This document discusses glycogen metabolism. It notes that glycogen is the major storage carbohydrate in animals, found mainly in the liver and skeletal muscle. Glycogen is a branched polymer of glucose that is synthesized from glucose-1-phosphate via glycogen synthase. It can be broken down to glucose-1-phosphate by glycogen phosphorylase to maintain blood glucose levels. The activities of glycogen synthase and phosphorylase are regulated by phosphorylation and dephosphorylation in response to hormones like insulin and glucagon to control glycogen synthesis and breakdown.

1. GLYCOGEN METABOLISM
Medical Biochemistry
SoM&D – UDOM
August 2021

2. Glycogen
• Glycogen is the major storage
carbohydrate in animals
• It is a rapidly mobilizable form of glucose
storage
• Glycogen guarantees a quick supply of
glucose to the body in response to falling
blood glucose levels

3. Glycogen
• The main stores of glycogen in the body
are found in skeletal muscle and the liver
• Glycogen makes up to 10% of the fresh
weight of a well fed adult liver and 1-2% of
the fresh weight of a resting muscle.

4. Glycogen
• It is a highly branched polymer of α-D-
glucose
• Linked linearly by (1→4) glycosidic
linkages with numerous  (1→6) linkages
at branch points
• The molecules of glycogen exists in
discrete cytoplasmic granules that
contain most of enzymes necessary for
glycogen synthesis and degradation

5. Glycogen
• Glycogen is stored in large cytosolic granules
• The elementary (single) particle of glycogen,
the β-particle, about 21 nm (10-40nm) in
diameter, consists of up to 55,000 glucose
residues with about 2,000 non-reducing ends
• Twenty to 40 of these particles cluster together
to form α-rosettes, especially in hepatocytes

6. Glycogen
• Muscle glycogen is a source of glucose for the
muscle itself. This is because muscle cells lack
the glucose-6-phosphatase enzyme needed for
liberating glucose from G-6-P
• Liver glycogen can be used to produce free
glucose for export to blood to maintain blood
glucose level between meals
• After 12-18 hrs of fasting liver glycogen is
almost totally depleted

7. A section of glycogen molecule

9. Glycogenesis
• Glycogen synthesis occurs in the cytoplasm,
and requires a supply of ATP and uridine
triphosphate (UTP)
•
• Glucose is phosphorylated to G-6-P
• Glucose + ATP  G-6-P by hexokinase in the
muscle and glucokinase in the liver
• G-6-P is isomerized to G-1-P by
phosphoglucomutase

10. Glycogenesis cont…
• G-1-P reacts with uridine triphosphate (UTP) to
form UDP-glucose
• UDP-glucose is the source of glucosyl residues
that are added to the growing glycogen
molecule
– UDP-glucose is the substrate of glycogen synthase
• G-1-P +UTP → UDP-Glucose + PPi

11. Glycogenesis cont…
• Synthesis of UDP-Glc is catalysed by enzyme:
UDP-glucose pyrophosphorylase
• The high energy pyrophosphate (PPi) group is
hydrolyzed to two inorganic phosphates (2Pi)
ΔG=-25kJ/mol
• Pyrophosphatase catalyses this reaction to
release 2moles of inorganic phosphate and this
helps to drive the previous reaction forward

12. Glycogenesis cont…
• Glucose residues are added to glycogen at the
non-reducing ends of the branched glycogen
molecule
• UDP is released as a reaction product
• Glycogen synthase is responsible for
polymerization of glucose residues into the
glycogen polymer
• It catalyzes transfer of the glucose from UDP-
glucose to the hydroxyl at C4 of the terminal
residue (non-reducing end) of a glycogen chain

13. Glycogenesis cont…
• This forms an (1→4) glycosidic linkage
• The enzyme cannot initiate a glucose chain
synthesis using free glucose as an acceptor of
a molecule of glucose from UDP-glucose
• An  (1→4) glucose chain primer having at
least four glucose residues must be present for
the enzyme to work
• A fragment of glycogen remaining in a cell can
serve as a primer in cells whose glycogen
stores are not completely depleted.

14. Glycogenesis cont…
• In the absence of glycogen fragment, to act as
a primer
• The primer is usually formed on and by the
protein gycogenin
• Glycogenin acts as a glucose acceptor and
catalyzes the transfer of the first few (7)
glucose residues from UDP-glucose
• Glycogenin stays associated with and is found
in the center of the completed molecule of
glycogen

15. Glycogenesis cont…
• At this point glycogen synthase takes over,
further extending the glycogen chain
• Glycogen synthase can not catalyze the
branching that is seen in glycogen molecules
because it can not make the (α1→6) bond
found at branch points
• Branching is done by the glycogen-branching
enzyme.
– also called amylo (1→4) to (1→6)
transglycosylase or glycosyl-(4→6)-transferase

16. Glycogenesis cont…
• The branching enzyme catalyses the transfer of
a terminal fragment of about 6-8 glucose
residues from the non reducing end of a
glycogen branch having atleast 11 residues
• The enzyme will attach it to the OH group of C-
6 at a more interior position on the same
chain it was broken off from or at a different
chain
• This fragment will constitute the initial chain of a
new branch

17. Glycogenesis cont…
• Then elongation continues at the non reducing
ends of the old and new branches
• Elongation and branching continues throughout
the macromolecule as described above
increasing its size.

18. Glycogenesis cont…
• The extensive branching makes the molecule
more soluble and increases the number of non
reducing ends
• Thus branching increase the number of sites
accessible to glycogen synthase and glycogen
phosphorylase both of which act only on non
reducing ends

19. Glycogenolysis
• Glycogen breakdown is catalyzed by glycogen
phosphorylase
• The glycogenolytic pathway cleaves off residues of
glucose, one by one, from the outer branches of
glycogen, i.e the non reducing ends
• The enzymes involved are: glycogen
phoshorylase which catalyzes a phosphorolysis
reaction through which the glucose residues in an
(α1→4) linkage are cleaved as glucose-1-
phosphate.

20. Glycogen phosphorylase
reaction

21. Glycogenolysis cont…
• In phosphorolysis reaction some of the energy
released when the glycosidic bond is broken is
conserved in the bond between phosphate and
glucose in the G-1-P molecule that is formed
• Glycogen phosphorylase acts repetitively on the
non reducing ends of glycogen branches until it
reaches a point four glucose residues away from
an (α1→6) branch point where its action stops.
• At this point the second enzyme of glycogenolysis
takes over. This is the debranching enzyme
– Also called oligo (α1→6) to (α1→4) glucantransferase

22. Glycogenolysis cont…
• The debranching enzyme catalyzes two
successive reactions
• A fragment of 3 residues out of the 4 glucose
residues remaining on the branch is hydrolysed
off and reattached at the main chain in an
(α1→4) linkage

23. Glycogenolysis cont…
• The remaining glucosyl residue at the
branching point in an (α1→6) linkage with the
main chain is hydrolysed and released as free
glucose
• After the debranching enzyme has done this,
glycogen phosphorylase activity can continues
until the next branching point is approached.

24. Glycogenolysis cont…
• The produced G-1-P is acted upon by a
third enzyme, the phosphoglucomutase
which isomerizes G-1-P to G-6-P
• The G-6-P can enter glycolysis, in case of
glycogenolysis in muscle cells or be used
for other functions in the same tissue

25. Glycogenolysis cont…
• In the liver cells G-6-P can be converted
to free glucose by glucose-6-phosphatase,
an enzyme found only in the endoplasmic
reticulum of the cells of the liver and
kidney cortex
• This glucose can then be transported into
the blood to maintain blood glucose levels
and supply tissues that preferentially or
exclusively oxidize glucose for energy

26. Regulation of glycogen metabolism
• The synthase and phosphorylase are
reciprocally regulated
• The enzymes are regulated both allosterically
and by covalent modification (hormonal control)
• The synthesis and degradation enzymes can
exist in an active or inactive form
– Phosphorylase b (dephosphorylated)(inactive) and
Phosphorylase a (phosphorylated) (active)
– Glycogen synthase a (active form)
(dephosphorylated) and Glycogen synthase b
(inactive form) (phosphorylated)

29. • In Muscle cells
– Ca2+, the signal for muscle contraction, binds to and
activates phosphorylase b kinase, promoting conversion of
phosphorylase b to the active a form
– AMP, which accumulates in vigorously contracting muscle
as a result of ATP breakdown, binds to and activates
phosphorylase, speeding the release of glucose 1-
phosphate from glycogen
– When ATP levels are adequate, ATP blocks the allosteric
site to which AMP binds, inactivating phosphorylase.
– When the muscle returns to rest, a second enzyme,
phosphorylase a phosphatase, also called
phosphoprotein phosphatase 1 (PP1), removes the
phosphoryl groups from phosphorylase a, converting it to the
less active form, phosphorylase b.

30. • In hepatocytes
– When blood glucose levels return to normal,
glucose enters hepatocytes and binds to an
inhibitory allosteric site on phosphorylase a
– This binding also produces a conformational
change that exposes the phosphorylated Ser
residues to PP1, which catalyzes their
dephosphorylation and inactivates the
phosphorylase

34. • Glycogen synthase is also under hormonal mediated
regulation by covalent modification
– Glucagon/epinephrine causing its phosphorylation and
inactivation
– Insulin causing its dephosphorylation and activation
• Allosteric regulation
• In hepatocytes
– Glucose 6-phosphate binds to an allosteric site on
glycogen synthase b, making the enzyme a better
substrate for dephosphorylation by PP1 and
causing its activation