SUBJECT: BIOCHEMISTRY

TOPIC: CARBOHYDRATE METABOLISM 2

(GLYCOGENESIS AND GLYCOGENOLYSIS)

LECTURER: DRA. UY

DATE: DECEMBER 2010

Glycogenolysis
 Breakdown of glycogen to glucose in the form of G6P

Glycogenesis
 Synthesis of glycogen
 Only occurs in the muscles & liver

The formation of glucose from glycogen in the form of glucose-1-phosphate

 Glycogen = the storage form of glucose in humans
- Composed of both α-1,4-glycosidic linkages and α -1,6-glycosidic linkages
- Highly branched
 Starch = the storage form of glucose in plants
- Composed of α-1,4-glycosidic linkages
- Longer than glycogen

Glycogenesis will only be occurring in the muscles and liver while Gluconeogenesis can occur in any organ, but only the muscles
and liver will supply glycogen. The muscles supply glycogen only for its own use while the liver will be more generous because it
can supply any other organs in the body.

Glycogen is stored in the form of granules. That is why when we do the dissection in anatomy, we can see glycogen granules.
This is abundant in the liver during the well-fed state. But it will be absent for about 24 hours. So that’s why during the night,
after eating and during sleeping, the brain still needs glucose, which came from the process of glycogenolysis in the liver. When
exercising, the glycogen in the muscles will be utilized. After 24 hours of fasting, there will be few glycogen granules. These
granules contain enzymes that catalyze these granules.

STORAGE:
The polymeric nature of glycogen allows energy to be sequestered without the
problems of osmotic effects that glucose would cause.
- Glucose is hydrophilic which attracts electrolytes and water. So that is why
when we have diabetes, we have lots of glucose in blood vessels and goes
to kidneys and draws water and sodium—causing polyuria and fatigue
because no ATP is produced.
- Primarily stored in the MUSCLE and LIVER.
o Liver has the most glycogen supply.
o Muscles have the highest glycogen content because muscle is
more abundant than the liver.
- In humans, liver glycogen stores are typically adequate for up to 12 hours.,
without the support of gluconeogenesis.
o Between 12 hours between 24 hours, we will have glycogenolysis
and gluconeogenesis, but after 24 hours, all of it will be
gluconeogenesis.

Glycogen
- storage form of fuel
- Composed of glucosyl residues, mostly linked together by - 1,4 –
glycosidic linkages. Branches arise from frequent - 1,6 – glycosidic
linkages

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 Cellulose
- Has β-1,4 glycosidic linkages that is why we don’t have the enzyme for that, and we will not be able to digest it.

Glycogen “Tree”
- Branches at every 4th glucosyl residue within the more central core (glycogenin) of the molecule and less in the outer
region
o The branches, 1,6-glycosidic bond and α-1,4-glycosidic bonds.
- Imagine glycogen as the tree and at the middle is the glycogenin

Muscle glycogen = fuel reserved for ATP production within a particular tissue
Liver glycogen = glucose reserve for the maintenance of blood concentration

After breakfast, there is an elevation of glycogen in the liver (well-

fed state), and it goes down during lunch. Before lunch, there is a
decrease of glycogen supply, hence the giddiness, so the body
has to undergo glycogenesis, and for this to occur, one must eat.
By 4 o’clock, it starts to go down again. The most important part is
breakfast because you have to break the fast. :>

G6P in glycolytic pathway or gluconeogenesis has to be

converted to G1P by the enzyme phosphoglucomutase.
Then, you invest ATP. And then by the glucokinase in
the liver, glucose will be converted to G6P. G6P can
either go to glycolysis or to other alternate pathway like
pentose phosphate pathway. By the enzyme
phosphoglucomutase, we convert G6P to G1P because
the enzyme, UDP glucosephosphorylase only reacts on
G1P. If there is a mutation in this enzyme, there will be
no glycogenesis occurring. Body will depend on
glycolysis and pentose phosphate pathway as supplier
of ATP, so we feed them every now and then but these
children will not last long and die before the age of 2.
G1P is the molecule that is the basis of glycogenesis.
This G1P will enter a pathway with the help of a
cofactor which is UTP (Uridine Triphosphate, a high
energy compound) and UDP-glucose
pyrophosphorylase to form UDP-glucose, liberating 2
PPi. UDP-glucose will be attached to a glycogenin
(protein primer of glycogenesis) in a (14) glucosydic
bond and the UDP will be liberated. This is due to the
enzyme glycogen synthase. More UDP-glucose are
added in the glycogenin in the non-reducing ends with
the help of glycogen synthase. Glycogen synthase
transfers the activated glucosyl moiety of UDP –
glucose to the carbon 4 of a glucosyl residue of the
growing chain to form a new glycosidic bond at the
hydroxyl group of C1 of the activated sugar. The

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reducing end of glucose (C1) is always added to the non- reducing end (C4 of a glucosyl residue) of the glycogen chain to form
14 glycosidic bond.

Glycogen synthase should have the assistance of branching enzyme (46 transferase) because glycogen synthase will only
form 14 glucosyl units. We have to have a branching enzyme so that it will also add 16 glucosyl residue so that it’s not
linear. Glycogen synthase is regulated by insulin, glucagon and ephinephrine. In glucose or carbohydrate metabolism, memorize
insulin and glucagon. Glucagon and epinephrine in the muscles.

Linear glycogen, hence, decrease solubility and will not be utilized.

Glycogen synthase cannot form the  - 1,6- glycosidic linkages

Once an amylose chain of at least 11 residues has been formed, a “branching enzyme” called glucosyl (-4:6) transferase
removes a block of about 7 glucosyl residues from a growing chain of amylase chain and transfer it to another chain to produce
an - 1,6 – linkage until we form the glycogen tree.

How does the branching enzyme work?

- Transfers approximately 5-8 glucosyl residues from the non-reducing end of the glycogen chain to another residue within
the chain and attaches the residues via an α-1,6 linkage.
- If there is a mutation or deficiency in the enzyme, there will be hepatomegaly because everything is linear. It will further
develop into fibrosis.

Glycogenesis is an activity of 2 important enzymes: glycogen synthase

and branching enzyme.

The new branch has to be introduced at least 4 glucosyl residues to

the nearest branch points

What is the purpose of branching of glycogen molecules?

- To facilitate the breakdown of glycogen and aid in solubility
- When used as a fuel during strenuous exercise in muscle and in
liver in the fasted state (of only about 12 hours to 24 hrs, there
will be glycogenolysis and gluconeogenesis[mostly after 24
hours])

Glycogenin is Required as a Primer for Glycogen Synthesis

- protein
- It is self-glucosylating, it will form and add glucose
- We have concerted effort of glycogen synthase and branching
enzyme with cofactor UTP to form UDP-glucose. And UDP will be
liberated
- Then we have the glycogenin-glycogen complex

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 Phosphoglucomutase is needed in glycogenesis, glycogenolysis,
glycolysis, gluconeogenesis, glycogenolysis, pentosephosphate
pathway.
We already have a glycogen chain, now we have our glycogen
phosphorylase. This enzyme phosphorylates, to form G1P, releasing
it from the glycogen molecule. Through the help of
phosphoglucomutase it will turn G1P to form G6P. From the
glycolytic pathway, G6P can be utilized to form glucose or glycolysis
to form pyruvate, and later on lactate to glucose in
gluconeogenesis.
The control of enzyme glycogen phosphorylase and glycogen
synthase: The glycogen phosphorylase is allostericaly inhibited by
glucose and ATP, and G6P because we don’t need the energy
anymore and will have a feedback on the enzyme. Glycogen
synthase is activated by G6P in the liver. What inhibits the
degradation activates the formation.

In the muscle on the other hand, it’s the same principle but except in the muscles, we have the calcium and the AMP which are
activators of glycogen phosphorylase. The calcium and AMP works by activating the contraction of muscles. G6P activates
glycogen synthase. The hydrolytic action of the glycogen phosphorylase is in the non-reducing end (C4).

ACTION OF GLYCOGEN PHOSPHORYLASE

- The hydrolytic action will always be at the non-reducing end
- The α 1-4 glycosidic link is cleaved by phosphorolysis.

ACTION OF DEBRANCHING ENZYME

- Debranching enzyme is required for glycogenolysis
- Glycogen phosphorylase is specific -1,4 glycosidic linkages
- It stops attacking -1,4 - glycosidic linkages 4 glucosyl residues from an -1,6- branch point
- Phosphorylase-limit dextrin is the glycogen molecule that has been degraded to the limit.
o If there is no debranching enzyme, there will be lactase deficiency.
- Allows phosphorylase to continue to degrade glycogen
- Bifunctional enzyme
o 1,4-1,4-glucan transferase activity
o -1,6 – glucosidase activity
- The cooperative and repetitive action of phosphorylase and debranching enzyme result in the complete breakdown of
glycogen into G1P and glucose. Glucose in the liver, while G6P in the muscles.

Special Features of Glycogenolysis & Glycogenesis

Why store glucose as glycogen and not fat?

1. Fat cannot be mobilized nearly as rapidly as glycogen
- We need 19 cycles in fat metabolism, in glycogen to glucose, we only need 2 enzymes
2. Fat cannot be used as a source of energy in the absence of O2
3. Fat cannot be converted to glucose to maintain blood glucose levels required
by the brain

Why not Store it as Free Glucose? Why Waste ATP Making a Polymer Out of Glucose?
- It would cost ATP to “pump” glucose into a cell against a concentration gradient, and its concentration would have to
reach about 400 mm in liver cells to match the “glucose reserve” provided by the usual liver glycogen content.
- Unless balanced by outward movement of some other osmotically active compound accumulation of glucose would
cause considerable uptake of water with osmotic lysis of the cell.
- Patients with diabetes have so much free glucose circulating in the blood vessels. They are not absorbed
because transporters such as GLUT4 are downregulating and insulin resistance. This results in so much free
glucose and a corresponding hyponatremia.

Glycogen Synthesis and Degradation are Highly Regulated

 Glycogen synthase and glycogen phosphorylase are the regulatory enzymes of glycogen synthesis and degradation
respectively.
 Both catalyze non-equilibrium reactions, & both are subject to control by allosteric effectors and covalent modification

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 Regulation of Glycogen Synthase and Glycogen Phosphorylase
- Glycogen Synthase
 Main regulatory enzyme for synthesis
- Glycogen Phosphorylase
 Main regulatory enzyme for degradation
- Both will catalyze the non-equilibrium
- Both are subjected to allosteric effectors and covalent modification
- In the liver and muscles, the 2 enzymes important
- The glucagon, (for glycogenolysis)
- G-protein is a receptor for glucagon in the liver
 Has 7-membrane spanning domain
- Adenylyl Cyclase
 2nd messenger
 Helps to form cAMP
 cAMP acts on cAMP-dependent protein kinase A
 cAMP-dependent protein kinase A has 2 ends -- the catalytic and regulatory portion.
 When we have the abundance of cAMP, this will activate cAMP-dependent protein kinase A
(which cleaves the regulatory and catalytic domain).
 The catalytic portion activates the glycogen phosphorylase kinase B.
 Kinase B  inactive
 Kinase A  active
 Phosphorylase kinase, once phosphate is added, it becomes active
 Synthase – opposite of kinase
 Glycogen phosphorylase B is activated by addition of ATP.
 Glycogen phosphorylase kinase A will now again activate glycogen phosphorylase B into
glycogen phosphorylase A and glycogen is degraded. (Regulation of glycogenolysis in the liver)
 The same is true in the muscles and liver if there are a lot of epinephrine. cAMP activation, and
then we will have glycogen phosphorylase B is activated further to degrade glycogen.
 In the muscles, we have conditions of extreme anoxia (ATP depletion). AMP activates
phosphorylase B without it being phosphorylated.
 In the muscles, we have phosphorylation and at the same time addition of AMP, activating
phosphorylase B without it being phosphorylated.
 When we have muscle contraction, Ca is released from sarcoplasmic reticulum and calcium
binds to calmodulin. Calmodulin is a subunit of phosphorylase kinase.
 Always remember that calmodulin in the muscles is associated with phosphorylase kinase
(refers to breakindg down). Phosphorylase kinase is activated without phosphorylation in the
muscles. Muscles are endowed with so many regulation to help it in contraction.
Phosphorylase kinase can then activate glycogen phosphorylase, and so break down proceeds.
 In the liver, the activation of phosphorylase is through phosphorylation through ATP. In muscles
on the other hand, activation is without phosphorylation through calcium calmodulin and AMP
activation.
 Soda and coffee
 You will also have an enzyme, phosphodiesterase
 cAMP is rapidly degraded to 5’-AMP (not useful in contraction of muscles) by
phosphodiesterase
 Phosphodiesterase inhibitors:
 Antiasthma drugs:
 Theophilin inhibits phosphodiesterase so that there is cAMP elevation
 Viagra is a phosphodiesterase inhibitor, it inhibits cAMP degradation so that
cAMP continues to elevated and will form relaxation of muscles of blood
vessels of the penis to have perfect erection.
 AMPLIFICATION OF HORMONE REGULATION:
 1 mole of glucagon is being secreted by pancreatic alpha cells activates
hundreds of cAMP. Hundreds of cAMP activates thousands of protein kinase
A. Active protein kinase A activates tens of thousands of phosphorylase
kinase B. Phosphorylase kinase A activates hundreds of thousands of
molecules of glycogen degradation.
 When you have glycogen breakdown, your glycogen synthesis has to be
inhibited, otherwise we will have a futile cycle.

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  When we have glucagon, adenylyl cyclase to form cAMP from ATP, inactive
cAMP-dependent protein kinase will be activated so that we will have the
catalytic portion. Glycogen synthase A is active, this will be phosphorylated
and will be inactive.
 A glycogen synthase is inactive when it is phosphorylated.
 Phosphorylase is active when it is phosphorylated.
 Synthase, when we have a phosphate attached to it is inactive.
 A phosphorylase when a phosphate is attached to it, is active.
 So when we have synthase B, which is inactive, glycogen synthesis is
inhibited and glycogen breakdown is activated.
 Phosphorylase kinase B  is inactive, and once it is phosphorylated it will be
activated. It is activated by protein kinase A which will split into 2—a
regulatory and catalytic domain. Once the catalytic domain is activated, this
will now catalyze and cleave glycogen phosphorylase kinase B to add a
phosphate group to phosphorylase kinase to be activated. When it is
activated, glycogen phosphorylase B is activated again and glycogen is
degraded.
What is the role of insulin?
 Glycogen synthase B (inactive and phosphorylated) will be acted upon by a
protein phosphatase so that Pi is released and by addition of water, it will be
transformed into glycogen synthase A (active)
 Insulin is an allosteric activator of protein phosphatase.
 Insulin acts on the protein phosphatase so that when it is activated,
glycogen synthase will be activated so glycogen synthesis proceeds.
 Activates the protein phosphatase
 It will also somehow activates phosphodiesterase

Regulation of glycogen breakdown

In a few minutes, all the substrates will be available:
1. We have allosteric activators an inhibitors
2. covalent modification of enzymes
3. synthesis of new molecules (gluconeogenesis)

Glycogenesis, glucogenesis,

ENZYMES ACTIVE IN DEPHOSPHORYLATED STATE:

 Irreversible
 They are for the synthesis and glycolysis
 For the production of ATP
1. Glycogen synthase
a. Formation of glycogen from UDP-glucose
2. Phosphofructokinase 2
3. Pyruvate kinase
4. Pyruvate dehydrogenase
5. Acetyl CoA Carboxylase

ENZYMES INACTIVE IN DEPHOSPHORYLATED STATE OR ACTIVE IN PHOSPHORYLATED STATE:

1. Glycogen phosphorylase kinase
2. Glycogen phosphorylase
3. Hormone sensitive lipase

In the liver:
- Will have a high glucose levels by increasing phosphorylation of glucose by glucokinase
- Glucokinase has very high Km for glucose.

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Abundance of insulin-independent GLUT2
- GLUT2 are insulin independent. Whether we have insulin or not, it will continuously transport glucose enzyme inside the
liver
- GLUT4 in the muscles and adipose tissues will not transport glucose inside the cell if there is no insulin.
- In diabetics, they have the down-regulation of GLUT4 transporters that’s why even if they have insulin secretion, it will
not be transported inside the cell.
- Diabetes Type 1 – no secretion of insulin at all, these glucose will not be transported inside the cell because there is no
insulin. So patient will be starving, hence thin appearance. Glucose cannot be absorbed by the muscles and adipose
tissues because they do not have insulin, GLUT are dependent of insulin.
- Amino acids from the gut, glucose from the gut, chylomicron remnants serve as fuel on the liver
- Adipose on the other hand, we have Insulin-dependent GLUT4 transporters, by hexokinase to form glucose trapped
inside as a source of energy
- We eat, and in the intestines, this will be degraded. Final digestive products will be glucose or monossaccharides for
carbohydrates, amino acids for proteins, chylomicrons or fatty acids for fats.
- The role of insulin which is secreted by pancreas is an anabolic signal which will promote glycogen synthesis, protein
synthesis, and triacylglycerol synthesis
- Immediately after eating, an hour or two, we have a high glucose content of the liver. The hormone insulin is then
elevated. The hormone insulin allows glycolysis (activation of pyruvate kinase). If there is too much of ATP is present,
there will be glycogenesis.
- Glycogen will now be utilized as a source of fuel in the starving state. In 24 hours, an individual undergoes
gluconeogenesis.
- First thing the patient will feel if we have controlled diabetes  person will gain weight
o Because there is a signal for the synthesis of glycogen, protein, and triacylglycerol
o Insulin is not just for glucose, it will also have the effect of synthesis of glycogen, protein, and triacylglycerol
o Insulin is not just a drug for glucose metabolism, it affects all the intermediary metabolism of fats, glucose,
proteins
o Glycogen will now be utilized as a source of fuel in the starving state. In 24 hours, an individual undergoes
gluconeogenesis.
- Amino acids, glycerol, lactate as a source of glucose  GLUCONEOGENESIS
- Fatty acids utilized to form acetyl coA. If acetyl coA is utilized it gluconeogenesis, then we will form ketone bodies, and it
will be utilized by the body. There will also be an elevation of acetoacetic acid, acetone, beta-hydroxybuterate. Among
the 3 ketone bodies, the acetoacetic acid is the most abundant. But the hydroxybutyric acid is detected in the test.

- Umbilical vein which carries oxygenated blood

- Release of insulin and decrease of glucagon, leading to synthesis
- Tissues involved in metabolism
- In the fasting state, there will be no nutrients absorbed, decreased glucose, decreased insulin, increased counter
regulatory hormone which is glucagon so that there will be release of fatty acids for hydrolysis, release of glucose in
gluconeogenesis, release of fatty acids and ketone bodies to provide for the starving tissues
- There are 12 glycogen diseases.
1. Von Gierke’s Disease or Type 1 - Not a defect on glycogenesis or
- most common glycogenolysis, but rather a defect in
- deficiency of liver, intestinal mucosa & lysosomes
kidney G-6 – Phosphatase except muscles i. Lysosomes are abundant in the GIT
because the muscles don’t have G6P. (there is also in kidneys and muscles)
Muscles sequester its own glucose - accumulation of glycogen mostly in
phosphate for energy for its contraction lysosomes in virtually every tissue
- diagnosis possible by intestinal biopsy - Severe hypoglycemia, massive
- Manifestation: cardiomegaly & cardiomyopathy occur &
a. fasting hypoglycemia death results from heart failure
b. lactic acadosis i. There is severe hypoglycemia because
- hyperlipidemia, & hyperuricemia (nucleic there is no formation of glucose
acid metabolism is affected) with ii. Cardiac muscles are abundant of
- gouty arthritis lysosomes
- Not that severe and not common.
2. Pompe’s Disease – Type II
- caused by the absence of  - 1,4 –
glucosidase (or acid maltase), normally
found in lysosomes

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 3. Cori’s Disease or Type III (not the PNoy’s
disease :> )
- caused by deficiency of glycogen
debranching enzyme, α-1,6 glucosidase.
- Glycogen accumulates because only the
outer branches can be removed by
- phosphorylase.
- hepatomegally & other clinical
manifestation are similar to, but milder
than those in Von Gierke’s disease
4. Anderson’s Disease or Type IV
- Opposite of Cori’s disease
- Deficiency of the branching enzyme,
glucosyl 4:6 transferase
- Normal amount of glycogen but with very
long outer branches
- Liver cirrhosis and death before 2 years of
age
5. McArdle’s Disease or Type V
- caused by the absence or deficiency of
skeletal muscle glycogen phosphorylase
- The liver enzyme is normal
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- patients suffer from painful muscle
cramps and are unable to perform
strenuous exercise because muscle
glycogen stores are not available to the
exercising muscle
- the normal increase in plasma lactate
following exercise is absent
6. Her’s Disease or Type VI
- Deficient enzyme is liver phosphorylase
- Mild hepatomegaly and hyperlipidemia
- Mild hypoglycemia or no symptoms at all
7. Tarui’s disease or Type VII
- Enzyme deficient is phosphofructokinase
- Patients have painful muscle cramps with
exercise
8. GSD Type VIII
- Phosphorylase kinase (liver) is the enzyme
deficient
- Mild hepatomegaly and hypoglycemia
- Cerebral palsy, growth retardation,
delayed motor development and
increased blood lipids