Glycogen metabolism in muscle and liver Flashcards
What is glycogen?
- Polysaccharide: storage form of glucose in the body
- Stored in granules predominantly in liver and muscle as an energy reserve
How is glycogen formed?
•Glycogen is formed from dietary glucose by the process of glycogenesis
How is glycogen utilised?
- Liver glycogen is utilised to maintain plasma glucose levels between meals, whereas muscle glycogen is required to sustain muscle contraction
- 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.
Is more glycogen stored in the liver or muscle?
In the fed state glycogen constitutes:
10% of the weight of the liver
2% of the weight of muscle
BUT
40% of human body weight is muscle
2.5% of human body weight is liver
SO
Overall, more glycogen stored in muscle
Why is gluconeogenesis required?
The liver contains less glycogen than is required to sustain glucose metabolism for 24 hours therefore require de novo synthesis by gluconeogenesis
What is 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
Label the linkages on glycogen
Why is it important for glycogen to be branched?
•Important to provide large number of ends at which phosphorylase and glycogen synthase can act to ensure rapid breakdown and resynthesis
What molecule is this?
Which linkages are used to form glycogen?
What is Glycogen breakdown?
Glycogen breakdown (glycogenolysis)
- In time of metabolic need, cells switch on the breakdown of stored glycogen very rapidly using a combination of signals
- This process is often known as mobilisation
- The breakdown products meet different needs in liver and muscle
What is the reaction for glycogenolysis?
When does glycogen breakdown occur in the muscle?
Muscle mobilises glycogen to fuel its own energy requirements via glycolysis to support contraction
Complete the diagram on glycogen breakdown in the muscle
When does glycogen breakdown occur in the liver?
Liver glycogen is converted to glucose between meals for export to other tissues
What glycogenolysis enyme does the liver have which the muscle does not?
Liver can convert gluc-6-phosphate into glucose because it expresses the enzyme glucose-6-phosphatase which muscle does not
Complete the diagram on glycogen breakdown in the liver
Complete the graph axis labels
What is 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 is 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
Complete the diagram on glycogen breakdown
Is ATP involved in this reaction?
No
What is phosphorolysis?
•PHOSPHOROLYSIS is analogous to hydrolysis (with phosphate acting like water in hydrolysis reactions).
How does glycogen degradation occur?
- 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.
Complete the diagram on glycogen degradation
How does Cleavage of α-1,6-linkages at branch points work?
- The α1-6 linkages are broken by the α-1,6-GLUCOSIDASE enzyme activity of the debranching enzyme
- It cleaves the bond to form free GLUCOSE by hydrolysis, does not involve phosphate
About 10% of glucose mobilized from glycogen is _______, rather than glusoe-1-phosphate
‘free’ glucose
Label the structures in the diagram on glycogenolysis
Summarise glycogenolysis
- Occurs in response to low glucose in the plasma or muscle contraction
- Major enzyme responsible for controlling the rate of breakdown is glycogen phosphorylase which breaks the bond between the (α1-4) linked glucose residues by the addition of phosphate to produce Glucose-1-phosphate
- Phosphorylase cannot break (α1-6) bonds and therefore breakdown also requires a debranching enzyme to complete the removal of (α-1,6)glucose links. This is a hydrolysis reaction and produces glucose.
- In muscle the Glu-1-P enters glycolysis, after conversion to Glu-6-P, to produce energy to sustain contraction. Cannot be exported to the blood as muscle lacks Glucose-6-phosphatase. In liver, it is converted to glucose and exported into the bloodstream to maintain plasma glucose levels.
What is glycogen synthesis?
Glycogen synthesis (glycogenesis)
Glycogen is formed from UDP-glucose
What is UDP?
•UDP-glucose is a high energy form of glucose
Consumption of UTP is energetically equivalent to ATP consumption i.e. the process requires energy input
Complete the diagram of glycogenesis
How does the Formation of glycogen from UDP-glucose occur?
•Glycogen synthase adds glucose units in α-1,4-linkage onto the glycogen chain using UDP-glucose
Complete the diagram on the formation of glycogen from UDP-glucose
How does glycogen synthesis start?
- 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
- Glycogenin extends the glucose chain by up to 7 additional residues from UDP-glucose via α-1,4-linkages
How does the Introduction of branches occur?
- 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 α-1,6-linkage
- The new branch does not form within 4 residues of a pre-existing branch
Complete the diagram on the introduction of branches in glycogenesis
How can glycogen 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.
Why is glycogen a bad energy store?
BUT it is a BAD store because glucose is hydrophilic and associates with water increasing the overall weight and bulk
Glycogen mobilisation (glycogenolysis) is greatly accelerated….
- In liver in between meals or during extended fasting, when glucose is required for glycolysis by the brain and red blood cells
- In muscle to fuel glycolysis during vigorous exercise
Glycogen synthesis (glycogenesis) is activated….
- To replenish liver glycogen stores after feeding or muscle stores when exercise ceases.
- The pathway for glycogen synthesis is not a simple reversal of breakdown and requires energy input
How is glycogen phosphorylase allosterically regulated?
- 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.
Complete the diagram on allosteric regulation of phosphorylase
How is glycogen synthase allosterically regulated?
- Glycogen synthase is allosterically activated by glucose-6-phosphate (the opposite to the effect on phosphorylase)
- Thus, glycogen synthesis is activated when glucose-6-phosphate is plentiful.
Complete the diagram on the allosteric regulation of glycogen synthase
What is the difference in allosteric control between the muscle and the liver?
•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).
Complete the diagram on allosteric control of phosphorylase and glycogen synthase in liver and muscle
How is glycogen metabolism regulared 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 does cAMP-dependent phosphorylation activate phosphorylase?
- The cAMP cascade results in phosphorylation of a hydroxyl group in a serine residue of 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
Complete the diagram on the activation of phosphorylase by cAMP-dependent phosphorylation
What effect doses the Induction of 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
Complete the diagram on the induction of the cAMP cascade on glycogen synthase
How does the Reciprocal regulation of phosphorylase and glycogen synthase work?
What are the ‘a’ and ‘b’ forms of enzymes?
- ‘a’ is the form of the enzyme that tends to be active, and independent of allosteric regulators (e.g. the phosphorylated form of glycogen phosphorylase)
- ‘b’ is the form of the enzyme that is dependent on local allosteric controls (the dephosphorylated form of glycogen phosphorylase)
When are which forms of enzymes active?
- With metabolic enzymes if it is involved in an catabolic reaction (breaking down), the phosphorylated form is the active form
- If it is involved in an anabolic reaction (building up), the phosphorylated form is the inactive form
