Glycogen

metabolism
Glycogen metabolism
• Session objective
• At the end of the session you should be able to:
• Define glycogenesis and glycogenolysis
• Describe glycogenesis and glycogenolysis
• Identify the role of glycogen in the skeletal muscle and
liver.
• Identify regulation of glycogen metabolism in the liver
and skeletal muscle.

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• What will happen in the glucose level after a meal
which contain high carbohydrate diet?

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Structure of Glycogen

• Glycogen, the storage form of glucose, is a branched glucose

polysaccharide composed of chains of glucosyl units linked by α-1,4
bonds with α-1,6 branches every 8 to 10 residues.
• In a molecule of this highly branched structure, only one glucosyl
residue has an anomeric carbon that is not linked to another glucose
residue.
• This anomeric carbon at the beginning of the chain is attached to the
protein glycogenin.
• The other ends of the chains are called nonreducing ends because they
cannot form a carbonyl group when converted to straight chain form.
• The branched structure permits rapid degradation and rapid synthesis
of glycogen.
• because enzymes can work on several chains simultaneously from the
multiple nonreducing ends.
• Glycogen is present in tissues as polymers of very
high molecular weight collected in glycogen
particles.
• The enzymes involved in glycogen synthesis and
degradation and some of the regulatory enzymes
are bound to the surface of the glycogen particles.
What is the function of glycogen
in liver and skeletal muscle?
• In the Muscle:
• Glycogen stores serve as a fuel source for the generation
of ATP.
• In the liver:
• Glycogen stores serve as a source of blood glucose.
• During fasting or during extreme need (e.g., exercise).
 Glycogenesis (glycogen
synthesis)
 Glycogen is synthesized initially by phosphorylation of glucose
to glucose-6-phosphate. In the liver, the enzyme is glucokinase.
In muscle, the enzyme is hexokinase. Both enzymes achieve the
same chemical end-point.

 Glucose + ATP Glucose-6-phosphate + ADP

 In the second step, glucose-6-phosphate is converted to
glucose-1-phosphate by phosphoglucomutase.

 Glucose-6-phosphate Glucose-1-phosphate
 Phosphoglucomutase is the only enzyme common to
glycogenesis and glycogenolysis.

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Uridine diphosphate glucose (UDP-glucose) is formed
from glucose-1-phosphate during glycogenesis.
Formation of UDP-glucose: The enzyme, UDP-
glucose pyrophosphorylase catalyses the
reaction of glucose-1-phosphate with UTP to
form UDP-glucose. Note that pyrophosphate
(PPi) formed is rapidly converted to phosphate
by pyrophosphatase and this drives the reaction
in one direction.
UDP-glucose serves as the molecule that “adds” a glucose moiety
to the growing glycogen molecule during synthesis. A primer is
needed for this process: this primer is made on a protein called
glycogenin, which is part of the glycogen molecule. Glycogenin is
glucosylated by UDP glucose on a tyrosine residue hydroxyl group
of glycogenin. Glycogenin is itself an enzyme that phosphorylates
itself by autocatalysis. Further glucose residues are added (by
glycogenin autocatalysis) to form a chain of 6 or 7 glucose units
joined by alpha(1->4) links.
Glycogen synthesis (glycogenesis)
• After about 6 or 7 glucose residues, to form a glucan chain attached to
glycogenin, have been added to glycogenin, glycogen synthase takes
over the process.
• Glycogen synthase then adds further glucose residues as alpha(1->4)
units, using UDP-glucose as a substrate.
• Branching enzyme creates the alpha(1->6) branches of glycogen by
transferring groups of at least 6 residues from one chain to a nearby
residue or a residue in the same chain, creating branch points.
• Each branch point then grows as more glucose residues are added
from UDP-glucose in alpha(1->4) linkages. At the same time, branching
enzyme creates branches at new branch points. This continues till
molecules up to 50,000 or more glucose residues are made.
Glycogen synthesis (glycogenesis): Growing chains with
branch points and branches
Glycogen synthesis (glycogenesis): further elongation and branching occur with glycogen
synthase and branching enzyme to create a large glycogen molecule.
Regulation of glycogenesis
• The rate limiting step of glycogenesis is glycogen
synthase.
• Glycogen synthase is two forms:
• phosphorylated form, inactive form.
• dephosphorylated form, active.
• Glycogen synthesis is occur after a carbohydrate
meal → increased blood glucose level→ stimulate
the pancreases to secrete insulin→ promotes
glycogenesis
• Glucagon inhibits glycogenesis.
Glycogenolysis (glycogen
breakdown)
• At least 3 enzymes are involved in breakdown of
glycogen into monosaccharide (glucose-1-phosphate)
subunits.
• Glycogen phosphorylase
• Hydrolyses alpha(1->4) bonds between glucose molecules to
form glucose-1-phosphate.
• Removes residues from the terminal branches, sequentially
until there are 4 glucose residues joined to an alpha(1->6)
branch point.
• This requires pyridoxal phosphate as a coenzyme.
• This step is a rate limiting
• Phosphoglucomutase converts G-1P into G-6P.
• Glucan transferase:
• transfers 3 glucose residues at a time from the branch
point to another one.
• α-1,6-glucosidase (debranching enzyme)
• removes the one residue joined to the branch point with
an alpha(1->6) link, releasing glucose as a product
• Phosphoglucomutase converts G-1P into G-6P.
• The glucose 6-phosphate derived from the
breakdown of glycogen has three possible fates:
1. It can be metabolized by glycolysis,
2. it can be converted into free glucose for release
into the bloodstream, and
3. it can be processed by the pentose phosphate
pathway to yield NADPH and ribose derivatives.
Regulation of
glycogenolysis
• The key step for rate limiting of glycogenolysis is
glycogen phosphorylase enzyme.
• Glycogen phophorylase has two isoforms
• Glycogen phosphorylase a
• active form
• phosphorylated from
• By phosphorylase kinase
• Glycogen phosphorylase b
• Inactive form
• dephosphorylated form
• by phosphoprotein phosphatase
• Glycogen phosphorylase regulation is different in
the liver and muscle.
• In the liver:
• Glucose is the inhibitory of glycogen degradation in the
liver.
• Glucose binds to the phosphorylase a and making them
to inactive forms.
• Thus, glycogen is not mobilized when glucose is already
abundant.
• In the muscle: the default form is phosphorylase b.
• This muscle phosphorylase is active during muscle
contraction.
• High concentration of AMP is allosteric activators of
muscle phophorylase.
• Glucose-6phosphate and ATP are inhibitory of muscle
phosphorylase.
• By stabilizing phosphorylase b.
• Muscle lacks glucose-6 phosphatase, which catalyze
G6P to glucose. Therefore, muscles can not deliver
glucose to the blood.
• Glycogen metabolism also regulated by hormones.
• Insulin prevents glycogenolysis.
• Glucagon and epinephrine promotes glycogenolysis.
Glucagon is secreted in response to low blood glucose
level such as during fasting and starvation.
• Difference between liver and muscle glycogenolysis
regulation
 Glucagon has no effect on muscle
 AMP is an allosteric activator of the muscle
glycogen phosphorylase but not liver glycogen
phosphorylase.
 Glucose is inhibitor of glycogen phosphorylase a in
liver but not muscle glycogen phosphorylase.
Glycogen storage disease
Gluconeogenesis
• Learning objective
• Define gluconeogenesis
• Describe gluconeogenesis pathway
• Identify the precursors of gluconeogenesis
• Identify conditions of gluconeogenesis occur in our body
• Identify regulation of gluconeogenesis

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• What will happen in the body if Glucose level goes
to down?

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Gluconeogenesis
• Gluconeogenesis is synthesis of glucose from non-
carbohydrate sources.
• such as pyruvate, lactate, glycerol, amino acids ( alanine
and glutamine and other gluconeogenic amino acids).
• Occurs mainly in the liver and to some extent in the
kidney cortex and small intestines.
• Most enzymes of Gluconeogenesis are present in Cytosol,
but
• Pyruvate Carboxylase is located in Mitochondrial matrix,
whereas
• Glucose-6-Phosphatase is bound to the smooth endoplasmic
reticulum
Significance of
gluconeogenesis
• Gluconeogenesis produces glucose when carbohydrate is
not available in sufficient amounts from the diet.
• Glucose produced is for maintenance of blood glucose
levels during starvation or during vigorous exercise .
• Brain and RBCs depend almost entirely on blood glucose
as energy source
• Glucose is required in Adipose Tissues as a source of
Glycerol
• Under Anaerobic conditions glucose is the major fuel for
energy production in the Skeletal muscle.
• Glucose is the precursor of Lactate in Mammary gland.
Relationship beteween
glycolysis and
glucneogenesis
• Gluconeogenesis is not exactly the reversal of
Glycolysis.
• Three Irreversible reactions in Glycolysis must be
bypassed for Gluconeogenesis to occur.
• The three irreversible reaction are Hexokinase,
Phosphofructokinase and Pyruvate kinase
reactions.
• Therefore, “new” enzymes are needed to reverse
gluconeogenesis.
• There are 4 enzymes that are unique to gluconeogenesis
that bypass the 3 irreversible enzymes of glycolysis:
• Pyruvate carboxylase (pyruvate to oxaloacetate)
• Phosphoenolpyruvate carboxykinase (PEPCK)
(oxaloacetate to phosphoenolpyruvate)
• Fructose-1,6-bisphosphatase (fructose-1,6-bisphosphate
to fructose-6-phosphate)
• Glucose-6-phosphatase (G-6-P to glucose)
• The remaining enzyme steps are reversible and so are the
same in both glycolysis and gluconeogenesis.
• The following points must be noted about the
pathway of Gluconeogenesis:
• Glucose-6-Phosphatase (G-6-Phosphatase):
• Present in Liver and Kidney, but absent in Skeletal
Muscle and Adipose Tissues
• G-6-Phosphatase allows tissue to release Glucose
into the blood.
• Reaction catalyzed by G-6-Phosphatase is as follows:
• G-6-Phosphate + H2O → Glucose + Pi
Pathways of
gluconeogenesis
• Enzymes that are
unique to
• glycolysis (left) are
shown in red.
• Enzymes unique to
gluconeogenesis (right)
are shown in blue.
• Energy Requirements
• Conversion of 2 pyruvate molecule to one molecule of
glucose require 6ATP.
• As 2 moles of pyruvate are carboxylated by pyruvate
carboxylase, 2 moles of ATP are hydrolyzed.
• PEPCK requires 2 moles of GTP (the equivalent of 2
moles of ATP) to convert 2 moles of oxaloacetate to 2
moles of PEP.
• 2 moles of ATP are used when 2 moles of 3-
phosphoglycerate are phosphorylated, forming 2 moles
of 1,3-bisphosphoglycerate.
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• Gluconeogenesis needs NADH for the reduction of
1,3-bis-P-glycerate to triose-P. For most precursors
this is formed in the mitochondria and transported
across the mitochondrial membrane via malate.
• Lactate is unique in that lactate dehydrogenase
only occurs in the cytosol so that NADH is directly
available in the cytosol for gluconeogenesis.
• Under fasting conditions, the energy required for
gluconeogenesis is obtained from β-oxidation of
fatty acids.
Gluconeogenesis from
lactate
• Lactate can be converted to glucose by gluconeogenesis
by first being converted to pyruvate (lactate
dehydrogenase).
• Lactate dehydrogenase reaction supplies the NADH for
the glyceraldehyde-3-phosphate dehydrogenase step to
form glyceraldehyde-3-phosphate.
• Lactate from RBCs glycolysis can be made into glucose,
mainly in the liver, by gluconeogenesis.
• Lactate production in muscle can be cleared and
resynthesized into glucose by liver gluconeogenesis, and
the glucose can be reused by skeletal muscle as a source
of energy.
Gluconeogenesis and the Cori cycle:
When there is excessive
build-up of lactate in skeletal
muscle, the lactate enters
the bloodstream and is taken
up by the liver, where it
undergoes gluconeogenesis:
the glucose so formed can
then be reused by the
muscle. This is called the Cori
cycle.

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Gluconeogenesis from
alanine
• Glucose-Alanine cycle
• Pyruvate can be converted to alanine by transamination in
muscle and other tissues.
• The alanine enters the bloodstream and is taken up by the
liver, where its undergo gluconeogenesis to glucose and its
amino group gets converted to urea by the urea cycle for
excretion.
• The glucose formed from the alanine can enter the
bloodstream and be used as a fuel by other tissues.
• The glucose-alanine cycle therefore serves to allow
excretion of nitrogen from amino acids as well as to produce
glucose from the carbon skeleton of alanine.
Glucose-alanine cycle cont’d

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Gluconeogenesis from Glycerol

• Glycerol enters gluconeogenesis:

• At the level of triose phosphates
• Following release of glycerol & fatty acids from adipose tissue
into plasma
• The glycerol is taken up into liver& phosphorylated by glycerol
kinase
• Then enters the gluconeogenic pathway as dihydroxyacetone
phosphate
• Only the glycerol component of fats can be converted into
glucose:
• Acetyl CoA & even c-chain number fatty acids:
• Can’t serve as substrates for net gluconeogenesis
• Odd C-chain number & branched-chain fatty acids
• yield propionyl-CoA, which can serve as a minor precursor for
gluconeogenesis
• Propionyl-CoA is first carboxylated to methylmalonyl CoA;
• w/c undergoes racemase & mutase rxn’s to form succinyl
CoA
• Succinyl CoA is converted into malate.
• Then malate exits the mitochondrion & is oxidized to
oxaloacetate.
• Then oxaloacetate is decarboxylated by PEPCK, the 3-C of
propionate appear intact in PEP for gluconeogenesis
Regulation of Gluconeogenesis

• Gluconeogenesis occurs
• During fasting (after 12 hr fasting)
• During prolonged exercise
• By a high-protein diet
• Under conditions of stress.
• The factors that promote the overall flow of carbon
from pyruvate to glucose include:
• The availability of substrate and
• Changes in the activity or amount of certain key
enzymes of glycolysis and gluconeogenesis.

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• Regulation of gluconeogenesis in the liver:
• Pyruvate carboxylase:
• activated by acetyl-CoA
• Phosphoenolpyruvate carboxykinase:
• induced by glucagon, epinephrine and glucocorticoids.
• Repressed by insulin
• Frucktose 1, 6 Bisphosphatase:
• inhibited by F2,6bisphosphate and AMP
• Induced during fasting
• Glucose-6-phosphatase:
• induced during fasting
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Gluconeogenesis and glycolysis regulation

Enzymes
2.7.1.1= Hexokinase
2.7.1.11= 6-
Phosphofructokinase
2.7.1.40 Pyruvate kinase
3.1.3.9 Glucose-6-
phosphatase
3.1.3.11 Fructose-bis-
phosphatase
4.1.1.32
Phosphoenolpyruvate
carboxykinase (PEPCK)
6.4.1.1. Pyruvate carboxylase
Summary
• What is glycogen?
• What is glycogenesis?
• What is glycogenine?
• When glycogenesis will be takes place in the cell?
• What is glycogenolysis?
• What is the metabolic difference b/n muscle and liver
cell in glycogen?
• What is gluconeogenesis?
• What is the precursor for gluconeogenesis?
•
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Study Questions

1. Why is Glycolysis important?

2. What are the different types of Glycolysis?
3. What are the major functions of Glycolysis?
4. What is the fate of Pyruvate (a) Under
Anaerobic conditions, (B) Under Aerobic
conditions?
5. Give the total and net amounts of ATP
formed when One Glucose is metabolized via
Anaerobic Glycolysis?
6. What are the Total and Net amounts of ATP
formed when One Molecule of Glucose is
metabolized via Aerobic Glycolysis?
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9. What is the function of Pyruvate
Dehydrogenase (PDH) Complex?
10. What is the significance of TCA cycle?
11. How many molecules of ATP are produced
when One Acetyl-CoA goes through the TCA
cycle?
12. What is the significance of
Gluconeogenesis?
13. What is the Cori cycle (Lactic acid cycle)?

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14. What is the major role of PPP shunt in Red
Blood Cells?
15. Why does a person with G-6-PD deficiency
suffer from hemolytic anemia?
16. What are some of the functions of
Glycogen?
17. What happens to G-6-P in Liver, Kidneys
and Skeletal Muscle?
18. What is gluconeogenesis?
19. What are the precursor of
gluconeogenesis?
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