Glycogen metabolism

Biochemistry for Medics
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Biochemistry For Medics 8/12/2012 1

Glycogen is a readily mobilized storage
form of glucose.
It is a very large, branched polymer of
glucose residues that can be broken down to
yield glucose molecules when energy is
needed.
Most of the glucose residues in glycogen
are linked by α-1,4-glycosidic bonds.
Branches at about every tenth residue are
created by α-1,6-glycosidic bonds.


Glycogen is present in the cytosol in the form
of granules ranging in diameter from 10 to 40
nm.
It has a molecular mass of 10 7 Da and consists
of polysaccharide chains, each containing about
13 glucose residues.
The chains are either branched or unbranched
and are arranged in 12 concentric layers.
The branched chains (each has two branches)
are found in the inner layers and the unbranched
chains in the outer layer. (G, Glycogenin, the
primer molecule for glycogen synthesis.)


The highly
branched
structure of
glycogen provides
a large number of
sites for
glycogenolysis,
permitting rapid
release of glucose
1-phosphate for
muscle activity.

Glycogenin


It is stored mainly in liver and
muscle
The liver content of glycogen is
greater than that of muscle,
Since the muscle mass of the body is
considerably greater than that of the
liver, about three-quarters of total
body glycogen is in muscle

Percentage of Tissue Weight Body Content
Tissue Weight

Liver glycogen 1.8 kg 90 g
5.0

Muscle 0.7 35 kg 245 g
glycogen

Extracellular 0.1 10 L 10 g
glucose


Glycogen serves as a buffer to maintain
blood-glucose levels.
Glucose is virtually the only fuel used by the
brain, except during prolonged starvation.
The glucose from glycogen is readily
mobilized and is therefore a good source of
energy for sudden, strenuous activity.
Unlike fatty acids, the released glucose can
provide energy in the absence of oxygen and
can thus supply energy for anaerobic activity.


 Glycogenesis is the synthesis of glycogen
from glucose.
 Glycogenesis mainly occurs in muscle and
liver.
 Muscle glycogen provides a readily
available source of glucose for glycolysis
within the muscle itself.
 Liver glycogen functions to store and
export glucose to maintain blood glucose
between meals.


oAlanine and
lactate
transported from
muscle are used
for glucose
production in
liver by
gluconeogenesis.
oGlucose is
poured in blood
to maintain
homeostasis.


1) Activation of Glucose
2) Initiation
3) Elongation
4) Glycogen branching


Synthesis of glycogen from glucose is
carried out by the enzyme glycogen
synthase.
This enzyme utilizes UDP-glucose as one
substrate and the non-reducing end of
glycogen as another.
 UDP-glucose, the glucose donor in the
biosynthesis of glycogen, is an activated
form of glucose.


UDP-glucose is formed from glucose-1-
phosphate:

Spontaneous hydrolysis of the ~P bond in PPi
(P~P) drives the overall reaction.
Cleavage of PPi is the only energy cost for
glycogen synthesis (one ~P bond per glucose
residue).


As in glycolysis, glucose is
phosphorylated to glucose 6-
phosphate, catalyzed by hexokinase in
muscle and glucokinase in liver.
Glucose 6-phosphate is isomerized to
glucose 1-phosphate by
Phosphoglucomutase.
Glucose 1-phosphate reacts with
uridine triphosphate (UTP) to form
the active nucleotide uridine
diphosphate glucose (UDPGlc) and
pyrophosphate. The reaction is
catalyzed by UDPGlc pyro
phosphorylase.


Glycogen synthase can add
glucosyl residues only if the
polysaccharide chain already
contains more than four
residues.
Thus, glycogen synthesis
requires a primer.
This priming function is carried
out by glycogenin,
A protein composed of two
identical 37-kd subunits, each
bearing an oligosaccharide of
alpha-1,4-glucose units.


A glycosidic bond
is formed between
the anomeric C1
of the glucose
moiety derived
from UDP-glucose
and the hydroxyl
oxygen of a
tyrosine side-
chain of
Glycogenin.
UDP is released as
a product.

Each subunit of glycogenin catalyzes the addition of eight glucose units to its
partner in the glycogenin dimer. At this point, glycogen synthase takes over to
extend the glycogen molecule.

New glucosyl units are added to the nonreducing
terminal residues of glycogen.

The activated glucosyl unit of UDP glucose is transferred
to the hydroxyl group at a C-4 terminus of glycogen to
form an α-1,4-glycosidic linkage.

Inelongation, UDP is displaced by the terminal hydroxyl
group of the growing glycogen molecule.

This reaction is catalyzed by glycogen synthase, the key
regulatory enzyme in glycogen synthesis.


Both synthesis & breakdown of glycogen are spontaneous.
If both pathways were active simultaneously in a cell, there would be
a "futile cycle" with cleavage of one ~P bond per cycle (in forming
UDP-glucose).To prevent this both pathways are reciprocally
regulated

Glycogen Synthesis
UTP UDP + 2 Pi
glycogen(n) + glucose-1-P glycogen(n + 1)

Glycogen Phosphorylase Pi


Glycogen synthase catalyzes only the synthesis of
α-1,4 linkages.
Another enzyme is required to form the α-1,6
linkages that make glycogen a branched polymer.
Branching occurs after a number of glucosyl
residues are joined in α-1,4 linkage by glycogen
synthase.
A branch is created by the breaking of an α-1,4 link
and the formation of an α-1,6 link.


A block of residues, typically 7 in number, is
transferred to a more interior site.
The branching enzyme that catalyzes this
reaction is quite exacting.
The block of 7 or so residues must include the
nonreducing terminus and come from a chain at
least 11 residues long.
In addition, the new branch point must be at
least 4 residues away from a preexisting one.


Branching is important because it increases the solubility of glycogen.
Furthermore, branching creates a large number of terminal residues,
the sites of action of glycogen phosphorylase and synthase. Thus,
branching increases the rate of glycogen synthesis and degradation.


Glycogen degradation consists of three
steps:
(1) The release of glucose 1-phosphate from
glycogen,
(2) The remodeling of the glycogen substrate
to permit further degradation, and
(3) The conversion of glucose 1-phosphate
into glucose 6-phosphate for further
metabolism.


The efficient breakdown of glycogen to provide
glucose 6-phosphate for further metabolism
requires four enzyme activities:
one to degrade glycogen,
two to remodel glycogen so that it remains a
substrate for degradation, and
 one to convert the product of glycogen
breakdown into a form suitable for further
metabolism.


a) Phosphorylase- Glycogen phosphorylase,
the key enzyme in glycogen breakdown,
cleaves its substrate by the addition of
orthophosphate (Pi) to yield glucose 1-
phosphate. The cleavage of a bond by the
addition of orthophosphate is referred to as
phosphorolysis.


b) Transferase and Debranching enzyme-
The Transferase shifts a block of three glucosyl
residues from one outer branch to the other.

This transfer exposes a single glucose residue
joined by an α -1,6-glycosidic linkage.

α-1,6-Glucosidase, also known as the
debranching enzyme, hydrolyzes the α -1, 6-
glycosidic bond, resulting in the release of a free
glucose molecule.


c) Phosphoglucomutase- Glucose 1-
phosphate formed in the phosphoroylytic
cleavage of glycogen must be converted into
glucose 6-phosphate to enter the metabolic
mainstream. This shift of a phosphoryl group
is catalyzed by Phosphoglucomutase.


1) Release of Glucose-1-P

Phosphorylase catalyzes the sequential
removal of glucosyl residues from the
nonreducing ends of the glycogen molecule (the
ends with a free 4-OH group.
Orthophosphate splits the glycosidic linkage
between C-1 of the terminal residue and C-4 of
the adjacent one.


The phosphoroylytic cleavage of glycogen is
energetically advantageous because the released
sugar is already phosphorylated.
 In contrast, a hydrolytic cleavage would yield
glucose, which would then have to be
phosphorylated at the expense of the hydrolysis of a
molecule of ATP to enter the glycolytic pathway.
 An additional advantage of phosphoroylytic
cleavage for muscle cells is that glucose 1-
phosphate, negatively charged under physiological
conditions, cannot diffuse out of the cell.


The α-1,6-glycosidic bonds at the branch
points are not susceptible to cleavage by
phosphorylase.
Glycogen phosphorylase stops cleaving α -1,4
linkages when it reaches a terminal residue four
residues away from a branch point.
Because about 1 in 10 residues is branched,
glycogen degradation by the phosphorylase
alone would come to a halt after the release of
six glucose molecules per branch.


 Transferase shifts a
block of three glycosyl
residues from one outer
branch to the other.
This transfer exposes a
single glucose residue
joined by an α-1,6-
glycosidic linkage.
Debranching enzyme,
hydrolyzes the α -1, 6-
glycosidic bond,
resulting in the release
of a free glucose
molecule.


Transferase and α-1,6-glucosidase, remodel the glycogen
for continued degradation by the phosphorylase.
 The free glucose molecule released by the action of
debranching enzyme is phosphorylated by the glycolytic
enzyme hexokinase.
Thus, the Transferase and α-1,6-glucosidase convert the
branched structure into a linear one, which paves the way for
further cleavage by phosphorylase.


Phosphoglucomutase
converts glucose 1-
phosphate into glucose 6-
phosphate in a reversible
reaction.
Glucose 6-phosphate
derived from glycogen can
(1) be used as a fuel for
muscle; (2) be converted
into free glucose in the
liver and subsequently
released into the blood;
(3) be processed by the
pentose phosphate
pathway.


The liver contains a hydrolytic enzyme, glucose 6-
phosphatase, which cleaves the phosphoryl group
to form free glucose and orthophosphate.

Glucose 6-phosphatase is absent from most
other tissues.
Consequently, glucose 6-phosphate is retained
for the generation of ATP.
The liver releases glucose into the blood during
muscular activity and between meals to be taken
up primarily by the brain and skeletal muscle.

Pyridoxal phosphate (PLP), a derivative of
vitamin B6, serves as prosthetic group for
Glycogen Phosphorylase.

H O
O C
O H2
P C OH
O
O

N CH3
H
pyridoxal phosphate (PLP)


Pyridoxal phosphate (PLP)
is held at the active site by a Enz
Schiff base linkage, formed (CH2)4
by reaction of the aldehyde
of PLP with the -amino N+
group of a lysine residue. O
O
H2
HC H

In contrast to its role in
P C O
O
other enzymes, the O
phosphate of PLP is involved
in acid/base catalysis by N
H
CH3

Phosphorylase. Enzyme (Lys)-PLP Schiff base


one ATP is hydrolyzed incorporating glucose 6-
phosphate into glycogen.
The energy yield from the breakdown of glycogen is
highly efficient.
 About 90% of the residues are phosphorolytically
cleaved to glucose 1-phosphate, which is converted
at no cost into glucose 6-phosphate.
The other 10% are branch residues, which are
hydrolytically cleaved.
One molecule of ATP is then used to phosphorylate
each of these glucose molecules to glucose 6-
phosphate.


The principal enzymes controlling glycogen
metabolism—glycogen phosphorylase and
glycogen synthase—are regulated by
allosteric mechanisms and covalent
modifications due to reversible
phosphorylation and dephosphorylation of
enzyme protein in response to hormone
action


Glycogen Synthase is allosterically activated by
glucose-6-P.
Thus Glycogen Synthase is active when high
blood glucose leads to elevated intracellular
glucose-6-P.
Itis useful to a cell to store glucose as glycogen
when the input to Glycolysis (glucose-6-P), and
the main product of Glycolysis (ATP), are adequate.


The hormones glucagon and epinephrine
activate G-protein coupled receptors to trigger
cAMP cascades.
Both hormones are produced in response to low
blood sugar.
Glucagon, which is synthesized by -cells of
the pancreas, activates cAMP formation in liver.
Muscle cells lack Glucagon receptors

Epinephrine activates cAMP formation in muscle


Glycogen synthase exists in both
phosphorylated or nonphosphorylated states
Active glycogen synthase a is
dephosphorylated and inactive glycogen
synthase b is phosphorylated
The cAMP cascade results in phosphorylation of a
serine hydroxyl of Glycogen synthase, which
promotes transition to the inactive state.


Phosphorylation of
Glycogen Synthase Glycogen Glucose
promotes the "b" (less Hexokinase or Glucokinase
active) conformation.
The cAMP cascade thus Glucose-6-Pase
inhibits glycogen synthesis. Glucose-1-P Glucose-6-P Glucose + Pi
Glycolysis
 Instead of being Pathway
converted to glycogen,
glucose-1-P in liver may be Pyruvate
converted to glucose-6-P,
and dephosphorylated for Glucose metabolism in liver.
release to the blood.


Insulin, produced in response to high blood glucose,
triggers a separate signal cascade that leads to
activation of Phosphoprotein Phosphatase.
Thisphosphatase catalyzes removal of regulatory
phosphate residues from Glycogen Synthase enzyme.
Thus insulin antagonizes effects of the cAMP cascade
induced by glucagon & epinephrine.
cAMP is hydrolyzed by phosphodiesterase, so
terminating hormone action; in liver insulin increases
the activity of phosphodiesterase.


Glycogen Synthase and Glycogen Phosphorylase
are reciprocally regulated, by allosteric effectors
and by phosphorylation.
The control of phosphorylase differs between
liver & muscle
In the liver the role of glycogen is to provide free
glucose for export to maintain the blood
concentration of glucose;
 In muscle the role of glycogen is to provide a
source of glucose 6-phosphate for glycolysis in
response to the need for ATP for muscle
contraction.


 Glycogen Phosphorylase in muscle is subject to
allosteric regulation by AMP, ATP, and glucose-6-
phosphate.
A separate isozyme of Phosphorylase expressed in
liver is less sensitive to these allosteric controls.
AMP (present significantly when ATP is depleted)
activates Phosphorylase, promoting the relaxed
conformation.
ATP & glucose-6-phosphate, which both have binding
sites that overlap that of AMP, inhibit Phosphorylase
Thus glycogen breakdown is inhibited when ATP and
glucose-6-phosphate are plentiful.


The cAMP cascade results in phosphorylation of a serine
hydroxyl of Glycogen Phosphorylase, which promotes
transition to the active state.
The phosphorylated enzyme is less sensitive to allosteric
inhibitors.
Thus,even if cellular ATP & glucose-6-phosphate are high,
Phosphorylase will be active.
The glucose-1-phosphate produced from glycogen in liver
may be converted to free glucose for release to the blood.
With this hormone-activated regulation, the needs of the
organism take precedence over needs of the cell.


The enzyme phosphorylase is activated by
phosphorylation catalyzed by phosphorylase
kinase (to yield phosphorylase a) and
Inactivated by dephosphorylation catalyzed
by phosphoprotein phosphatase (to yield
phosphorylase b), in response to hormonal
and other signals.


Hormone (epinephrine or glucagon)
via G Protein (G -GTP)

Adenylate cyclase Adenylate cyclase
(inactive) (active)
catalysis
ATP cyclic AMP + PPi
Activation Phosphodiesterase
AMP
Protein kinase A Protein kinase A
(inactive) (active)
ATP
ADP

Phosphorylase kinase Phosphorylase kinase (P)
(b-inactive) (a-active)
Phosphatase ATP
Pi ADP

Phosphorylase Phosphorylase (P)
(b-allosteric) (a-active)
Phosphatase
Biochemistry For Medics
Pi 8/12/2012 49

Increasing the concentration of cAMP activates cAMP-
dependent protein kinase, which catalyzes the
phosphorylation by ATP of inactive phosphorylase kinase b
to active phosphorylase kinase a, which in turn,
phosphorylates phosphorylase b to phosphorylase a.

In the liver, cAMP is formed in response to glucagon,
which is secreted in response to falling blood glucose;
muscle is insensitive to glucagon.

In muscle, the signal for increased cAMP formation is the
action of norepinephrine, which is secreted in response to
fear or fright, when there is a need for increased
glycogenolysis to permit rapid muscle activity.


Ca++ also regulates glycogen breakdown in
muscle.
During activation of contraction in skeletal
muscle, Ca++ is released from the sarcoplasmic
reticulum to promote actin/myosin interactions.
The released Ca++ also activates Phosphorylase
Kinase, which in muscle includes calmodulin as its
subunit.
Phosphorylase Kinase is partly activated by
binding of Ca++ to this subunit.


Muscle phosphorylase kinase, which activates glycogen
phosphorylase, is a tetramer of four different subunits-α, β ,Υ and
δ.
The α and β subunits contain serine residues that are
phosphorylated by cAMP-dependent protein kinase. The δ subunit
is identical to the Ca2+-binding protein calmodulin.
The binding of Ca2+ activates the catalytic site of the subunit even
while the enzyme is in the dephosphorylated b state; the
phosphorylated a form is only fully activated in the presence of
Ca2+.
Phosphorylase Kinase inactive

Phosphorylase Kinase-Ca++ partly active

P-Phosphorylase Kinase-Ca++ fully active


Both phosphorylase a and phosphorylase kinase a
are dephosphorylated and inactivated by protein
phosphatase-1.
Protein phosphatase-1 is inhibited by a protein,
inhibitor-1, which is active only after it has been
phosphorylated by cAMP-dependent protein kinase.
Thus, cAMP controls both the activation and
inactivation of phosphorylase.
Insulin reinforces this effect by inhibiting the
activation of phosphorylase b.
It does this indirectly by increasing uptake of
glucose, leading to increased formation of glucose
6-phosphate, which is an inhibitor of phosphorylase
kinase.


Glycogen Synthase & Phosphorylase activity are
reciprocally regulated
At the same time as phosphorylase is activated by a
rise in concentration of cAMP (via phosphorylase
kinase), glycogen synthase is converted to the
inactive form;
both effects are mediated via cAMP-dependent
protein kinase .
Thus, inhibition of glycogenolysis enhances net
glycogenesis, and inhibition of glycogenesis
enhances net glycogenolysis


Glycogen Storage Diseases
"Glycogen storage disease" is a generic term
to describe a group of inherited disorders
characterized by deposition of an abnormal
type or quantity of glycogen in tissues, or
failure to mobilize glycogen.


Symptoms in addition to excess glycogen
storage:
When a genetic defect affects mainly an
isoform of an enzyme expressed in liver, a
common symptom is hypoglycemia, relating to
impaired mobilization of glucose for release to
the blood during fasting.
When the defect is in muscle tissue, weakness
& difficulty with exercise result from inability to
increase glucose entry into Glycolysis during
exercise.
Additional symptoms depend on the
particular enzyme that isBiochemistry For Medics 8/12/2012
deficient. 56

Name Enzyme Clinical Features
Type Deficiency

— Glycogen Hypoglycemia;
0 synthase hyperketonemia;
early death

Von Gierke's Glucose 6- Glycogen
disease phosphatase accumulation in
liver and renal
I tubule cells;
hypoglycemia;
lactic acidemia;
ketosis;
hyperlipemia
Pompe’s Disease Lysosomal 14 Accumulation of
and 16 glycogen in
glucosidaseFor Medics 8/12/2012
Biochemistry (acid lysosomes: 57

Type Name Biochemical Clinical Features
defect
III Limit dextrinosis, Debranching Fasting
Forbe's or Cori's enzyme hypoglycemia;
disease hepatomegaly in
infancy;
accumulation of
characteristic
branched
polysaccharide
IV Amylopectinosis, Branching Hepatosplenome
Andersen's enzyme galy;
disease accumulation of
polysaccharide
with few branch
points; death
from heart or
liver failure in
first year of life

Type Name Biochemical defect Clinical Features

V Myophosphorylase Muscle Poor exercise
deficiency, phosphorylase tolerance; muscle
McArdle's glycogen
syndrome abnormally high
(2.5–4%); blood
lactate very low
after exercise

VI Hers' disease Liver Hepatomegaly;
phosphorylase accumulation of
glycogen in liver;
mild
hypoglycemia;
generally good
prognosis


VII Tarui's disease Muscle and Poor exercise
erythrocyte tolerance; muscle
phosphofructokina glycogen
se 1 abnormally high
(2.5–4%); blood
lactate very low
after exercise; also
hemolytic anemia

VIII Liver Hepatomegaly;
kinase glycogen in liver;
mild
hypoglycemia;
generally good
prognosis

IX Liver and muscle Hepatomegaly;
kinase glycogen in liver
and muscle; mild
hypoglycemia;
generally good
prognosis

X cAMP-dependent Hepatomegaly;
protein kinase A accumulation of
glycogen in liver


Glycogen represents the principal storage form of
carbohydrate in the body, mainly in the liver and muscle.
Glycogen is synthesized from glucose by the pathway of
glycogenesis.
It is broken down by a separate pathway, glycogenolysis.
Glycogenolysis leads to glucose formation in liver and
lactate formation in muscle owing to the respective
presence or absence of glucose 6-phosphatase.
Cyclic AMP integrates the regulation of glycogenolysis
and glycogenesis by promoting the simultaneous
activation of phosphorylase and inhibition of glycogen
synthase.
Insulin acts reciprocally by inhibiting glycogenolysis and
stimulating glycogenesis.
Inherited deficiencies in specific enzymes of glycogen
metabolism in both liver and muscle are the causes of
glycogen storage diseases.


Glycogen metabolism

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