Glycogenesis is the process of glycogen synthesis, in which glucose molecules are added to chains of glycogen for storage.
Glycogenesis occurs in liver and muscle cells when glucose and ATP are present in relatively high amounts to store glucose molecules by adding simultaneously together to form glycogen molecules. This process is activated during rest periods following the cori cycle, in the liver, and also activated by insulin in response to high glucose levels, for example after a carbohydrate-containing meal.
This process is energetically unfavourable without free energy input. This pathway is activated by insulin when body senses high glucose levels normally after a carbohydrate rich diet.
18.1. Steps of Glycogenesis
18.1.1. Activation of glucose Monomers
Glucose is converted into glucose-6-phosphate by the action of glucokinase or hexokinase, Glucose-6-phosphate is converted into glucose-1-phosphate by the action of Phosphoglucomutase. Now the Uridine tri phosphate binds with Glucose–1–Phosphate and forms the uridine diphosphate glucose which is an activated compound that can donate its glucosyl unit to extending glycogen chain.
Glucose-1-phosphate + UTP ----UDP-glucose + pyrophosphate
18.1.2. Primer formation and Extension of Glycogen Chain
Primers for the glycogen synthesis are formed by glycogenin which acts as glucosyl transferase and having Tyr at its active site. It forms 7 residue long residues and then further reaction is carried out by glycogen synthase.
Glycogen synthase is the enzyme which transfers the glucosyl residue from the UDPG to the non reducing end of the growing chain of glycogen and forming a 1-4 glycogen bond.
Glycogen (n res) + UDPG -------glycogen synthase----- Glycogen (n+1 res) + UDP
The free UDP is replenished to the UTP for activation of next glucosyl residue is done by the nucleotide diphosphate kinase. This enzyme is able to catalyze reversible reaction which equals the utilization of UTP and ATP in cell.
UDP + ATP <--------UTP + ADP
Glycogen synthase is inhibited by the 1–5 gluconolactone, that mimics the oxonium ion’s half chair geometry. It also inhibits glycogen phosphorylase and lysozyme.
18.1.3. Branching of glycogen
Glycogen synthase is not able to form branches it forms only near chains so other enzyme called as branching enzyme. This creates a 1-6 bonds by transferring seven residue segments. Every branch point at least four residue away from other branch point. Glycogen is formed with several no reducing ends and one reducing end.
18.1.4. Glycogen Synthase
Glycogen Synthase is a typical allosteric enzyme. It is composed of four identical subunits (multiple subunits). The enzyme exist in two conformations named as R and T. These conformations are in equilibrium R T. The substrates bind when the enzyme is in the R state. ATP, ADP and Pi are allosterically inhibitor Glycogen synthase and bind to the T state and stabilize it shifting the equilibrium to the right.
Glucose-6-phosphate are allosterically activator of glycogen synthase and bind to the R state and stabilize it shifting the equilibrium to the left. Glycogen phosphorylase is activated by phosphorylation, whereas glycogen synthase is inhibited. Glycogen phosphorylase is converted from its less active "b" form to an active "a" form by the enzyme phosphorylase kinase. This latter enzyme is itself activated by protein kinase A and deactivated by phosphoprotein phosphatase-1. Like glycogen phosphorylase, allosteric controls are overridden by reversible covalent phosphorylation. In this case the phosphorylated glycogen synthesis, form b is less active than the orginal dephosphorylated form a. The phosphorylase kinase that phosphorylates glycogen synthase. The phosphorylation is reversible. The dephosphorylation is carried out by the enzyme called phosphoprotein phosphatase 1.
Protein kinase A itself is activated by the hormone adrenaline. Epinephrine binds to a receptor protein that activates adenylate cyclase. The latter enzyme causes the formation of cyclic AMP from ATP; two molecules of cyclic AMP bind to the regulatory subunit of protein kinase A, which activates it allowing the catalytic subunit of protein kinase A to dissociate from the assembly and to phosphorylate other proteins.
Returning to glycogen phosphorylase, the less active "b" form can itself be activated without the conformational change. 5'AMP acts as an allosteric activator, whereas ATP is an inhibitor, as already seen with phosphofructokinase control, helping to change the rate of flux in response to energy demand.
Epinephrine not only activates glycogen phosphorylase but also inhibits glycogen synthase. This amplifies the effect of activating glycogen phosphorylase. This inhibition is achieved by a similar mechanism, as protein kinase A acts to phosphorylate the enzyme, which lowers activity. This is known as co-ordinate reciprocal control.
18.1.5. Glycogen storage disorders
(1) Von Gierke’s Disease –
Clinical manifestations is fatty liver -> distended abdomen
Many different kinds depending on mutated enzyme
This disease is caused by of mutation in G 6-Pase.
This disease is characterized by normal glycogen level but high levels of trapped phospho-sugars in the form of glucose 6 phosphate.
(2) McArdle’s disease
This is because of mutation in phosphorylase kinase in muscle however the isoenzyme present in the liver is normal.
ATP availability is decrease resulted into damage of muscle.
(3) Pompe's Disease
Caused due to mutation in glucosidase enzyme which is usually found in lysosomes.
Leads to large increases in glycogen found in lysosomes in nearly every tissue in the body. Once the glycogen particles are in the lysosome it can no longer function normally. and death occurs at an early age from heart failure.
- Book COVER AND ABOUT US
- CHEMICAL BONDING
- AMINO ACIDS
- PROTEIN STRUCTURE
- RAMACHANDRAN PLOT
- PROTEIN STABILITY
- KINETIC ANALYSIS
- REGULATION OF GLYCOLYSIS
- TRICARBOXYLIC ACID CYCLE (TCA CYCLE)
- REGULATION OF THE CITRIC ACID CYCLE
- GLYOXYLATE CYCLE OR KREBS KORNBERG CYCLE
- ELECTRON-TRANSPORT CHAIN
- MECHANISMS OF OXIDATIVE PHOSPHORYLATION
- PENTOSE PHOSPHATE PATHWAY
- LIPID METABOLISM
- FATTY ACID OXIDATION
- DNA STRUCTURE
- NUCLEOTIDE BIOSYNTHESIS