Glycogen synthesis and Breakdown Pathway

Glycogen is a polysaccharide consist of glucose linked together by glycosidic linkage. In animals and humans; glucose is stored in the form of glycogen in the liver (~10%) and muscles (~2%). These stored glycogen molecules can readily be degraded into glucose molecules and enter into the glycolytic pathway for energy. Liver glycogen can also contribute to the maintenance of normal blood glucose.  The glycogen synthesis and breakdown pathway are highly regulated and, the synthesis and breakdown do not occur at the same time. 


Figure 1: Overview of Glycogen synthesis (Glycogenesis)

Synthesis of Glycogen
The addition of glucose to form glycogen requires a primer molecule where the glucose can be added to the non-reducing ends. During de novo synthesis, glucose molecules are added to tyrosine residues of primer protein glycogenin. The enzyme Glycogen synthase catalyzes the addition of glucose molecules at the nonreducing end of core glycogen molecule  In this reaction, an activated UDP-glucose molecule forms 1-4 glycosidic linkage with existing glucose moiety of glycogen molecule and free UDP is liberated. This results in the elongation of a glycogen molecule with the addition of one glucose moiety in each reaction. 

Figure 2: Glycogen Synthase-addition of glucose from UDP-glucose to core glycogen molecules.


Figure 3: Overview of Glycogen Breakdown(Glycogenolysis)

Figure 4: Glycogen phosphorylase-removal of glucose from glycogen molecules.

Regulation of Glycogen Metabolism

-Glycogen synthesis occurs when the glucose and ATP are abundant in the cells. In contrary, glycogen breakdown release glucose for muscle contraction and regulation of blood glucose. 

-Glycogen metabolism is regulated by allosteric modification and covalent modifications. 

-The glycogen synthesis and breakdown are reciprocally regulated to ensure that both pathways do not occur at the same time in the cell.

Glycogen phosphorylase regulation

Allosteric modification: 

-The glycogen phosphorylase exists in two different conformations. T-state or inactive state and R-state or active state. 
-In muscle, the binding of an AMP molecule to glycogen phosphorylase enzyme shifts the T-state glycogen phosphorylase to R-state. 
-ATP and Glucose-6-phosphate exert an inhibitory effect by favoring the T-state of glycogen phosphorylase (inactive form).
-In the liver, the presence of glucose shifts the R-state glycogen phosphorylase to T-state (inactive). 

Allosteric Modification of glycogen phosphorylase in muscle 

Allosteric Modification of glycogen phosphorylase in liver

Covalent modification:
-Insulin and glucagon reciprocally regulate glycogen phosphorylase by adding/removing phosphate group to the enzyme glycogen phosphorylase. 
- During muscle contraction, in addition to low glucose and ATP, the release of calcium from sarcoplasmic reticulum activates calcium-dependent protein kinase that inturns phosphorylate and activate glycogen phosphorylase. 
- Calcium ions partially activate calcium-dependent protein kinase that requires phosphorylation by protein kinase A for full activity. Epinephrine binding to its receptor induces the signaling cascade to activate protein kinase A. 
- In the liver, glucagon and epinephrine induce the signaling cascade to phosphorylate activate phosphorylase kinase and activate downstream protein glycogen phosphorylase.
-In response to high blood glucose concentration, insulin is released from beta cells of the pancreas.
-Insulin binds to tyrosine kinase receptors and induces the signaling pathway to activate protein phosphatase 1. The protein phosphatase 1 catalyzes the removal of the phosphate group from glycogen phosphorylase and deactivates it. 


Phosphorylation activates glycogen phosphorylase enzyme and increases glycogen breakdown in exercising muscle and liver when blood glucose is low. 


Dephosphorylation inactivates glycogen phosphorylase enzyme and decreases glycogen breakdown in resting muscle and liver when blood glucose is abundant. 

Glycogen synthase regulation
Covalent Modification:
-The glycogen synthase is the regulatory enzyme of glycogen synthesis.
-Insulin induces glycogen synthesis by activating the enzyme glycogen synthase (in a dephosphorylated state).
- In contrast, glucagon and epinephrine deactivate the enzyme (increasing phosphorylation) thereby reducing glycogen synthesis. 


Dephosphorylation activates glycogen synthase enzyme and increases glycogen synthesis in resting muscle and liver when blood glucose is abundant. 


Phosphorylation inactivates glycogen synthase enzyme and decreases glycogen synthesis in exercising muscle and liver when blood glucose is low. 

Glycogenesis is the biosynthetic pathway for synthesis of glycogen from glucose molecules.  This biosynthetic pathway can be divided into two stage i.e activation of glucose and addition of glucose to core glycogen molecules at a nonreducing end.

Activation of glucose molecules: 
The precursor glucose molecules are first activated by an enzyme hexokinase/glucokinase to form glucose-6-phosphate. The next step is the conversion of glucose-6-phosphate to glucose-1-phosphate which is catalyzed by enzyme phosphoglucomutase. This enzyme catalyzes the transfer of phosphate group 6-carbon group to 1- carbon resulting in glucose-1-phosphate. 

The second reaction is the formation high energy UDP-glucose catalyzed by an enzyme UDP-Glucose pyrophosphorylase. In this reaction, the uridine monophosphate group from UTP to form UDP-glucose and pyrophosphate. The pyrophosphate formed is subsequently hydrolyzed to inorganic phosphates to release energy. 

The glycogen molecule is highly branched. The branching glycogen molecule is introduced by branching enzyme that transfers the oligopeptide glucose moieties from 1-4 glycosidic linkage to form 1-6 glycosidic linkage with the interior glucose moiety of glycogen molecule. This results in branching of glycogen molecule at every 8-10 residues and compact helical structure.

Glycogenolysis is the breakdown of glycogen to glucose-6-phosphate and involve a series of enzyme catalyzed reactions.

Phosphorolysis of Glycogen to glucose-1-phosphate
The first reaction of glycogen breakdown is the phosphorolysis of glycogen molecule to liberate one glucose-1-phosphate. This phosphorolysis reaction is catalyzed by a pyridoxal-5-phosphate requiring enzyme Glycogen phosphorylase. During this reaction, the inorganic phosphate is incorporated to the glucose molecules allowing the intermediates to directly enter other metabolic pathways (glycolysis and pentose phosphate pathway)

Conversion to Glucose-6-phosphate
Glucose-1-phosphate is converted into glucose-6-phosphate catalyzed by an enzyme phosphoglucomutatse as described above. In liver, glucose-6-phosphate formed are converted into free glucose by enzyme glucose-6-phosphatase and contributes to blood glucose maintenance. In contrast, muscle tissue lacks an enzyme glucose-6-phosphatase and glucose-6-phosphate produced in the muscle tissues do not contribute to the blood glucose maintenance. The function of glycogen in muscle is to feed glucose-6-phosphate into glycolytic pathway for ATP required for muscle contraction during exercise. 

(Note: The hydrolysis to glucose during this step would have required ATP for the activation. Therefore, the phosphorolysis captures the inorganic phosphate and conserve one ATP in energy-deprived cells.  that may would have required if the hydrolysis of glycogen to glucose.)

Removal of glucose by debrancing enzyme
As the glycogen are highly branched, and glycogen phosphorylase only removes glucose from nonreducing end of 1-4 glycosidic linkage; an additional enzyme 1,6-glucosidase  (debranching enzyme) hydrolyzes the 1-6 glycosidic linkage at branch site release free glucose. 

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