Glycogen metabolism in muscle and liver Flashcards
What is glycogen and how is it stored?
Polysaccharide storage form of glucose in the body
Stored in granules predominantly in liver and muscle as an energy reserve
How is glycogen broken down?
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.
How is glycogen made?
Glycogen is formed from dietary glucose by the process of glycogenesis
What is the difference between liver and muscle glycogen?
Liver glycogen is utilised to maintain plasma glucose levels between meals, whereas muscle glycogen is required to sustain muscle contraction
Describe the structure of glycogen
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
Where is most glycogen stored?
In the muscle
What is the consequence of the liver having low glycogen stores?
The liver contains less glycogen than is required to
sustain glucose metabolism for 24 hours therefore require de novo synthesis by gluconeogenesis
Which linkages are used to form glycogen?
alpha-1,4
alpha-1,6
Describe the general process of mobilisation
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
Describe mobilisation in muscle cells
Muscle mobilises glycogen to fuel its own energy requirements via glycolysis to support contraction
Describe mobilisation in liver cells
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
Give the relationship between blood glucose and liver glycogen stores throughout the day
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
What does the liver cells contain which muscle cells do not?
Glucose-6-phosphatase
What does the phosphate do to the glucose?
Keeps it within the cell so when acted upon by the glucose-phosphatase the molecules can leave the cell
Describe the mechanism of glycogen breakdown
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.
How are the alpha-1,6- linkages cleaved?
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
How does glycogen synthesis occur?
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
What is UDP?
A high energy form of glucose
What does glycogen synthase do?
Glycogen synthase adds glucose units in α-1,4-linkage onto the glycogen chain using UDP-glucose
How do the branches of glycogen form?
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
How is glycogen a good energy store?
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.
How is glycogen a bad energy store?
BAD store because glucose is hydrophilic and associates with water increasing the overall weight and bulk
When is glycogen mobilisation accelerated?
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
When is glucose metabolism activated?
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
Describe how Glycogen phosphorylase in muscle is subject to allosteric regulation by AMP, ATP and glucose-6-phosphate
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
Describe how Glycogen synthase is allosterically activated by glucose-6-phosphate (the opposite to the effect on phosphorylase)
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
How does allosteric control differ in both liver and muscle cells?
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).
What is allosteric regulation?
‘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.
Describe the regulation of glycogen metabolism by covalent modification
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
How is phosphorylase activated?
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
If the enzyme is involved in an catabolic reaction (breaking down), the phosphorylated form is the … form
Active
If the enzyme is involved in an anabolic reaction (building up), the phosphorylated form is the … form
Inactive form
What does the activation of the cAMP cascade have on glycogen synthase?
Phosphorylation of glycogen synthase converts the enzyme to the ‘b’ (less active’) conformation
Therefore glycogen synthesis is inhibited when protein kinases are activated
