glucose

Answer 17

1. Glucose enters cells and is phosphorylated to G6P by hexokinase/glucokinase (ATP provides the phosphate group)
2. Phosphoglucomutase converts G6P to G1P
3. G1P reacts with UTP, forming UDP-glucose (catalyzed by UDP-glucose pyrophosphorylase). Inorganic pyrophophate (PPi) is released

Question 18

What helps drive the glycogen synthesis?

Answer 18

PPi is cleaved by pyrophosphatase to 2 Pi (this removal of product helps to drive the process in the direction of glycogen synthesis)

PPi is produced in the last step of UDP-glucose synthesis

Question 19

Glycogen synthase

Answer 19

The key regulatory enzyme for glycogen synthesis; it transfers glucose residues from UDP-glucose to the nonreducing ends of a glycogen primer (UDP is released and reconverted to UTP by reaction with ATP)

The primers, which are attached to glycogenin, are glycogen molecules that were partially degraded in the liver during fasting or in muscle during exercise

Question 20

Formation of branches

Answer 20

1. When a chain contains 11 or more glucose residues, an oligomer, six to eight residues in length, is removed from the nonreducing end of the chain and is reattached via an α-1,6 linkage to a glucose residue with an α-1,4-linked chain
2. Glucosyl 4:6 transferase breaks α-1,4 bonds and forms α-1,6 bonds
3. The new branches are at least 4 residues and an average of 7-11 residues from previously existing branch points

Question 21

Where is glycogen found in cells?

Answer 21

Cytosol

Question 22

How many glycogen residues are in each molecule?

Answer 22

20,000 - 30,000

7-10% at nonreducing termini
60% in outer branches
30% in inner branches

Single glycogen particle is a β-particle, about 300 Angstroms in diameter (β particles cluster for form α-particles)

Question 23

Why is glucose stored as a polymer?

Answer 23

Without branches, glucose would precipitate out of the cell (liver cirrhosis)

Also allows for many different attack sites (good during physical activity when you need to degrade it)

The polymer form does not disrupt normal osmosis

Question 24

How much glucose is in the blood at any given time?

Answer 24

Only 20 Cal (even during intensive exercise)

This is why the liver is a crucial organ in maintaining blood glucose levels

Question 25

Which organs have glucose-6-phosphatase action?

Answer 25

The liver (main one we are concerned with), but also the cortex of the kidney

Question 26

Why is the synthesis and degradation of glycogen kept separate (i.e., different pathways)

Answer 26

It allows for reciprocal regulation

The same pathway for both steps would be thermodynamically unfavorable

Question 27

What happens during the addition of new glucosyl residues if the primers run out?

Answer 27

Glycogenin can make a primer, allowing glycogen synthase to keep building

Question 28

Energetics of Storage

Answer 28

It requires 2 ATP to store 1 glucose residue as glycogen

Glucose to Glycogen (6% loss)

Glucose to FA (25% loss)

Question 29

Mechanisms of regulating committed enzymes

Answer 29

1. Phosphorylation/ dephosphorylation (10-15 min)
2. Allosteric activation and inhibition (seconds)
3. Induction/repression (hours)

Question 30

Key regulatory enzymes in glycogenolysis

Answer 30

Phosphorylase

Question 31

Key regulatory enzyme in glycogenesis

Answer 31

Glycogen synthase

Question 32

What activates the protein kinase?

Answer 32

Glucagon and epinephrine

Question 33

What activates the protein phosphatase?

Answer 33

Insulin

Question 34

Transduction of Signal

Answer 34

1. Glucagon or epinephrine is the first messenger (extracellular)
2. cyclic AMP is the second messenger (intracellular)

Question 35

Effect of insulin:

Answer 35

Dephosphorylation

Activates PP-1

Question 36

Key Exercise Signals

Answer 36

Epinephrine (external): flight or fight response

Ca (internal): from neuronal impulse

AMP (internal): from ATP hydrolysis for contraction

Question 37

Von Gierke’s Disease

Answer 37

Glucose-6-phosphatase deficiency

Affects the liver and kidney

Increased amount of glycogen leads to massive enlargement of the liver; failure to thrive; hypoglycemia; and ketosis

Question 38

Pompe’s Disease

Answer 38

1,4-glucosidase deficiency that affects all organs [lysosomal storage disease]

Massive increase in glycogen that causes cardio respiratory failure and death (usually before age 2)

Question 39

Andersen’s Disease

Answer 39

Branching enzyme deficiency that results in very long outer branches of glycogen

Progressive cirrhosis of the liver, liver failure, and death before age 2

Question 40

McCardles’s Disease

Answer 40

Phosphorylase deficiency that affects muscle

Increased amounts of glycogen leads to limited ability to preform strenuous exercise because of painful muscle cramps

Question 41

Clinical features of McCardle’s Disease

Answer 41

• Exercise Intolerance
• Cramps
• Myoglobin in urine after exercise from muscle disintegration
• “second wind”