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Suraj Prakash Sharma | Ekta Chotia


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 \leftrightarrow 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.

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