Structure of glycogen
* Glycogen: branched-chain homopolysaccharide made of α-Dglucose linked by α-1,4 linkage.
After every 8-10 glucose residues there
is a branch containing α-1,6 linkage.
Glycogen molecules exist in cytoplasmic granules that contain the
enzymes for synthesis and degradation of glycogen.
Glycogen metabolism
Glucose is the main source of energy for brain, cells without mitochondria
(RBC) and essential source of energy for exercising muscles because it
substrate for anaerobic glycolysis
Diet
Source of Blood glucose
Glycogen
gluconeogenesis
1) Dietary intake of glucose or glucose precursors as starch,
monosaccharides (Fructose), disaccharides (Sucrose, maltose, lactose)
2) Glycogen: provide a rapid supply for glucose in the absence of dietary
glucose. Glycogen is rapidly degraded into glucose
3) Gluconeogenesis: provide sustained synthesis of glucose stimulated by
low blood glucose (slow)
Structure and function of glycogen
The main store of glycogen in the body is liver (100 g) and skeletal
muscles (400g)
In muscle: glycogen
Glucose to produce ATP and energy
In liver: Glycogen
Maintain blood glucose
Why NOT store excess glucose as free glucose instead of glycogen?
Fluctuation of glycogen stores
-Liver glycogen stores increase during the well-fed state and are
depleted during a fast
-Muscle glycogen is NOT affected by short periods of fasting and is
moderately decreased in prolonged fasting while it is affected by
exercise.
Synthesis of Glycogen (Glycogenesis)
α-D- glucose is the monomer
 Occurs in the cytosol
 Requires energy supplied by ATP and UTP
α-D- glucose attached to UDP
(glucose-UDP) is the source of all
the glycosyl residues that are
added to the growing glycogen
UDP-glucose synthesis
UDP-glucose is the source of
glucosyl groups that used in
glycogen synthesis
Glycogen synthase is
responsible for making
α-1  4 linkage. It can
only elongate existing
chains and cannot
initiate chain synthesis.
* Fragment of glycogen
can serve as a primer
Elongation of glycogen chains
by Glycogen Synthase
Involve transfer of glucose
units from UDP-glucose to the
non-reducing end of the
growing chain forming α-14
glycosidic linkage (anomeric
hydroxyl of carbon 1 of the
activated glucose and carbon
4 of accepting glucose
residue).
UDP + ATP
nucleoside diphosphate kinase
UTP + ADP
* Formation of branches in glycogen
* Glycogen is highly branched molecule (every 8 residues)  increase
solubility and size compared to the non-branched amylose.
* Branching increases the number of non-reducing ends to which glucosyl
residues can be added or removed  accelerate the rate of glycogen
synthesis or degradation.
* Synthesis of branches by glycosyl 4:6 transferase
Branches are made by “branching enzyme” that called
Amylo-(α14)(α16)transglycosylase
or Glucosyl(4:6)transferrase
This enzyme transfers 5-8 glycosyl residues from the non-reducing
end to another residue forming α-1 6 linkage.
Old and new non-reducing ends are available to be further elongated
by Glycogen Synthase
* Fragment of glycogen
can serve as a primer
In absence of glycogen,
The OH gp of specific
tyrosine side chain is the
initial site of attachment
specific protein
glycogenin can serve as
an acceptor of glucose
residues.
* Glycogen initiator synthase:
transfer the first molecule of
glucose from UDP-glucose to
glycogenin.
Then additional glucose unit is
transferred to form short
chain
Degradation of Glycogen (glycogenolysis)
Glycogen phosphorylase cleaves α- 1,4 glycosidic bond at the non-reducing ends
by phosphorolysis.
* Glycogen phosphorylase
sequentially degrades the
glycogen chains at their nonreducing ends until 4 glucosyl
units remain on each chain
before a branch poin, it is
called limit dextrin,
phosphorylase cannot
degrade it.
* Small amount of glycogen is
degraded by lysosomal αglucosidase
Glucosyl (4:4)
transferase
Removal of branches
Branches are removed by
two enzymic activities:
The outer three of four
glucosyl residues
attached at a branch and
transferrs them to the
non-reducing end at
another chain, thus the
new chain is subjected to
glycogen phosphorylase.
The enzyme Glycosyl
(4:4) transferase
Remaining single glucose
residue attached in an α1,6 – linkage is removed
by amylo α –(1,6)–
glucosidase releasing
free glucose
* Conversion of glucose 1phosphate to glucose 6-phosphate
by “Phosphoglucomutase”
Degradation of Glycogen
(glycogenolysis)
Remaining single glucose residue
attached in an α- 1,6 – linkage is
removed by amylo α –(1,6)–
glucosidase releasing free
glucose
* Glycogen synthase and Glycogen phosphorylaseare reciprocally regulated.
Glycogen synthase
glycogen synthase a (active: unphosphorylated)
glycogen synthase b (less active: phosphorylated)
ATP
ADP
Protein kinase
glycogen synthase a
glycogen synthase b
Phosphoprotein phosphatase
H2O
Pi
ADP
ATP
Phosphatase
b kinase
Phosphorylase
a phosphatase
Pi
Glycogen phosphorylase
H2O
Glycogen phosphorylase a
(active: phosphorylated)
Glycogen phosphorylase b
(Inactive: Unphosphorylated)
* Regulation of Glycogen Synthesis and
Degradation
To maintain the blood glucose level, the
glycogen synthesis and degradation is
highly regulated.
Well fed state
glycogen synthesis
Fasting
accelerated
activation of
degradation of glucose is
In skeletal muscle:
degradation is activated
during exercise while
glycogen accumulation
activated at the rest
*Both glycogen synthase and
phosphorylase are allosterically and
hormonally regulated.
Regulation of glycogen phosphorylase
glycogen phosphorylase is
subject to allosteric activation
by AMP and allosteric inhibition
by glucose and ATP
Phosphorylase kinase is responsible
for phosphorylation and activation of
phosphorylase. And it is regulated by
phosphorylation – dephosphorylation
mechanism
Glycogen
Glycogen
Activation of glycogen degradation by cAMP-directed pathway
* Activation of glycogen degradation in muscle by Ca+2 and AMP
A. During muscle contraction  urgent need for ATP… what happens?
Nerve impluses cause membrane depolarization  Ca+2 is released from
sarcoplasmic reticulum  Ca+2 bind to calmidulin subunit of phosphorylase kinase
and activate it with the need for it’s phosphorylation.
Phosphorylase kinase is maximally active when both phosphorylated and bound to Ca+2
B. During exercise  ATP is depleted  AMP will increase  AMP bind to inactive
form (phosphorylase b and activate it without phosphorylation)
Phosphorylase kinase is multisubunits protein, one subunit is Ca+2- binding
regulatory protein (Calmodulin)
* Calmodulin also found in free form in the cells and act as Ca+2 receptors.
* Binding of Ca+2 to calmodulin part of phosphorylase kinase induce conformational
change to make it more active.
* Ca+2 bind to both the phosphorylated and unphosphorylated forms of
phosphorylase kinase
* Maximum activity obtained by phosphorylation and binding of Ca+2 to
phosphorylase kinase.
Regulation of glycogen synthase
Glycogen synthase
needs to be turned on
and glycogen
phosphorylase turned
off during the glycogen
synthesis
* Inhibition of glycogen synthesis
by cAMP-directed pathway
Glucagon
Epinephrine
Epinephrine
c-AMP
active
Glucagon
a
b
inactive
active
active
inactive
The End
* Regulation of glycogen synthase
Glycogen synthase needs to be turned on and glycogen phosphorylase
turned off during the glycogen synthesis.
* Glycogen synthase a (active form unphosphorylated) and not
affected by the presence of G6P
* Glycogen synthase b (inactive, phosphorylated) and it’s activity is
affected by the presence of G6P
G6P is allosterically activator for glycogen synthase b
* Glycogen synthase a can be converted into b form with several
kinases, these kinases are regulated by second massengers of
hormone actions including cAMP, Ca+2, diacylglycerol
Different kinase reflect different sites of phosphorylation
Effector control of glycogen metabolism:-
* Glycogen itself –ve feedback on synthesis
* Glucose
High glucose level in blood  activate glycogenesis by two mechanisms:
1- high glucose level  stimulate insulin release from pancreas
insulin
inhibit hepatic glycogen phosphorylase and activate glycogen synthase.
2- hormone independent mechanism, direct inhibition of glycogen
phosphorylase a by binding the glucose to this enzyme  stimulate the
dephosphrylation of this enzyme  inactivation of it.
So “phosphorylase a function as glucose receptor”
* Glucagon: stimulate glycogen degradation in the liver at response of low blood
glucose  glucagon is released  stimulate glucagon mobilization from liver.
* Epinephrine: stimulate glycogen degradation, epinephrine is released from
adrenal medulla  interact with plasma receptors  activate adenylate
cyclase  increase cAMP  activation of glycogenolysis and inhibition of
glycogenesis and glycolysis to increase the release of glucose from liver.
Epinephrine + β- adrenergic receptor  stimulate adenylate cyclase
Epinephrine + α- adrenergic receptor  activation of phospholipase C
* Coordinated regulation of glucagon synthesis and degradation:-
- Glycogen synthesis and degradation are regulated by the same hormonal signals.
High level of insulin  increase glycogen synthesis, decrease glycogen
degradation
High glucagon or epinephrine  increase glycogen degradation and decrease
glycogen synthesis.
* The effect of these hormones are mediated by cAMP level
Insulin
Glucagon
Epinephrin
decrease cAMP
increase cAMP
cAMP activate some protein kinases that phosphorylate the key enzymes 
Phosphorylation of the enzymes may activate or inactivate this enzyme
Phosphoprotein phosphatase: reduce the phosphorylation state of both glycogen
phosphorylase and phosphorylase kinase
* Regulation of phosphoprotein phosphatase is linked to cAMP.
* Glucagon and epinephrine increase cAMP  promote activation of phosphorylase kinase
and inactivation of phosphoprotein phosphatase.
* Insulin exerts opposite effect on phosphorylase by promoting activation of phosphoprotein
phosphatase activity.
* Insulin stimulates glycogen synthesis in muscle and liver.
High blood glucose level  increase insulin secretion and decrease glucagon
Low blood glucose level  decrease insulin and increase glucagon
* Glucagon & Insulin have opposite effect on glycogen metabolism
* Insulin increase glucose utilization by promoting glycogensis and inhibiting
glycogenolysis in muscle & liver
* Insulin is essential for the entrance of glucose into muscle cell NOT hepatocyte
because hepatocytes have insulin insensitive glucose transport system (GLUT-2)
* While muscle cells and adipocytes have glucose transport system (GLUT-4) that is
insulin dependent.
* Glycogen metabolism disorder
Glycogen storage disease !!!