Biochemie-6-2-metabolismus_sacharidů
Glycogen
- synthesis and degradation
1
Biochemie-6-2-metabolismus_sacharidů
• The synthesis and degradation of glycogen occurs in most cells,
the greatest extent is in the liver and muscles.
• Glycogen is a supply of glucose in the cells, which is very readily
available
• In muscles - weight of glycogen is about 1(-2)% of muscle mass,
degradation occurs during hard work or stress
•In the liver: about 5 (-10)% weight of the liver after a meal,
degradation occurs when glucose level in blood is decreased
about 0.1% weight of the liver after 24 hours of fasting
Glycogen supplies
2
Biochemie-6-2-metabolismus_sacharidů
The formation of glycogen allows the
preservation of a large number of glucose
molecules in the cell, without creating a
hyperosmotic environment
3
Biochemie-6-2-metabolismus_sacharidů
Glycogen is stored in cytoplasmic granules of cells.
Enzymes involved in synthesis and degradation bind to the surface of the granules.
Glycogenolysis is not the opposite of synthesis.
Glycogen molecules
have mass Mr ~108
Localization of glycogenolysis and synthesis of glycogen
Články a informace z různých oblastí lékařství: Tvorba glykogenu. [online]. 20.6.2006 [cit. 2014-07-18].
Dostupné z: http://www.biology.estranky.cz/clanky/biochemie/tvorba-glykogenu.html
4
Biochemie-6-2-metabolismus_sacharidů
Types of linkages in glycogen
NOVÁK, Jan. Biochemie I. Brno: Muni, 2009, s. 99.
5
glycosidic linkage
glycosidic linkage
Biochemie-6-2-metabolismus_sacharidů
Glycogen synthesis (glycogenesis)
1. activation of glucose to UDP-glucose
2. transfer of activated molecules to 4-end of
existing primer or glycogen chain
3. creation  -1,4 glycosidic bond
4. branching
Takes place after a meal, insulin activation
6
Biochemie-6-2-metabolismus_sacharidů
1. UDP-glucose synthesis
• Glucose-6-P Glucose -1-P
phosphoglucomutase
• Glucose-1-P + UTP UDP-glucose + PPi
PP i + H2O 2Pi NOVÁK, Jan. Biochemie I. Brno: Muni, 2009, s. 100.
7
UDP-glucose
Biochemie-6-2-metabolismus_sacharidů
2. Primer is needed for glycogen synthesis
glycogen fragment specific protein, if glycogen
is completely depleted
(glycogenin)
Auto glycosylation at serine
residue
8
Biochemie-6-2-metabolismus_sacharidů
• Initiation - binding of glucose to primer by  -1,4
glycosidic bond (glycogensynthase)
• Elongation - formation of linear chains with -1,4
bond (glycogensynthase)
• UDP-glucose + [glucose]n  [glucose]n+1 + UDP
3. Formation of  -1,4 glycosidic bonds
9
Biochemie-6-2-metabolismus_sacharidů
4. Branching
(branching enzyme)
5-8 terminal glucose residues at the non-reducing end is
transferred and bound by1,6 bond
G-G-G-G-G
G-G-G-G-G-G-G-G-G-G-G-G-G  -G-G-G-G-G-G-G-G
-1,6 bond
Further elongation by glykogensynthase on
non-reducing ends
Further branching by branching enzyme
10
Biochemie-6-2-metabolismus_sacharidů
The significance of branching:
• increase the solubility of glycogen
• increasing the number of non-reducing ends
acceleration of synthesis (and degradation)
11
Biochemie-6-2-metabolismus_sacharidů
Degradation of glycogen (phosphorolyse)
1. Phosphorolytic digestion -1,4 glykosidic bonds
(phosphorylase)
2. Deletion of -1,6 branching (debranching enzyme)
Proceeds during starvation (liver), muscle work
(muscle) or stress (liver and muscle).
Compare:
Hydrolysis x phosphorylolysis
12
Biochemie-6-2-metabolismus_sacharidů
1. Phosphorylase
Phosphorolytic digestion -1,4 glykosidových glykosidic bonds
from non-reducing ends
Glycogenn + Pi glucose-1-P + glycogenn-1
digestion proceeds until phase of "limit dextrin" (typically 4
glucose units before -1,6 bond)
Rob's web: Glycogeen metabolisme [online]. [cit. 2014-07-18]. Dostupné z:
http://www.robkalmeijer.nl/voedingsleer/metabolisme/glycogeenmetabolisme/
n residues n – 1residues
13
Biochemie-6-2-metabolismus_sacharidů
Phosphorylase effect leads to the formation of limit
dextrins:
Degradation of glycogen
NOVÁK, Jan. Biochemie I. Brno: Muni, 2009, s. 103.
14
Biochemie-6-2-metabolismus_sacharidů
2. Debranching enzyme
transferase activity: enzyme transferes 3 of the
remaining 4 glucose bound on chain by -1,6
bond to the non-reducing end of another chain
glucosidase activity: cleavage of glucose bound
by -1,6 bond
(Free glucose is released! No Glc-1-P)
15
Biochemie-6-2-metabolismus_sacharidů
Following the effect of phosphorylase
Effect of debranching enzyme
NOVÁK, Jan. Biochemie I. Brno: Muni, 2009, s. 103.
16
Enzyme TRANSGLYCOSYLASE
transferes 3 of the remaining 4 glucose
bound on chain by -1,6 bond to the nonreducing
end of another chain
glucose-1-P
Biochemie-6-2-metabolismus_sacharidů
NOVÁK, Jan. Biochemie I. Brno: Muni, 2009, s. 103.
17
DEBRANCHING ENZYME glucosidase activity: cleavage of glucose bound by -1,6 bond
(Free glucose is released! No Glc-1-P)
glucose-1-P
glucose-1-P
Biochemie-6-2-metabolismus_sacharidů
The fate of glucose-1-phosphate generated from
glycogen
release into the blood
NOVÁK, Jan. Biochemie I. Brno: Muni, 2009, s. 103.
18
glucose-1-P glucose-6-P
glucose-6-phosphatase
All
Glucose-6-P can not pass across the
cytoplasmic membrane, transfer is
possible only for glucose
The enzyme glucose-6-phosphatase
is only in the liver (kidney) - not in
muscle.
liver (kidney
Glucose-6-P,
which can be
metabolized only
inside the cell
(glycolysis) can be
obtained by
cleavage of
glycogen in
muscle and other
cells
Biochemie-6-2-metabolismus_sacharidů
Glucose-6-P can not pass across the cytoplasmic membrane,
transfer is possible only for glucose
The enzyme glucose-6-phosphatase is only in the liver
(kidney) - not in muscle.
The blood glucose level can be supplied only by
cleavage of liver glycogen
Glucose-6-P, which can be metabolized only inside
the cell (glycolysis) can be obtained by cleavage of
glycogen in muscle and other cells
utilization of glucose-6-P
19
Biochemie-6-2-metabolismus_sacharidů
Lysosomal degradation of glycogen
lysosomal acidic glucosidase (pH optimum 4)
- degrades 1,4 bonds from non-reducing ends
- glucose is released
degradation 1-3 % of cellular glycogen (viz též
Pompeho choroba)
20
Biochemie-6-2-metabolismus_sacharidů
Regulation of metabolism of glycogen
Glycogensynthase X glycogenphosphorylase
hormonal control
Allosteric regulation
21
Biochemie-6-2-metabolismus_sacharidů
Hormones affecting the synthesis and degradation of
glycogen
Hormone synthesis degradation
Insulin
Glucagon
Adrenalin






Hormones operates through its "second messengers"
22
Biochemie-6-2-metabolismus_sacharidů
Phosphorylation and dephosphorylation of proteins
plays an important role in the regulation of
glycogen metabolism
• phosphorylation by kinases and ATP
• dephosphorylation through phosphatases
23
Biochemie-6-2-metabolismus_sacharidů
H2O
Pi
proteinfosfatase
OH
O-P
ATP
ADP
proteinkinase
Enzyme inactive
Enzyme active
H2O
Pi
proteinfosfatase
OH
O-P
ATP
ADP
proteinkinase
Enzym active
Enzyme inactive
Common examples of activity changes induced by
phosphorylation and dephosphorylation
24
Biochemie-6-2-metabolismus_sacharidů
Activation and inactivation of glycogenphosphorylase
NOVÁK, Jan. Biochemie I. Brno: Muni, 2009, s. 105.
phosphorylase b
(phosphorylated
form - not very
active)
Phosphorylase a
(phosphorylated form -
active)
25
Phosphorylase in the liver and muscles varies
Biochemie-6-2-metabolismus_sacharidů
Activation and inactivation of glykogensynthase
NOVÁK, Jan. Biochemie I. Brno: Muni, 2009, s. 105.
Glykogensynthase a
(phosphorylated -
active)
Glykogensynthase b
(phosphorylated -
inactive)
26
Biochemie-6-2-metabolismus_sacharidů
the effect of hormones:
Liver:
glucagon (cAMP),
adrenaline (cAMP, Ca2+ kalmoduline)
Degradation of glycogene
Muscle:
adrenaline (cAMP) under stress
allosteric regulation
AMPNo effect of glucagon!
 Ca2+ during
muscle contraction
27
Biochemie-6-2-metabolismus_sacharidů
Activation of phosphorylase takes place in stages
Proteinkinase A
(inactive)
cAMP
Proteinkinase A
(active)
Phoosforylase
kinase
(inactive)
Fosforylase
kinase
(active)
ATP
ADP
P
Glykogenfosforylase
b (inactive) ATP ADP
Glykogenfosforylase a
(active)
P
Liver - activation of glycogenphosphorylase by glucagon and
adrenaline -mediated by cAMP
Glucose, ATP, Glc-6P:
allosteric inhibition
Glukagon
(adrenaline)
28
Biochemie-6-2-metabolismus_sacharidů
Liver - activation of glycogen phosphorylase by adrenaline,
mediated by increase of intracellular Ca2+
Adrenaline 1  Ca2+
 Ca2+-calmodulin
Ca- kalmodulin
dependentní
fosforylasakinasa
(neaktivní)
Ca-calmodulin
dependent
fosforylasakinase
(inactive)
P
ATP ADP
Glykogenphosphoryl
ase b (inactive)
Glykogenphosphoryla
se a (active)
calmodulin
Proteinfosfatase (activation  cAMP )
Adrenaline and
glucagon can act
synergistically
29
Biochemie-6-2-metabolismus_sacharidů
Proteinkinase A
(inactive)
cAMP
Proteinkinase A
(active)
Phosphoryla
se kinase
(inactive)
phosphoryla
se kinase
(active)
ATP
ADPPGlykogenfosforylase b
(inactive)
ATP ADP
Glykogenphosphoryla
se a (active)
P
Adrenaline -stress
Muscle - activation of glycogenphosphorylase by adrenaline,
Ca2+ and AMP
muscle
contraction ↑ Ca2+
Glycogenphosphorylase b (active) (non-phosphorylated)
AMPDecrease
of
energy
P
Proteinphosphatase (activation 
cAMP )
Glycogenphosphorylase b (inactive)
30
Biochemie-6-2-metabolismus_sacharidů
Glykogensynthase a
(dephosphorylated, active)
Glykogensynthase b
(phosphorylated,
inactive)
Proteinfosfatase 1
(activation by insuline,
allosterically glucose-6-P
inactivation ↑ cAMP )
Activation and inactivation of glycogensynthase in liver
ATP
ADP
Proteinkinase (activation
by glucagon /cAMP/ or
adrenaline /Ca-
calmoduline/
inactivation activation
Pi
31
Biochemie-6-2-metabolismus_sacharidů
Check of glycogensynthase in muscle is more complex and is also
regulated by glycogen content.
Glycogen functions as a reverse inhibitor of synthesis
32
Biochemie-6-2-metabolismus_sacharidů
Glycogenoses
 Enzymes that play a role in glycogen metabolism,
are often damaged in any way - it is usually a
inherited deficiency of enzymes. These
deficiencies manifest themselves in different ways
- it depends on which particular enzyme it is and
also on specific isoform (disorders may therefore
be tissue specific - e.g. isoform in muscle is
damaged and metabolism of glycogen in muscle
will be disturbed, on the other hand isoform in
liver will be fine, so glycogen metabolism in them
will proceed normally).
NOVÁK, Jan. Biochemie I. Brno: Muni, 2009, s. 108.
33
Biochemie-6-2-metabolismus_sacharidů
Glycogenoses – enzymes disorders
Inherited deficiency of enzymes. Since different isoenzymes can occur in various
tissues, thus the disorders can be tissue specific. (F - fatal)
Type Enzyme defect Organ Characteristic
0
I
II
III
IV
V
VI
VII
Glykogensythase
Glc-6-phosphatase
Lysosome. α-glukosidase
Branching enzyme
Branching enzyme
Muscle phosphorylase
Liver phosphorylase
phosphofruktokinase
liver
liver, kidneys
muscles, heart
liver, muscle,
heart
liver
muscle
liver
muscles
Hypoglycemia F
Enlarged liver, kidneys. Hypoglycemia. Cells are
overcrowded by glycogen
The accumulation of glycogen in lysosomes F
Accumulation of charact. branching polysach.
Accumlation of non-branched polysacharide F
High glycogen content in muscle decreased
ability body exertion
High glycogen content in the liver, a tendency to
hypoglycaemia
Same as type V
34
Biochemie-6-2-metabolismus_sacharidů
Von Gierkes disease (glykogenose type I)
The most common of glycogenoses
Deficiency of glucose-6-phosphatase or transporter for
glucose-6-P
Consequences:
hypoglycaemia during a short starvation
lactacidemia
(hyperlipidemia, hyperurikemia)
Examples of glycogenoses
35
Biochemie-6-2-metabolismus_sacharidů
Pompes disease (glykogenose type II)
Absence of -1,4-glucosidase in lysosomes
Glycogen accumulation in lysosomes
Loss of function of lysosomes
Damage to muscle, glycogen accumulates in the cytoplasm of
muscle  muscle weakness
Mainly affects the muscles of the respiratory system and heart
Type I a - in infants (fatal)
Type II b - in older children and adults, shortens life
36
Biochemie-6-2-metabolismus_sacharidů
McArdles disease (type V)
Absence of of muscle phosphorylase
Glycogen stores are not available for energy production
The muscle is unable to perform permanent work
The muscle is easily damaged (myoglobin in the blood)
37