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GLYCOGEN METABOLISM

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Hours Days. mM glucose. 8. 4. Glycogen ... glucose in fasting or for providing ... Fasting state. Stress. Fed state. Liver. Key regulatory enzyme of ... – PowerPoint PPT presentation

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Title: GLYCOGEN METABOLISM


1
GLYCOGEN METABOLISM
Learning objectives Describe composition and
glycosidic bonds in glycogen Describe the
biochemical pathway of glycogen
synthesis Describe the biochemical pathway of
glycogenolysis Discuss regulation of glycogen
metabolism
2
Glycogen
Glycogen is a branched homopolysaccharide
composed of a-D-glucose units bound by a-1,4 and
(at branch points) a-1,6 glycosidic bonds. On
average, there are branches for every 8-10
glycosyl residues.
3
Glycogen
A single molecule can have a molecular mass of up
to 108 Da with more than 500,000 glucosyl
residues. Glycogen forms intracellular glycogen
granules in the cytoplasm.
4
Electron micrograph of a section of a liver cell
showing glycogen deposits as accumulations of
electron dense particles (arrows).
5
Glycosyl residue attached by an a-1,6 glycosidic
bond Glycosyl residue at a non-reducing end
Glycosyl units are attached and mobilized from
the reducing ends
6
Glycogen is an intracellular storage form of
readily available glucose Main stores of
glycogen in the human body Liver - Approximately
100 g or 10 of the fresh weight Muscle
- Approximately 400 g or 1-2 of the fresh
weight Most other cells have small amounts of
glycogen stored
7
LIVER
MUSCLE
Glycogen Glucose 6-P Glucose
Glycogen Glucose 6-P
G6Pase
GLYCOLYSIS
Energy
Blood glucose
8
Sources of blood glucose after a meal
mM glucose
8 4
Meal Glycogen Gluconeogenesis
8 16 24 2
7 30
Hours Days
9
Glycogen synthesis Glycogenesis
Glycogen is synthesized from molecules of
a-D-glucose. Synthesis occurs in the
cytosol Synthesis requires energy ATP for
phosphorylation of glucose UTP for generating
an activated form of glucose UDP-glucose
10
Glycogen synthesis - Glycogenesis
Glucose Glucose 6-phosphate Glucose
1-phosphate UDP-glucose Glycogenn1 Glycoge
nn1 with an additional branch
ATP ADP
Hexokinase/Glucokinase Phosphoglucomutase UDP-
glucose pyrophosphorylase Glycogen
synthase Branching enzyme
UTP PPi
Pyrophosphatase
2 Pi H2O
Glycogenn
11
CH2OH
CH2OPO32-
Glucokinase Hexokinase
O
O
H
H
H
H
H
H
ATP
ADP
OH H
OH H
OH
OH
OH
OH
H OH
H OH
Glucose
Glucose 6-phosphate
Same reaction, same enzymes, and same regulation
as in glycolysis Irreversible
Hexokinase Glucose 6-phosphate (low
phosphofructokinase activity) Glucokinase
High blood glucose (release from GKRP, High
Km) Insulin stimulates gene
transcription (only in liver)
-



12
Phosphoglucomutase
OPO32-
Ser
CH2OPO32-
O
H
H
H
CH2OPO32-
OH H
O
OH
OH
H
H
OH
H
Ser
H OH
OH H
Glucose 6-phosphate
OH
OPO32-
CH2OH
H OH
O
H
H
Glucose 1,6-bisphosphate
H
OH H
OH
OPO32-
H OH
OPO32-
Ser
Glucose 1-phosphate
13
CH2OH
O
O O O O- O-
O-
H
H
H

O- P - O P O P O - uridine
OH H
OH
OPO32-
H OH
UTP
Glucose 1-phosphate
UDP-glucose pyrophosphorylase
CH2OH
O
H
H
H
O O O- O-
O O O- O-
OH H
O- P O P O-
OH
O P O P O - uridine

H OH
Pyrophosphate (PPi)
UDP-glucose
14
O O O- O-
Pyrophosphatase
O- P O P O-
H2O
2 Pi
NB Irreversible reaction
Pyrophosphate (PPi)
Glucose 1-phosphate UTP
UDP-glucose PPi
PPi H2O 2 Pi
Glucose 1-phosphate UTP H2O
UDP-glucose 2 Pi
The irreversible hydrolysis of pyrophosphate
drives the synthesis of UDP-glucose
15
CH2OH
CH2OH
O
O
H
H
H
H
H
H
O O O- O-
OH H
OH H

O - R
OH
O P O P O - uridine
HO
a-1,4
H OH
H OH
UDP-glucose
Glycogen (n residues)
Glycogen synthase
CH2
CH2OH
O
O
H
H
H
H
O O O- O-
H
H
OH H
OH H

O- P O P O - uridine
O - R
O
HO
a-1,4
a-1,4
H OH
H OH
UDP
Glycogen (n1 residues)
16
Priming of glycogen synthesis
Glycogen synthase can NOT add glucosyl residues
to free glucose or to oligosaccharides of less
than 8 glucosyl residues Priming is catalyzed
by the protein GLYCOGENIN The first glucosyl
residue is attached in an O-glycosidic linkage to
the hydroxyl group of tyrosine of Glycogenin
itself 7 additional residues are attached by
glycogenin Glycogenin remains attached to the
reducing end of the glycogen molecule
17
Tyr
HO
8 UDP-glucose
Glycogenin
Glycogenin
Tyr
O
Glycogenin
18

Cleaveage of a-1,4 bond
Non-reducing end
Branching enzyme Amylo-a(1,4) ?
a(1,6)-transglucosidase
a-1,6 bond
Non-reducing ends

19
Stoichiometry Glucose ATP UTP H2O
Glycogenn ? Glycogenn1 ADP UDP 2 Pi
20
Degradation of glycogen Glycogenolysis
Occurs in cytoplasm Major product is glucose
1-phosphate from breaking a-1,4 bonds Minor
product is glucose from breaking a-1,6
bonds Glucose 1-phosphate Glucose 101
21
Glycogen synthesis - Glycogenesis
Glycogenn Glycogenn-1
Glycogen with branch
Glucose Glycogen with
one less branch
Pi
Glycogen phosphorylase
Glucose 1-phosphate Glucose 6-phosphate Glucos
e
Phosphoglucomutase G6Pase

H2O
Debranching enzyme
Pi
H2O
Glycolysis
22
CH2OH
CH2OH
CH2
O
O
O
O O-
H
H
H
H
H
H
H
H
H

O- P OH
OH H
OH H
OH H
O - R
O
O
HO
a-1,4
a-1,4
H OH
H OH
H OH
Phosphate
Glycogen with n residues
Glycogen phosphorylase
CH2
CH2OH
CH2OH
O
O
O
H
H
H
H
H
H
H
H
H

OH H
OH H
OH H
O - R
O
OH
HO
OPO32-
a-1,4
H OH
H OH
H OH
Glucose 1-phosphate
Glycogen with n-1 residues
23
Lys
N
H
C
OH CH3
2-O3PO-CH2

NH
Pyridoxal phosphate is a coenzyme for the
phosphorylase reaction. Pyridoxal phosphate is
bound to a nitrogen of a lysyl residue of
glycogen phosphorylase The phosphate of
pyridoxal phosphate exchanges protons with the
phosphate reactant, which allows the reactant to
donate a proton to the oxygen atom on carbon 4.
24
CH2OH
Phosphoglucomutase
O
OPO32-
H
H
Ser
H
OH H
OH
OPO32-
CH2OPO32-
H OH
O
H
H
Glucose 1-phosphate
OH
H
Ser
OH H
OH
OPO32-
H OH
CH2OPO32-
Glucose 1,6-bisphosphate
O
H
H
H
OH H
OH
OH
OPO32-
Ser
H OH
Glucose 6-phosphate
25
Glucose-6- phosphatase (G6Pase)
CH2OH
CH2OPO32-
O
O
H
H
H
H
H
H
H2O
Pi
OH H
OH H
OH
OH
OH
OH
H OH
H OH
Glucose
Glucose 6-phosphate
Same reaction as in gluconeogenesis Occurs in
endoplasmic reticulum and involves a glucose
6-phosphatase transporter and a catalytic
subunit The catalytic subunit is regulated at
the level of transcription
26
Glycogen phosphorylase stops when 4 glucosyl
units remain on each chain from a branch point
a
b
c
a-1,6 bond
d

b
c
a
d
e
Oligo-a(1,4)?a(1,4)-glucan transferase (debranchin
g enzyme) Amylo-a(1,6)-glucosidase (debranchin
g enzyme)
a-1,6 bond
d

b
c
a
b
c
a
d
e
H2O
d


b
c
a
b
c
a
d
e
Glucose
27
Approximate Stoichiometry
Glycogenn11 10 Pi H2O ? Glycogenn 10
Glucose 6-phosphate Glucose
28
LIVER
MUSCLE
Glycogen Glucose 6-P Glucose
Glycogen Glucose 6-P
G6Pase
GLYCOLYSIS
Energy
Blood glucose
29
Regulation of glycogen metabolism
Skeletal muscle Glycogen must be broken down to
provide ATP for contraction, when the muscle is
rapidly contracting, or in anticipation of
contractions in stress situations like fear or
excitement. In rapidly contracting muscle Low
ATP, High AMP
High Ca Stress
High Epinephrine Glycogen
stores are replenished when muscles
are resting. Resting state Low AMP, High
ATP
30
Hormonal regulation of metabolism
Hormone Type Secreted by Secreted in response
to Insulin Protein Pancreatic beta cells High
blood glucose Glucagon Polypeptide Pancreatic
alpha cells Low blood glucose Epinephrine Catec
holamine Adrenal medulla Stress (adrenalin) Ner
vous system Low blood glucose Glucocorticoids
Steroid hormone Adrenal cortex Stress Low
blood glucose
Glucagon is the most important hormone
signaling low blood glucose concentration, while
epinephrine and glucocorticoids play secondary
roles.
31
Regulation of glycogen metabolism
Liver Glycogen must be broken down to provide
glucose for maintaining blood glucose in fasting
or for providing additional glucose for skeletal
muscles in stress situations. Fasting High
Glucagon Stress High
Epinephrine Glycogen stores must be
replenished in the fed state Fed state High
Insulin High Glucose
32
Muscle
Glycogen Glucose 6-phosphate
Glycogen Glucose 6-phosphate
Rapidly contracting state Stress
Resting state and with abundant energy
Liver
Glycogen Glucose 6-phosphate
Glycogen Glucose 6-phosphate
Fasting state Stress
Fed state
33
Key regulatory enzyme of glycogen
breakdown Glycogen phosphorylase Key
regulatory enzyme of glycogen synthesis Glycogen
synthase
34
Glycogen phosphorylase is a dimer of identical
subunits. Glycogen phosphorylase can exist in an
active R (relaxed) and an inactive T (tense)
state. In the T state, the catalytic site is
partly blocked
35
Red active site Yellow Glycogen binding
site Red site Allosteric site for AMP
binding Blue/green sites Phosphorylation sites
36
Allosteric regulation of glycogen phosphorylase
Regulation by energy state.
AMP (binding favors the active R state) ATP
(binding favors the inactive T state)

-
Regulation by feedback inhibition.
Glucose 6-phosphate (G6P) G6P concentration
increases when G6P is generated faster than it
can be further metabolized, e.g. by glycolysis
-
Regulation by high blood glucose
Glucose (Only liver glycogen phosphorylase) In
the fed state with a high blood glucose
concentration, there is no need for the liver to
secrete glucose
-
37
Regulation of glycogen phosphorylase by
phosphorylation
Phosphorylase kinase
ATP
ADP
P
Glycogen phosphorylase b
Glycogen phosphorylase a
P
Inactive
Active T state
R state
Pi
H2O
Protein phosphatase 1 (PP1)
Phosphorylation occurs in the fasted or stressed
state Dephosphorylation is stimulated in the fed
state
38
Phosphorylase kinase is regulated by
phosphorylation and Ca binding
One subunit is the Ca -binding calmodulin
Ca
Ca
Inactive
Partly active Fully active
Phosphorylation occurs in the fasted or stressed
state. Dephosphorylation is stimulated in the fed
state. Ca binding occurs when the Ca is
high, e.g. during rapid muscle contractions
39
Cell membrane
40
cAMP
Adenylyl cyclase
ATP cAMP PPi
H2O
Phosphodiesterase
AMP
41
Glucagon receptors and epinephrine receptors
are G-protein-coupled receptor
GDP
Adenylyl cyclase
GDP
Receptor
beta and gamma subunit of G-protein
alpha subunit of G-protein
GTP
When hormone is no longer present, intrinsic GTP
hydrolase activity of the G-protein alpha
subunit hydrolyzes GTP to GDP, the alpha subunit
re-associates with the beta and gamma subunits,
and stimulation of adenylyl cyclase ends. cAMP is
converted to AMP by phosphodiesterase. Thus, in
the absence of hormone, the cAMP concentration
rapidly falls.
42
a
a
a
a
a
a
Insulin
ß
ß
ß
ß
ß
ß
P
P
Insulin receptor It functions as a tyrosine
kinase when insulin is bound
P
P
P
P
P
P
Autophosphorylation
P
Insulin receptor substrate
Activation of multiple signaling pathways
Activation of protein phosphatases
Activation of protein kinases
In general, the protein kinases activated by
insulin have opposite biological effects from
those activated by glucagon In general, the
protein phosphatases activated by insulin
dephosphorylate proteins that are phosphorylated
by glucagon-stimulated protein kinases, such as
PKA
43
Regulation of glycogen synthase
Regulation by feed-forward mechanism.
Glucose 6-phosphate (G6P) G6P concentration
increases at high glucose concentrations when
G6P is generated faster than it can be further
metabolized

NB Reciprocal regulation of glycogen
synthase and glycogen phosphorylase by glucose
6-phosphate
44
Regulation of glycogen synthase by phosphorylation
PKA and Glycogen synthase kinase
ATP
ADP
P
P
Active
Inactive
Pi
H2O
Protein phosphatase 1 (PP1)
Phosphorylation occurs in the fasted or stressed
state Dephosphorylation is stimulated in the fed
state
45
Reciprocal regulation of glycogen phosphorylase
and glycogen synthase by phosphorylation
Fasting/stress (glucagon/epinephrine)

PKA
Phosphorylase kinase
Active
Glycogen phosphorylase
Glycogen synthase

PP1
Fed state (insulin)
46
And it is even more complex..
Scaffolding proteins of different subtypes in
liver and muscle can bind the glycogen particle,
PP1, glycogen phosphorylase, and glycogen
synthase Binding brings participants of glycogen
metabolism together. Regulation of PP1 is itself
complex with various inhibitors responding to the
metabolic state of the organism.
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