Glycogen metabolism, glycogenesis and glycogenolysis Flashcards
(28 cards)
Why do animals store energy as glycogen?
Controlled breakdown and synthesis helps maintain blood-glucose levels (normal 5mM)
Important as glucose is only fuel for brain under non-starvation conditions
Glucose from glycogen is readily mobilised. Good source of energy for sudden, strenuous activity
Unlike fatty acids can provide energy anaerobic conditions
What are the 2 major sites of glycogen storage?
2 major sites of storage:
Liver (10% by weight)
Muscle (2% by weight)
Insoluble granules in cytosol
Pathways of glycogen metabolism the same in liver and muscle
Regulation differs
What is Glycogen synthesis-glycogenesis? What is GLUT 2+4?
Glucose uptake from the blood is facilitated by transport proteins
Glut 2 present in liver and b-cells of the pancreas
High capacity, low affinity transporter
Takes up a lot of glucose when there is a lot around eg after a meal
GLUT 4 present in muscle and fat cells
Insulin leads to rapid increase in number so increasing uptake
Amount of transporters in muscle membranes increased by exercise
What is glycogenesis? Role of hexokinase?
Conversion of glucose to glucose 6-P
Hexokinase phosphorylates glucose in order to trap it within cell. The product inhibits the enzyme
Glucose 6-P is the converted to Glucose 1-P by the enzyme phosphoglucomutase
Active mutase enzyme contains a phosphorylated serine residue
The glucose 1-P is activated by an enzyme UDP-glucose pyrophophorylase, which produces UDP-glucose
This is a reversible reaction, but the equilibrium is shifted towards UDP-glucose formation by hydrolysis of the pyrophosphate
What does the enzyme glucokinase do in glycogenesis?
Liver rich in an isozyme called glucokinase
Not inhibited by glucose 6P
High Km ie affinity 50x lower than Hexokinase
Role of glucokinase is to provide glucose 6P for synthesis of glycogen and formation of fatty acids
Gives brain and muscles first call of glucose when limited but ensures it is not wasted
What does glycogen synthase do?
Glycosyl units added to the non-reducing end of glycogen molecule to form an alpha-1,4 glycosidic bond
Reaction catalysed by the enzyme Glycogen synthase
A primer is required as the enzyme can only add glycosyl units if polysaccharide chain is greater than 4 residues
Primer function carried out by glycogenin
How is glucose taken into cells? (GLUT transporters)
GLUT2:
Found in the liver and pancreatic β-cells.
Has high capacity but low affinity, meaning it only works well when glucose is high (like after a meal).
The liver uses it to take up a lot of glucose when it’s available.
GLUT4:
Found in muscle and fat cells.
Insulin increases the number of these transporters on the cell surface, boosting glucose uptake.
Exercise also increases GLUT4 on muscle cells, helping glucose enter cells faster.
What are the 3 steps in turning glucose into glycogen?
a) Glucose → Glucose 6-phosphate (G6P)
b) Glucose 6-phosphate → Glucose 1-phosphate (G1P)
c) Glucose 1-phosphate + UTP → UDP-glucose
How’s glucose turned into glucose 6-phosphate? (hexokinase/glucokinase)
Hexokinase does this in most cells:
Adds a phosphate group to trap glucose in the cell.
It’s inhibited by its product (G6P) — a form of feedback regulation.
Glucokinase in the liver (an isozyme of hexokinase):
Not inhibited by G6P.
Has a lower affinity (works best when glucose is high).
This lets the liver store glucose when there’s plenty, but doesn’t compete with the brain/muscle when glucose is low.
How is glucose 6-phosphate turned into glucose 1-phosphate G1P?
Done by phosphoglucomutase.
This enzyme has a phosphorylated serine residue that helps move the phosphate group to the right position.
How is glucose 1-phosphate + UTP turned into UDP-glucose?
Done by UDP-glucose pyrophosphorylase.
The reaction is reversible, but the body uses pyrophosphate hydrolysis to push it forward (makes it essentially one-way).
How is the glycogen molecule built from UDP-glucose?
The glucose units from UDP-glucose are added to glycogen by the enzyme glycogen synthase.
Glycogen synthase:
Adds glucose to the non-reducing end of the chain.
Forms α-1,4 glycosidic bonds (the main link in glycogen).
Can’t start a new chain — it needs a small existing chain (a primer).
That primer is provided by glycogenin:
It’s a protein that self-glucosylates — starts the chain by attaching a few glucose units to itself.
After that, glycogen synthase takes over and builds the chain further.
What is Glycogenolysis?
It’s the breakdown of glycogen (a stored form of glucose) into glucose-1-phosphate, and eventually free glucose, especially in the liver (for the whole body) and muscles (for themselves).
How is glycogen turned into glucose-1-phosphate (G1P)? What enzyme is needed for this?
Enzyme: Glycogen Phosphorylase
Removes glucose units from the non-reducing end of glycogen.
Breaks α-1,4 glycosidic bonds by adding orthophosphate (Pi) — this is called phosphorolysis.
The product is glucose-1-phosphate, which carries a negative charge, so it can’t leave the cell.
Although the reaction is reversible, inside cells there is so much Pi compared to glucose-1-P that it strongly goes forward.
What is the second stage of glycogenolysis? (branches)
Glycogen phosphorylase cannot cleave α-1,6 bonds at branch points (it gets stuck when 4 glucose units are left near a branch).
That’s where the Debranching Enzyme comes in. It has 2 activities:
Transferase – moves 3 of the 4 remaining glucose units to another chain.
α-1,6-glucosidase – removes the last branch glucose, which is released as free glucose (not G1P).
Now the main chain is straightened out, and glycogen phosphorylase can continue breaking it down.
How is glucose-1-phoshate turned into glucose-6-phosphate in the third stage of glycogenolysis?
Enzyme: Phosphoglucomutase
Converts G1P → G6P, which is a key intermediate in metabolism.
What happens in the fourth stage of glycogenolysis - what happens to glucose-6-phosphate?
G6P is trapped in the cell due to its charge.
In the liver, G6P can be turned into free glucose:
Enzyme: Glucose 6-phosphatase (located in the endoplasmic reticulum).
Removes the phosphate so glucose can exit the liver cell into the blood to maintain blood sugar levels.
In muscles, G6P enters glycolysis instead to produce energy for that muscle cell itself. It is not shared with the rest of the body.
How is glycogen phosphorylase regulated?
It’s a dimeric enzyme regulated by:
Allosteric effectors (respond to energy state of the cell, like AMP, ATP).
Covalent modification (phosphorylation/dephosphorylation).
Hormones:
Glucagon (liver) and adrenaline (muscle & liver) stimulate breakdown.
Insulin opposes glycogen breakdown (promotes storage instead).
How are glycogenesis and glycogenolysis regulated?
Glycogenesis and glycogenolysis are reciprocally regulated
Synthesis and breakdown are regulated by hormone triggered (adrenaline and/or glucagon) cAMP cascade acting through protein kinase A
What is the role of protein phosphatase 1?
Activated by signal cascade brought about by high insulin levels
Reverses effect of protein kinase A
Inactivates phosphorylase kinase and phosphorylase a by removing covalent p group
Activates glycogen synthase by removing covalent P group
What are glycogen storage diseases?
Inherited genetic defects which mean enzymes needed to degrade stored glycogen aren’t working properly
What is Von Gierkes disease?
Most common form (type 1)
Autosomal recessive, 1 person in 200000
Glucose-6-phosphatase missing
Hypoglycaemia due to lack of liver gluconeogenesis and glycogenolysis
Need regular supply of glucose even when asleep
What is Cori’s disease?
Type III
Deficiency of glycogen debranching enzyme
Glycogen accumulates with short side branches as these can’t be utilised by phosphorylase
Much less severe symptoms than von gierkes disease
What is McArldes disease?
Type V
Muscle phosphoylase missing
Can’t break down stored glycogen in muscle
Muscle cramps (due to high levels of ADP and alkaline conditions) can’t perform strenuous exercise
No increase in lactate in muscle upon exercise
