Glycogen metabolism in muscle and liver

Question 1

What is glycogen and how is it stored?

Answer 1

Polysaccharide storage form of glucose in the body

Stored in granules predominantly in liver and muscle as an energy reserve

Question 2

How is glycogen broken down?

Answer 2

Glycogen is degraded between meals in the liver by the
glycogenolysis pathway to produce glucose-1-phosphate which
can be converted to free glucose and exported into the
bloodstream to maintain plasma glucose levels. It can also be broken down in muscle to provide the energy to support muscle contraction.

Question 3

How is glycogen made?

Answer 3

Glycogen is formed from dietary glucose by the process of glycogenesis

Question 4

What is the difference between liver and muscle glycogen?

Answer 4

Liver glycogen is utilised to maintain plasma glucose levels between meals, whereas muscle glycogen is required to sustain muscle contraction

Question 5

Describe the structure of glycogen

Answer 5

Found in the form of granules within cells. Highly branched polysaccharide of glucose consisting of (α-1,4)linked glucose
molecules with an (α-1,6)branch every 8-14 glucose residues

Important to provide large number of ends at which phosphorylase
and glycogen synthase can act to ensure rapid breakdown and resynthesis

Question 6

Where is most glycogen stored?

Answer 6

In the muscle

Question 7

What is the consequence of the liver having low glycogen stores?

Answer 7

The liver contains less glycogen than is required to

sustain glucose metabolism for 24 hours therefore require de novo synthesis by gluconeogenesis

Question 8

Which linkages are used to form glycogen?

Answer 8

alpha-1,4

alpha-1,6

Question 9

Describe the general process of mobilisation

Answer 9

In time of metabolic need, cells switch on the breakdown of stored glycogen very rapidly using a combination of signals
The breakdown products meet different needs in liver and muscle

Question 10

Describe mobilisation in muscle cells

Answer 10

Muscle mobilises glycogen to fuel its own energy requirements via glycolysis to support contraction

Question 11

Describe mobilisation in liver cells

Answer 11

Liver glycogen is converted to glucose between meals for export to other tissues
Liver can do this because it expresses
the enzyme glucose-6-phosphatase which muscle does not

Question 12

Give the relationship between blood glucose and liver glycogen stores throughout the day

Answer 12

Glycogen stores rise after a meal in response to an increase in blood glucose; between meals glycogen stores fall as glucose is released from liver glycogen to stabilize the concentration of glucose in the blood

Overnight glycogen stores are mobilized to help maintain blood glucose concentration

Question 13

What does the liver cells contain which muscle cells do not?

Answer 13

Glucose-6-phosphatase

Question 14

What does the phosphate do to the glucose?

Answer 14

Keeps it within the cell so when acted upon by the glucose-phosphatase the molecules can leave the cell

Question 15

Describe the mechanism of glycogen breakdown

Answer 15

The α1-4 linkages are broken by PHOSPHOROLYSIS, catalysed by the enzyme GLYCOGEN PHOSPHORYLASE

It removes single units from non-reducing ends of glycogen to form GLUCOSE-1-PHOSPHATE

PHOSPHOROLYSIS is analogous to hydrolysis (with phosphate acting like water in hydrolysis reactions).

ATP IS NOT INVOLVED IN THIS REACTION

Phosphorylase can only break α-1,4 links up to within 4 glucose units from a branch point

Transferase activity of the debranching enzyme removes 3 residues from the branch and transfers them to the end of another chain in α-1,4-linkage

The single glucose unit left at the branch is removed by the action of the α-1,6-glucosidase activity of the debranching enzyme

The chain can then be broken down by phosphorylase until it meets the next branch point.

Question 16

How are the alpha-1,6- linkages cleaved?

Answer 16

The α1-6 linkages are broken by a different enzyme α-1,6-GLUCOSIDASE,

It cleaves the bond to form free GLUCOSE by hydrolysis, does not involve phosphate

Question 17

How does glycogen synthesis occur?

Answer 17

Glycogen synthase can add glucose units only to a pre-existing chain of more than four glucosyl residues
The priming function is carried out by a protein, glycogenin
UDP-glucose donates the first glucosyl residue and attaches it to the amino acid tyrosine in the glycogenin
The remaining glucose units are added in an α-1,4-linkage from UDP-glucose to create a growing chain

Question 18

What is UDP?

Answer 18

A high energy form of glucose

Question 19

What does glycogen synthase do?

Answer 19

Glycogen synthase adds glucose units in α-1,4-linkage onto the glycogen chain using UDP-glucose

Question 20

How do the branches of glycogen form?

Answer 20

Glycogen synthase extends the chain in α1,4-linkages but cannot make branches
Branching enzyme transfers a block of 7 residues from a growing chain to create a new branch with an α1,6-linkage
The new branch must not be within 4 residues of a pre-existing branch

Question 21

How is glycogen a good energy store?

Answer 21

Can be mobilised very rapidly:

The enzymes phosphorylase and glycogen synthase are very sensitive to regulation by hormones, stress and muscle contraction
The branched structure provides a large number of ends at which the polymer can be added to or broken down.

Question 22

How is glycogen a bad energy store?

Answer 22

BAD store because glucose is hydrophilic and associates with water increasing the overall weight and bulk

Question 23

When is glycogen mobilisation accelerated?

Answer 23

In liver during starvation, when glucose is required for glycolysis by the brain and red blood cells
In muscle to fuel glycolysis during vigorous exercise

Question 24

When is glucose metabolism activated?

Answer 24

To replenish liver glycogen stores after feeding or muscle stores when exercise ceases. It is promoted by insulin

The pathway for glycogen synthesis is not a simple reversal of breakdown and requires energy input

Question 25

Describe how Glycogen phosphorylase in muscle is subject to allosteric regulation by AMP, ATP and glucose-6-phosphate

Answer 25

AMP (present when ATP is depleted during muscle contraction) activates phosphorylase

ATP and glucose-6-phosphate, which both compete with AMP binding, inhibit phosphorylase. They are signs of high energy levels.

Thus glycogen breakdown is inhibited when ATP and glucose-6-phosphate are plentiful

Question 26

Describe how Glycogen synthase is allosterically activated by glucose-6-phosphate (the opposite to the effect on phosphorylase)

Answer 26

Glycogen synthesis is activated when glucose-6-phosphate is plentiful.
The cell is programmed to store glucose as glycogen when the input to glycolysis (glucose-6-phosphate), and the product of glycolysis (ATP) are present

Question 27

How does allosteric control differ in both liver and muscle cells?

Answer 27

In liver allosteric control is mainly by the supply of glucose to the cell (Glucose and G-6-P), whereas in muscle it is controlled by energy status (ATP and AMP) and substrate availability (G-6-P).

Question 28

What is allosteric regulation?

Answer 28

‘Allosteric regulation’ refers to the modulation of enzyme activity through reversible binding of small molecules to the enzyme at sites distinct from the active site i.e. the catalytic site. This is a rapid process and tends to be the first response of cells to changing metabolic conditions.

Question 29

Describe the regulation of glycogen metabolism by covalent modification

Answer 29

Mediated by the addition (and removal) of a phosphate group

Addition of a phosphate group is known as phosphorylation and is catalysed by protein kinases

This is a reversible modification; removal of phosphate groups (dephosphorylation) is catalysed by protein phosphatases

Question 30

How is phosphorylase activated?

Answer 30

The cAMP cascade results in phosphorylation of a serine hydroxyl of muscle glycogen phosphorylase, which promotes transition to the active state

The phosphorylated enzyme is less sensitive to allosteric inhibitors, thus even if cellular ATP levels and glucose-6-phosphate are high, phosphorylase will be activated

Question 31

If the enzyme is involved in an catabolic reaction (breaking down), the phosphorylated form is the … form

Answer 31

Active

Question 32

If the enzyme is involved in an anabolic reaction (building up), the phosphorylated form is the … form

Answer 32

Inactive form

Question 33

What does the activation of the cAMP cascade have on glycogen synthase?

Answer 33

Phosphorylation of glycogen synthase converts the enzyme to the ‘b’ (less active’) conformation

Therefore glycogen synthesis is inhibited when protein kinases are activated