Lecture 15.

Metabolism of
Glycogen, Fructose and Galactose

• Glycogen Metabolism

• Fructose Metabolism

• Galactose Metabolism
 In animals
Glycogen Metabolism We store as glycogen
Glycogen is the storage form of glucose in all cells. However, it is especially because of osmosis and
abundant in liver and muscle. because ATP is not needed
Glycogen is present in cytosol in the form of granules ranging in diameter to pump the glucose and
from 10 to 40 nm and consists of ~ 55,000 glucose molecules.- very large because water would rush
polymer into the cell and cause lysis
Muscle Goes from high
1-2% glycogen by weight, 400g glycogen/ 35 kg muscle concentration to low
Liver concentration
10% glycogen by weight, 100g glycogen/ 1.6 kg liver Pressure is generated
Why store glucose as glycogen? Why not store as free glucose? between the 2 solutions and
Review it’s independent of the type
Osmosis is a colligative property. That is, it only depends on the number of and size of solutes, just the
solute (e.g., glucose) molecules. Osmosis is independent of the type or size number of solutes
of the solute molecule.
The concentration of glycogen in the
liver is .00001 mM. However, it is a
polymer of glucose. Therefore you
would need 400 mM glucose to match
glycogen. This would require using
ATP to pump glucose into the cell
against the concentration gradient.
More importantly, water would rush
into the cells and cause lysis.
 Why do we need a storage form of glucose?
Different
Answer depends on the type of tissue. tissues store
glycogen
Muscle glycogen serves as a fuel
differently
reserve for ATP synthesis during
muscle contraction. – when ATP is
needed the muscle glycogen is
broken down and goes to GCP
and then glycolysis to generate
more ATP

Liver glycogen serves as a source

of blood glucose. Glycogen is
broken down to make GCP and a
phosphate group is made and the
glucose is transported across the
membrane in order to maintain the
blood glucose
Red blood cells and the brain absolutely require glucose for energy metabolism. They
consume ~80% of the 200g of glucose metabolized in the body/day. There is only ~10g
of glucose in the plasma so the blood glucose must be replenished constantly.
Otherwise, hypoglycemia develops leading to confusion and coma.
 3 primary sources of blood glucose
A. food- sporadic and not reliable because it depends on the diet
B. Gluconeogenesis- slow to respond to a falling blood glucose level
C. Glycogen degradation- rapidly mobilized form of glucose

C- It reacts much faster than gluconeogenesis

Glycogen content in liver after meals, the glucose stores in the form of
glycogen
At night the glycogen starts to be broken down to glucose
Review of the Structure of Glycogen

Branch points every 4 to 6

glucose molecules. (caused by
16 glycosidic bond)

Branching provides numerous

sites for synthesis and
degradation

Biosynthesis of glycogen
occurs very fast because
many sites can happen at
the same time
Glycogen Breakdown (Glycogenolysis)

- Glucose to become G6P

then pyruvate- this is
glycolysis
- Pyruvate to glucose is
gluconeogenesis
- Glycogen breakdown to G6P
then goes to glucose or
glyclysis to become pyruvate
- Glycogen synthesis- starts
from G6P
- Pyruvate is key intermediate
 Glycogen Breakdown (Glycogenolysis)

NOTE: Anaerobic glycolysis from glycogen produces 3 ATP

for each glucose residue because the hexokinase reaction is
not required. - Left side- glycogen break
down- glycogen goes to G1P
then G6P and it’s 3 enzymes
involved
- First 2 enzymes break it
down to G1P and the last
moves it to be G6P
- Breakdown is much faster
than gluconeogenesis
- Right side- glycogen
synthesis- 4 enzymes work to
make it- it’s anaerobic and
produces 3 ATP

Glycogen phosphorylase is
the key enzyme
Glycogen Phosphorylase

Phosphoglucomutase
- Involved in glycogen
breakdown
- The first one catalyzes
the cleavage of the 1,4
glycosidic bond
- And then phosphate is
added to make G1P
- Then the 2nd enzyme
catalyzes the transfer of
the phosphate group to
the 6th carbon to make it
G6P and then it can enter
into glycolysis
- Don’t have to know the
mechanism

Phosphoglucomutase:
G1P to G6P
Debranching Enzymes
Has 2 activities
1. Transferase activity- transports 3
residues from the branch to the
main chain
2. Break the alpha 1,6 glycosidic bond
Theses are the debranching enzymes
When you reach the last 4 residues,
the debranching comes in and takes
the last 3 and then cleaves the last
one
 Glucose- 6- phosphatase

Glucoses are cleaved 1 by 1

G6P can enter into glycolysis
Glucose is then delivered to blood
G6P cannot be transported across the plasma membrane because there’s a
negative phosphate group so it must be dephosphorylated to become glucose to be
transported across the membrane
In the ER, there is glucose 6 phosphatase- this cleaves the phosphate and makes
glucose
GLUT2 delivers glucose to the blood circulation
Glycogen Synthesis – not the opposite of glycogen break down
How was it discovered that there was a separate pathway for glycogen synthesis? In
other words, what made us think that glycogen synthesis is not simply the reverse of
glycogen breakdown.

McArdle’s Disease
•Glycogen storage disease
•Inherited disorder, results in painful
muscle cramps upon strenuous exercise
•Patients have no glycogen
phosphorylase activity and thus no
glycogen breakdown.
•However, muscles contain high
quantities of glycogen.
•Thus, there must be separate pathways
for synthesis and breakdown

UDP-glucose pyrophosphorylase
Continue notes from last slide

- So if they do heavy exercise, the muscle contraction requires a huge

amount of ATP but they can’t break down glycogen so there isn't’ a
sufficient amount of ATP to be generated so they get muscle cramps
- The glycogen synthesis in their bodies was normal but the degradation
was abnormal so they have to use different pathways
- Understand McArdle’s disease- this is proof that synthesis and
breakdown and completely different reactions
- UDP- know the name- this is the intermediate in glycogen synthesis
and it’s related to galactose metabolism
- G1P- interacts with the UTP and diphosphate is the leaving group to
form UDP
 Glycogenin
Glycogenin is a 349 amino acid protein with glucosyltransferase activity. Extends
chain up to 7 glucose residues. There is one glycogenin molecule/glycogen
molecule. It is needed because glycogen synthase cannot use free glucose as a
substrate.

Reaction repeats
6 times so 7
glucose residues
are added to the
chain
 Glycogen Synthase

This is the enzymes that catalyzes this

reaction
Everytime 1 glucose is added
Branching Enzyme Transfer the residues
from the main chain to
the branch to make an
alpha 1-6 glycosidic
bond
 Regulation of Glycogen Metabolism
• Glycogen synthesis and breakdown are both exergonic.
• If both pathways operated simultaneously, all that would be achieved would be
wasteful hydrolysis of UTP.
• Thus, glycogen phosphorylase and glycogen synthesis are under stringent control.
Allosteric control
Allosteric control of glycogen
phosphorylase and glycogen synthase - Red negative means it’s an
allow adjustment of enzyme activity to inhibitor
meet the needs of the cell in which - When ATP is high, you don’t
enzymes are expressed. need to make more glucose
- G6P is an activator because
when it is high, it should be
converted to glycogen
Thus, when the demand for ATP is - Calcium and AMP are
high (ie. low ATP, low glucose-6-P activators in muscle
and high AMP), glycogen - When AMP is high, ATP is
phosphorylase is stimulated, and low
glycogen synthase is inhibited. - Calcium is an activator
because when it’s high, there
Conversely, when ATP and glucose-
is activity for the muscle that
6-P are high, glycogen requires energy and turns on
phosphorylase is inhibited and the phosphorylase
glycogen synthesis is favored.
 Regulation of Glycogen Metabolism
Hormonal Control

In contrast to allosteric control, hormonal control allows glycogen

metabolism to adjust to the needs of the entire organism.

Covalent modification of glycogen phosphorylase and glycogen

synthase.

Glycogen phosphorylase is activated by phosphorylation (b → a),

while glycogen synthase is inactivated by phosphorylation (a →b).
Dephosphorylation inactivates glycogen phosphorylase and activates
glycogen synthase.
 Regulation of Glycogen Metabolism
Control of Glycogen Phosphorylase Activity Don’t know
detail
 Regulation of Glycogen Metabolism
How is phosphorylase kinase regulated?
Protein kinase A is activated
by glucagon and then it
phosphorylated kinase and
makes it active and that
phosphorylates the glycogen
phos and makes it active
 Regulation of Glycogen Metabolism
Protein kinase A (cAMP-dependant protein kinase)

Glucagon can activate

the formation of cAMP
and then it can activate
the enzymes
 Regulation of Glycogen Metabolism
Where does cAMP come from?
 Regulation of Glycogen
Metabolism
What regulates adenylate cyclase?

Hormones (especially glucagon)

binds to receptors and active the
adenyl cyclase and it makes cAMP
 Regulation of Glycogen Metabolism
What hormones start this process?

Peptide hormone made in the pancreas used for maintaining the steady-state
level of blood glucose. Thus, it only activates glycogenolysis in liver, not
muscle.

Synthesized in and secreted

from the adrenal medulla.
Fight or flight hormone used
for generating energy very
rapidly (i.e., muscles) and
throughout the organism (i.e.
liver)
 Regulation of Glycogen Metabolism
Putting it all together
 Continue notes from last slide

Glucagon work in coordination and actives the cAMP formation and then it
binds to protein kinase A and it’s now activated and phosphor. The enzymes
glycogen phosphorylase to make it activate and can go into the glycogen
break down
So glucagon increases glyocgen break down
 Calcium regulates phosphorylase kinase
via calmodulin.
- Caused by the calcium
calmodulin
- When they bind there is a
conformational chain so it can
bind to phos. Kinase and
activates it and then glycogen
phosphoylase is
phosphorylated and it’s active
- 3 different things that active
this
1. ATP hydrolysis – AMP
directly activates the
enzyme- allosteric
2. Neuron cells signal release
of calcium and then it binds
to calmodulin and then binds
Calmodulin is a ubiquitous eukaryotic Ca2+ binding protein
to kinase
that participates in numerous cellular regulatory processes.
3. cAMP activates protein
Calcium binding to calmodulin induces a conformational
kinase A
change that exposes a patch of hydrophobic amino acids.
3 pathways all work together to
This patch allows calmodulin to bind to phosphorylase
degrade glycogen
kinase and activate it.
How do glucagon and epinephrine affect
glycogen synthesis?

Note: Insulin is antagonistic to glucagon and can reverse

all of the mechanisms of glucagon. The mechanism is still
under invesitgation. However, two mechanisms are:

1. Insulin promotes glucose transport into the cell which

inhibits glycogen phosphorylase activity.

2. Insulin stimulates protein phosphatase activity.- can

activate glycogen synthesis

***To remember whether a particular enzyme has been

activated or inhibited by cAMP-dependent phosphorylation,
consider whether it makes sense for the enzyme to be
active or inhibited under fasting conditions (In a PHast,
PHosphorylate).***
 Why is the mechanism of regulation so
complicated?

Because you have a small number

of hormone molecules, such as
epinephrine. However, in a fight or
flight situation, you need a massive
response. Thus, the cascade
system allows for amplification of a
small signal.

High conc of AMP and calcium

promote glycogen breakdown
 Only know McArdile
Glycogen Storage Diseases
Inherited disorders that result in glycogen that is abnormal either in
quantity or quality. Glycogen storage diseases that affect the liver cause
heptomegaly (enlarged liver) and hypoglycemia (low blood sugar).
Disorders that affect the muscles result in cramps and weakness.
This is the regulation for glycogen degratation and synthesis
Glycogen phosphorlyase is key to degradation
Glycogen synthase is key to synthesis
G6P is the activator of synthesis
Inhibition of glucagon activates the glycogen synthase and inhibit the glycogen
phosphorylase and inhibits the degradation
In fasting state, the glucose is low so inhibits insulin and releases glucagon and
increases protein kinase and phosphorlyates the enzymes and activates glycogen
breakdown
 Metabolism of Fructose

Fructose

10% of the calories in the Western diet are

supplied by fructose (~50 gms/ day)

Sources: Sucrose
high fructose corn syrup (55%
fructose/ 45% glucose)
fruits
honey
2 Different Pathways of Fructose
Metabolism
On the right is
glycolysis
Galactose is related to
G6P
Fructose goes through
2 different pathways,
in the muscle it goes
to F6P and in the liver
it goes to GAP
Fructose Metabolism
 Continue notes from last slide

- In muscle and liver it’s different

- In muscle it’s simple, fructose becomes F6P- phosphorylation occurs in the carbon 6
and it’s the second compound in glycolysis and the enzymes is hexokinase (for
phosphorylation of glucose and fructose)
- Hexokinase has higher affinity for glucose so it’s the major in muscles
- Fructose has lower activity for hexokinase
- In the liver fructose goes through complicated reactions fructose kinase
phosphorylates fructose at carbon 1 so it becomes F1P and then it can be cleaved
into 2 fragments (Glyceraldehyde) which becomes 2 GAP and it enters glycolysis
- Don’t need to know the reaction, just have an idea that in liver it’s more complicated
and then it goes to GAP to enter glycolysis
- In muscle hexokinase catalyzes the phosphorylation
 Fructose metabolism
• The metabolism of fructose occurs primarily in the liver because the
Km of hexokinase for fructose is 20 times higher than for glucose.
Thus, the V/K or catalytic efficiency of hexokinase for fructose is
much less than for glucose. The muscle pathway is only important
when fructose is high
• Note: fructose metabolism in the liver bypasses
phosphofructokinase that can lead to lipogenesis. This suggests a
link between high fructose soft drinks and obesity.

Hexokinase activity is lower for fructose and higher for glucose

Fructose usually can’t be metabolized in muscles so the major metabolism is
in liver
Fructose can be synthesized
by the Polyol Pathway

Fructose is the principal energy

source for spermatozoa in the
seminal fluid.

In nerves, the accumulation of

sorbitol contributes to
neuropathy in peripheral nerves.
Fructose can be synthesized
by the Polyol Pathway

Fructose is the principal energy

source for spermatozoa in the
seminal fluid.

Don’t know
detail

In nerves, the accumulation of

sorbitol contributes to
neuropathy in peripheral nerves.
 Galactose Metabolism
The major dietary source is from hydrolysis of lactose (milk sugar).
Unlike glucose and fructose, no catabolic pathway exists to metabolize
galactose. Therefore, galactose is converted into a metabolite of glucose by
the Leloir pathway.
First galactose
becomes G1P
Then G1P interacts
with UDP glucose to
become UDP
galactose
And then it becomes
G6P to enter
glycolysis
UDP galactose can
be converted to UDP
glucose by an
enzyme
 Homework Questions
• Why is glycogen the storage form of energy instead of free glucose in
animal cells?
– Higher molecular concentration of glucose to match glycogen would increase
osmosis, and would require using ATP to pump glucose into the cell against the
concentration gradient
• Describe three primary sources of blood glucose to maintain blood
glucose content.
– Food, gluconeogenesis, and glucogenolysis
• How was it discovered that there was a separate pathway for glycogen
synthesis from glycogen degradation?
– McArdle’s Disease: patients have no glycogen phosphorylase activity and thus
no glycogen breakdown. However, muscles contain high quantities of glycogen
• How does the secretion of glucagon affect glycogen degradation?
– Glucagon secretion will activate cAMP-dependent protein kinase A, resulting in
active glycogen phosphorylase, leading to glycogen degradation