Coordinated Regulation of Glycogen Metabolism
What is glycogenolysis?
● The breakdown of glycogen into glucose provides the body with energy.
● Glycogen is stored in the muscles (~450g) and in the liver (~100g)
○ Liver: glycogen regulates blood glucose levels
○ Muscle: glycogen is a rapid source of energy in hypoxic conditions
■ Stops at a certain point suffice for ~ 20 seconds (depletes after 90 min)
● Occurs during periods of fasting or exercise when blood glucose levels are low =
hypoglycemia
What is glycogenesis?
● The synthesis of glycogen from glucose
● Occurs in the liver and muscle
● Happens in a fed state (an increase in blood glucose can lead to hyperglycemia)
Describe the general structure of glycogen and relate this to the biological advantages
of glycogen as an energy-storage polymer. How are the glycosidic bonds involved in
branching different from the linear bonds?
● Glycogen is a branched polymer where glucose is linked by glycosidic bonds
○ Glycosidic bonds are when an anomeric carbon (C1 of glucose) is attached to a
nitrogen or oxygen of another molecule. In this case, the glycosidic bond is
attached to the oxygen of C1 in another glucose molecule
○ You react a hemiacetal OH of C1 with the alcohol OH from another glucose
molecule at C4 in a condensation reaction
○ This forms the α (1→4) linkage
● The other glycosidic bond present is an α (1→6) linked branch
○ These branches occur every 8-14 residues
○ Each branch point must be at least 4 residues away from other branch points
○ The branching pattern optimizes the storage and mobilization of glucose
● Glycogenin is a residue protein that acts as a glycotransferase by attaching a glucose
residue donated by UDPG to the OH of its tyrosine residue. It extends the glucose chain
up to seven additional UDPG residues to form a glycogen primer
○ If there is a mutation in glycogenin, the body can not effectively synthesize
glycogen. This is because there is no priming unit for glucose molecules to add
onto.
■ In the liver, glycogen is broken down into glucose during periods of
fasting for energy. With the lack of glycogen in the liver, there is nothing
to be broken down, which causes a depletion of glucose in the blood. Low
levels of glucose in the blood can lead to hypoglycemia
■ In the muscle, glycogen is used for muscle contraction during exercise.
The inability to synthesize glycogen will result in increased muscle
weakness and fatigue during periods of exercise since there is no glycogen
stores to break down, thus no glucose to provide energy.
, ● Has non-reducing ends, where glucose units are added and removed, and reducing ends,
where there is a free anomeric carbon not involved in glycosidic bonds
● Advantages:
○ Efficient storage = allows it to be compact enough
○ Mobilization = having more branching ends allows multiple glucose molecules to
be released at once because enzymes can work simultaneously
○ Non-reducing ends increase the ability for synthesis/degradation
○ Decreases osmotic pressure
Compare the physiological roles of glycogen in the liver and skeletal muscle.
● Liver: maintains blood glucose levels
● Muscle: provides energy during exercise (stores it to form ATP for muscle
contraction)
Explain why skeletal muscle does not have receptors for glucagon
● Glucagon is a hormone that regulates your blood glucose levels
○ Stimulates glycogenolysis (glycogen breakdown) and gluconeogenesis (glucose
formation)
● The muscles role in glucose metabolism is to store and utilize glucose and not release it
into the bloodstream
● The muscle lacks the enzyme glucose-6-phosphatase, which means that glucose can not
be released into the bloodstream, therefore, they do not need glucagon to act on the
muscle
Describe in detail the steps involved in glycogenolysis. Identify the rate-limiting
enzyme.
Reaction 1: Formation of Glucose-1-Phosphate (G1P)
● This reaction is catalyzed by glycogen phosphorylase
○ Glycogen phosphorylase cleaves the α (1→4) bond, removing a glucose
molecule from a non-reducing end.
○ It can only remove glucose residues to within 4 residues of an α (1→6) branch
point (it will stop once there are 4 residues left)
● This reaction is known as a phosphorolysis, as it adds a phosphate group (from inorganic
phosphate) to C1. This is known as the limit dextrin, which is the point in a glycogen
molecule where phosphorylase can no longer act
● As a result, you are left with the following reaction:
○ Glycogen (n residues) + Pi ⇌ Glycogen(n-1 residues) + G1P
● This is the rate-controlled step
Reaction 2: Debranching enzyme
● This is a bifunctional enzyme
● It removes glycogen branches to make more glucose molecules accessible to glycogen
phosphorylase
● The debranching enzyme will break the α (1→4) bond and transfer the 3 glucose
residues from the limit branch to the nonreducing end of another branch to form a new α
(1→4) linkage
● The remaining α (1→6) bond is hydrolyzed
, ○ This yields a free glucose and a debranched glycogen chain
Reaction 3: Phosphoglucomutase Inteconverts G1P and G6P
● Phosphorylase converts the glycogen units into G1P and phosphoglutomase converts G1P
into G6P
● The phosphoryl group is transferred to C6 through a phosphorylation reaction, forming
glucose-1,6-bisphosphate
● A second phosphorylation reaction occurs, causing the product to be G6P
○ G6P can continue into the glycolytic pathway, or it can go to the pentose
phosphate pathway
Reaction 4: Glucose-6-Phosphatase converts G6P into glucose and Pi
● G6P can continue into the ER of the liver through the T1 transporter
● Glucose-6-phosphotase hydrolyzes G6P
○ This enzyme is only present in the liver, kidneys, and GIT
○ Muscles lack G6Pase, therefore it retains G6P
○ G6P + H2O → Glucose + Pi
● Glucose then leaves the ER via the glucose transporter T2, and Pi leaves via the T3
transporter
● Glucose then enters the bloodstream through GLUT 2 to increase the blood glucose
concentrations and restore them from hypoglycemia
● A deficiency in glucose-6-phosphatase yields a disease known as Von Gierke’s Disease
○ G6Pase catalyzes the final step of releasing glucose into the bloodstream by the
liver
○ A deficiency in G6Pase results in the accumulation of G6P and glycogen in the
liver
○ Treatment: drug-induced inhibition of glucose uptake by the liver (increases
blood glucose) and liver transplantation
Identify the subcellular location of glucose 6-phosphatase and discuss its role in
the release of glucose from the liver.
● The enzyme glucose-6-phosphatase is located in the smooth ER within the liver.
● G6P enters the smooth ER from the liver via T1
● G6Pase hydrolyzes G6P, which causes the phosphate to be removed from the sixth
carbon. This releases a free glucose and Pi into the cytosol, where glucose can then be
transported back into the bloodstream to increase glucose levels
Describe in detail the steps involved in glycogen synthesis. Identify the
rate-limiting enzyme.
Reaction 1: Synthesis of G1P
● Glucose → G6P → G1P
● Glucose to G6P is catalyzed by glucokinase or hexokinase. This reaction utilizes an
ATP molecule, releasing ADP
○ In the liver, this process uses glucokinase
○ In the muscle, this process uses hexokinase
● G6P → G1P is catalyzed by phosphoglucomutase
○ This enzyme transfers the phosphate group from C6 to C1
Reaction 2: Conversion of G1P to UDP-glucose
, ● G1P + UTP → UDP-glucose
● Catalyzed via UDP-glucose pyrophosphorylase
● UDP donates glucose for glycogen synthesis
● G1P attacks the two phosphates on UTP, cleaving PPi
● UMP gets linked to G1P, forming UDP-glucose
● PPi undergoes hydrolysis via inorganic pyrophosphatase to form 2 Pi
● This reaction is irreversible
Reaction 3: Glycogen synthase
● UDP-glucose + glycogen (n residues) → UDP + glycogen (n + 1 residues)
● These UDPG molecules are added onto the glycogenin primer. Glycosyltransferase
transfers a glucose residue from UDPG onto the glycogenin primer, extending it up to
seven residues. Glycogen synthase can then attach glucose residues onto the primer
● UDPG is transferred to the nonreducing end of a C4 group of one of the glucose
molecules within the glycogen chain. This results in the formation of an α (1→4)
glycosidic bond via the enzyme glycogen synthase
○ This enzyme can only add glucose to a chain that is at least 4 residues long
○ This enzyme is under allosteric control
■ Inhibited by: ATP, ADP, Pi concentrations
■ The dephosphorylated form is activated by G6P
● To regenerate UTP, undergo a phosphoryl transfer
○ UDP + ATP → UTP + ADP
○ Catalyzed via nucleoside diphosphate kinase
Reaction 3: Glycogen Branching Enzyme
● Glycogen synthase adds glucose molecules to form α (1→4) bonds
● The branching enzyme transfers a block of 6-8 residues from a chain of at least 10
residues, leaving at least 4 behind, to the C6 of a glucose residue on another or the
same chain
● This forms α (1→6) glycosidic bonds, which allows glycogen to be more efficiently
stored and for easy mobilization of glucose
● When forming new branch points, they must be at least 4 residues away from an existing
branch point
● Branching Functions:
○ Makes it more soluble and compact
○ Decreases osmotic pressure
○ Creates no reducing ends that are accessible for synthesis and degradation
Compare glycogen synthesis to glycogen breakdown, noting points in common
and points of disparity.
● Key Common features: involves G6P, occurs in the liver and muscle, regulated by
hormones
● Key differences: stores glucose vs releases energy, stimulated by fed state vs
fasting or exercise, makes bonds vs breaks bonds, uses energy (UTP/ATP) vs has
no energy input requirement
Feature Glycogenesis Glycogenolysis
What is glycogenolysis?
● The breakdown of glycogen into glucose provides the body with energy.
● Glycogen is stored in the muscles (~450g) and in the liver (~100g)
○ Liver: glycogen regulates blood glucose levels
○ Muscle: glycogen is a rapid source of energy in hypoxic conditions
■ Stops at a certain point suffice for ~ 20 seconds (depletes after 90 min)
● Occurs during periods of fasting or exercise when blood glucose levels are low =
hypoglycemia
What is glycogenesis?
● The synthesis of glycogen from glucose
● Occurs in the liver and muscle
● Happens in a fed state (an increase in blood glucose can lead to hyperglycemia)
Describe the general structure of glycogen and relate this to the biological advantages
of glycogen as an energy-storage polymer. How are the glycosidic bonds involved in
branching different from the linear bonds?
● Glycogen is a branched polymer where glucose is linked by glycosidic bonds
○ Glycosidic bonds are when an anomeric carbon (C1 of glucose) is attached to a
nitrogen or oxygen of another molecule. In this case, the glycosidic bond is
attached to the oxygen of C1 in another glucose molecule
○ You react a hemiacetal OH of C1 with the alcohol OH from another glucose
molecule at C4 in a condensation reaction
○ This forms the α (1→4) linkage
● The other glycosidic bond present is an α (1→6) linked branch
○ These branches occur every 8-14 residues
○ Each branch point must be at least 4 residues away from other branch points
○ The branching pattern optimizes the storage and mobilization of glucose
● Glycogenin is a residue protein that acts as a glycotransferase by attaching a glucose
residue donated by UDPG to the OH of its tyrosine residue. It extends the glucose chain
up to seven additional UDPG residues to form a glycogen primer
○ If there is a mutation in glycogenin, the body can not effectively synthesize
glycogen. This is because there is no priming unit for glucose molecules to add
onto.
■ In the liver, glycogen is broken down into glucose during periods of
fasting for energy. With the lack of glycogen in the liver, there is nothing
to be broken down, which causes a depletion of glucose in the blood. Low
levels of glucose in the blood can lead to hypoglycemia
■ In the muscle, glycogen is used for muscle contraction during exercise.
The inability to synthesize glycogen will result in increased muscle
weakness and fatigue during periods of exercise since there is no glycogen
stores to break down, thus no glucose to provide energy.
, ● Has non-reducing ends, where glucose units are added and removed, and reducing ends,
where there is a free anomeric carbon not involved in glycosidic bonds
● Advantages:
○ Efficient storage = allows it to be compact enough
○ Mobilization = having more branching ends allows multiple glucose molecules to
be released at once because enzymes can work simultaneously
○ Non-reducing ends increase the ability for synthesis/degradation
○ Decreases osmotic pressure
Compare the physiological roles of glycogen in the liver and skeletal muscle.
● Liver: maintains blood glucose levels
● Muscle: provides energy during exercise (stores it to form ATP for muscle
contraction)
Explain why skeletal muscle does not have receptors for glucagon
● Glucagon is a hormone that regulates your blood glucose levels
○ Stimulates glycogenolysis (glycogen breakdown) and gluconeogenesis (glucose
formation)
● The muscles role in glucose metabolism is to store and utilize glucose and not release it
into the bloodstream
● The muscle lacks the enzyme glucose-6-phosphatase, which means that glucose can not
be released into the bloodstream, therefore, they do not need glucagon to act on the
muscle
Describe in detail the steps involved in glycogenolysis. Identify the rate-limiting
enzyme.
Reaction 1: Formation of Glucose-1-Phosphate (G1P)
● This reaction is catalyzed by glycogen phosphorylase
○ Glycogen phosphorylase cleaves the α (1→4) bond, removing a glucose
molecule from a non-reducing end.
○ It can only remove glucose residues to within 4 residues of an α (1→6) branch
point (it will stop once there are 4 residues left)
● This reaction is known as a phosphorolysis, as it adds a phosphate group (from inorganic
phosphate) to C1. This is known as the limit dextrin, which is the point in a glycogen
molecule where phosphorylase can no longer act
● As a result, you are left with the following reaction:
○ Glycogen (n residues) + Pi ⇌ Glycogen(n-1 residues) + G1P
● This is the rate-controlled step
Reaction 2: Debranching enzyme
● This is a bifunctional enzyme
● It removes glycogen branches to make more glucose molecules accessible to glycogen
phosphorylase
● The debranching enzyme will break the α (1→4) bond and transfer the 3 glucose
residues from the limit branch to the nonreducing end of another branch to form a new α
(1→4) linkage
● The remaining α (1→6) bond is hydrolyzed
, ○ This yields a free glucose and a debranched glycogen chain
Reaction 3: Phosphoglucomutase Inteconverts G1P and G6P
● Phosphorylase converts the glycogen units into G1P and phosphoglutomase converts G1P
into G6P
● The phosphoryl group is transferred to C6 through a phosphorylation reaction, forming
glucose-1,6-bisphosphate
● A second phosphorylation reaction occurs, causing the product to be G6P
○ G6P can continue into the glycolytic pathway, or it can go to the pentose
phosphate pathway
Reaction 4: Glucose-6-Phosphatase converts G6P into glucose and Pi
● G6P can continue into the ER of the liver through the T1 transporter
● Glucose-6-phosphotase hydrolyzes G6P
○ This enzyme is only present in the liver, kidneys, and GIT
○ Muscles lack G6Pase, therefore it retains G6P
○ G6P + H2O → Glucose + Pi
● Glucose then leaves the ER via the glucose transporter T2, and Pi leaves via the T3
transporter
● Glucose then enters the bloodstream through GLUT 2 to increase the blood glucose
concentrations and restore them from hypoglycemia
● A deficiency in glucose-6-phosphatase yields a disease known as Von Gierke’s Disease
○ G6Pase catalyzes the final step of releasing glucose into the bloodstream by the
liver
○ A deficiency in G6Pase results in the accumulation of G6P and glycogen in the
liver
○ Treatment: drug-induced inhibition of glucose uptake by the liver (increases
blood glucose) and liver transplantation
Identify the subcellular location of glucose 6-phosphatase and discuss its role in
the release of glucose from the liver.
● The enzyme glucose-6-phosphatase is located in the smooth ER within the liver.
● G6P enters the smooth ER from the liver via T1
● G6Pase hydrolyzes G6P, which causes the phosphate to be removed from the sixth
carbon. This releases a free glucose and Pi into the cytosol, where glucose can then be
transported back into the bloodstream to increase glucose levels
Describe in detail the steps involved in glycogen synthesis. Identify the
rate-limiting enzyme.
Reaction 1: Synthesis of G1P
● Glucose → G6P → G1P
● Glucose to G6P is catalyzed by glucokinase or hexokinase. This reaction utilizes an
ATP molecule, releasing ADP
○ In the liver, this process uses glucokinase
○ In the muscle, this process uses hexokinase
● G6P → G1P is catalyzed by phosphoglucomutase
○ This enzyme transfers the phosphate group from C6 to C1
Reaction 2: Conversion of G1P to UDP-glucose
, ● G1P + UTP → UDP-glucose
● Catalyzed via UDP-glucose pyrophosphorylase
● UDP donates glucose for glycogen synthesis
● G1P attacks the two phosphates on UTP, cleaving PPi
● UMP gets linked to G1P, forming UDP-glucose
● PPi undergoes hydrolysis via inorganic pyrophosphatase to form 2 Pi
● This reaction is irreversible
Reaction 3: Glycogen synthase
● UDP-glucose + glycogen (n residues) → UDP + glycogen (n + 1 residues)
● These UDPG molecules are added onto the glycogenin primer. Glycosyltransferase
transfers a glucose residue from UDPG onto the glycogenin primer, extending it up to
seven residues. Glycogen synthase can then attach glucose residues onto the primer
● UDPG is transferred to the nonreducing end of a C4 group of one of the glucose
molecules within the glycogen chain. This results in the formation of an α (1→4)
glycosidic bond via the enzyme glycogen synthase
○ This enzyme can only add glucose to a chain that is at least 4 residues long
○ This enzyme is under allosteric control
■ Inhibited by: ATP, ADP, Pi concentrations
■ The dephosphorylated form is activated by G6P
● To regenerate UTP, undergo a phosphoryl transfer
○ UDP + ATP → UTP + ADP
○ Catalyzed via nucleoside diphosphate kinase
Reaction 3: Glycogen Branching Enzyme
● Glycogen synthase adds glucose molecules to form α (1→4) bonds
● The branching enzyme transfers a block of 6-8 residues from a chain of at least 10
residues, leaving at least 4 behind, to the C6 of a glucose residue on another or the
same chain
● This forms α (1→6) glycosidic bonds, which allows glycogen to be more efficiently
stored and for easy mobilization of glucose
● When forming new branch points, they must be at least 4 residues away from an existing
branch point
● Branching Functions:
○ Makes it more soluble and compact
○ Decreases osmotic pressure
○ Creates no reducing ends that are accessible for synthesis and degradation
Compare glycogen synthesis to glycogen breakdown, noting points in common
and points of disparity.
● Key Common features: involves G6P, occurs in the liver and muscle, regulated by
hormones
● Key differences: stores glucose vs releases energy, stimulated by fed state vs
fasting or exercise, makes bonds vs breaks bonds, uses energy (UTP/ATP) vs has
no energy input requirement
Feature Glycogenesis Glycogenolysis
