Glycogen synthesis and Breakdown

What is glycogen?
 It is the form of storing excess glucose in animals
 Mainly in liver and skeletal muscles as glycogen granules in cytoplasm
 Glycogen is a branched polysaccharide formed by 10,000 to 50,000 glucose residues per
molecule
 Glucose molecules are attached together via alpha 1,4 glycosidic bonds
 At the branch points, branching residues are attached via alpha 1,6 glycosidic bonds

How is glycogen formed inside the body?

The process of glycogen synthesis is called Glycogenesis

Glycogenesis
Steps in glycogenesis

 Activation of glucose
 Initiation of glycogenesis
 Elongation
 Formation of branches

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Activation of glucose
 Inside the liver, glucose transported into the liver is converted to glucose-6-phsphate by
Hexokinase and Glucokinase
 In muscle cells it is done by Hexokinase
 This is an irreversible reaction
 Then, G6P is reversibly converted into Glucose-1-phosphate (G1P) by phosphoglucomutase
 G1P is added with a UTP forming, a UDP-glucose molecule
 This UDP-glucose molecule is called ‘Activated glucose’

Initiation
 There is an enzyme called Glycogenin inside the cells
 Glycogenin has tyrosine residues on it
 Glucose residue in the UDP glucose molecule is added to a specific tyrosine residue on
Glycogenin
 Glucose attached to and OH unit in the tyrosine reside in the glycogenin
 This is an autocatalytic reaction
 Then another UDP glucose molecule will attach to the OH at the 4 th carbon of the existing
glucose residue via alpha 1,4 glycosidic bond
 Likewise glycogenin extends the chain by 6-7 glycosyl units
 Glycogenin with 6-7 glucosyl residues is called the glucan primer/glycogen primer

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Elongation
 Adding more glucose residues to the primer occurs in elongation
 This is done by Glycogen synthase
 So, glycogen primer is further extended by Glycogen Synthase
 Glucose residues are connected via alpha 1,4 glycosidic bonds
 In each cycle glycogen extends by one glucose molecule and one UDP is released

It cannot initiate the synthesisis

Formation of branches
 Glycogen is a highly branched molecule
 There are branches about every 8 residues apart
 This high branching allows release of glucose easily, when needed
 Branching is done by a separate enzyme called the Branching enzyme

 When the glycogen molecule exceeds 8 residues from the primer, branching enzyme removes a
chain of 6-8 residues from the terminal end of the chain
 The it is connected to a non-terminal glucosyl residue somewhere in the middle of the glycogen
chain (usually 8 residues away from the previous branching point) via an alpha 1,6 glycosidic
bond

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We have discussed on the formation of glycogen

Now, we’ll see how it is breakdown to form glucose again

Glycogen breakdown is called Glycogenolysis

Glycogenolysis
 Glycogen breakdown or removing glucose is done from the non-reducing ends
 So, as glycogen is highly branched, there will be more non-reducing ends
 So, more glucose residues can be released at a given time

This is done by Glycogen Phosphorylase enzyme

 Removing of Glucose-1-phosphate from Glycogen molecule occurs when glycogen is breaking

down

There are 3 main steps

 Breaking alpha 1,4 glycosidic bonds

 Transferase activity
 Breaking alpha 1,6 glycosidic bonds

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Breaking alpha 1,4 glycosidic bonds
 This is done by Glycogen Phosphorylase enzyme
 It sequentially removes glucose residues from glycogen chains until 4 glucosyl units remain from
the branch point
 It cannot breakdown the glycogen further
 This molecule is called a Limit dextrin

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Transferase activity
 Transferase enzyme breaks the alpha 1,4 glycosidic bond between the 1 st and glucose residues
of the limit dextrin
 And transfer this 3 glycosyl units to the non-reducing end of the core
 There it adds the 3 glycosyl unit to the terminal glucose residue of the core via an alpha 1,4
glycosidic bond
 So, transferase both breakdown and form an alpha 1,4 glycosidic bond

Then glycogen phosphorylase will breakdown glycogen and release G1P from the non-reducing end

Breaking alpha 1,6 glycosidic bonds

 This is done by alpha 1,6 Glucosidase enzyme
 It removes a free glucose residue at the branching point by breaking the alpha 1,6 glycosidic
bond

 In eukaryotes Transferase activity and the alpha 1,6 glucosidase activity are present within one
bifunctional polypeptide molecule

That is called the ‘Debranching enzyme’

what happens next to G1P?

It is converted to G6P reversibly by Phosphoglucomutase

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  Then G6P is converted to Glucose by Glocose-6-phospatase present in liver cells
 This glucose will be added to the circulation and used by tissues for production of energy and
other functions

Regulation of Glycogen metabolism

 Glycogen metabolism is the synthesis and breakdown of glycogen
 This is regulated by regulating the 2 key enzymes involve in glycogen metabolism

They are

 Glycogen Synthase
 Glycogen Phosphorylase

These 2 enzymes are reciprocally regulated

 When one is activated the other is inactivated

 Which enzyme is activated at a given time is decided by fed and fasting status of the body
 Glycogen metabolism in muscles is decided by whether muscles are at rest or engage in
exercises

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Fed state/ resting state in muscles
 Excess glucose should be stored as glycogen
 So, glycogen synthesis takes place
 For that glycogen synthase should be activated and glycogen phosphorylase should be
inactivated

Regulation of glycogen synthase at fed state

Glycogen synthase a is the active form and it is a dephosphorylated form

Glycogen synthase b is the inactive form and it is a phosphorylated form

When insulin/ glucagon ratio is high,

 Insulin stimulates protein phosphatase activity

 It dephosphorylates glycogen synthase and convert it to glycogen synthase a form
 Thus, glycogen synthase is activated, and glycogen synthesis takes place

Regulation of glycogen phosphorylase during fed state

Glycogen phosphorylase a is the active form which is the phosphorylated form

Glycogen phosphorylase b is the inactive form which is the dephosphorylated form

When insulin/glucagon ratio is high,

 Insulin dephosphorylates the enzymes via protein phosphatase enzyme

 Glycogen phosphorylase is dephosphorylating in to glycogen phosphorylase b from which is the
inactive form
 So, glycogen breakdown is inactivated

This is the hormonal regulation during the fed state

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Allosteric regulation during fed state
 ATP and G6P allosterically inhibit glycogen phosphorylase despite it being phosphorylated
 G6P allosterically activates Glycogen synthase

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Fasting state/ during muscle exercises
Due to the low insulin/glucagon ration,

 Glucagon will phosphorylate both Glycogen synthase and Glycogen phosphorylase enzymes via
G protein coupled receptor second messenger system (via CAMP)

Forming

 Glycogen synthase b which is the inactive form

 Glycogen phosphorylase a which is the active form

Thus, glycogen synthesis inactivated, and glycogen breakdown is activated

This is the hormonal regulation during fasting state

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  As, we know muscles don does not have glucagon receptors
 So, above hormonal regulation does not occur in muscles

How muscles act during exercises?

 During muscle contraction, Calcium is released from Sarcoplasmic reticulum

 Calcium is an allosteric activator of Glycogen phosphorylase
 It allosterically binds to glycogen phosphorylase b and activate it

 When ATP levels reduce during exercises, AMP levels increase

 AMP also allosterically activate glycogen phosphorylase b

These 2 allosteric activators prevent the need for phosphorylation of glycogen phosphorylase to make
it active

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