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GLYCOGEN METABOLISM

• Glycogen is a chain of glucose subunits held together by( α 1,4 glycosidic bonds), glycogen is a branched structure. At the branch points, subunits are joined by ( α1g6 glycosidic bonds).

• Branches occur every 8-10 residues.

Glycogenesis is the process ofGlycogen synthesis

• Glycogen is synthesized when blood glucose levels are high .

• Glucose is converted into glucose-6-phosphate by the action of :Hexokinase catalyses this reaction in most tissues.In the liver and pancreas there is an extra enzyme; Glucokinase exhibiting different kinetic properties.

glucokinase

• This state is reflected inside liver cells by the presence of high levels of glucose-6-phosphate. G6P is converted to G1P by phosphoglucomutase.

• This reaction is analogous to the reaction catalyzed by phosphoglycerate mutase in of glycolysis, and proceeds by a similar mechanism, with a bisphosphate intermediate.

• Conversion of G1P into glycogen is energetically unfavorable, so another source of energy input is required.

• This comes in the form of hydrolysis of UTP (uridine triphosphate). The high-energy phosphoanhydride bonds in UTP are equivalent to those in ATP. First, UTP is combined with G1P by UDP-glucose pyrophosphorylase.

:::Next, glycogen synthase catalyzes the addition of this activated glucose subunit to the C4-hydroxyl group at the end of a glycogen chain (the non-reducing end).

• After the chain is more than four residues long, glycogen synthase takes over. Glycogenin remains bound to the reducing end of glycogen (the C1 hydroxyl group at the right side of the pictures). Glycogen synthase works efficiently only when it is bound to glycogenin.

• Thus the number of glycogen granules in a cell is determined by the number of glycogenin molecules available, and the size of the granules is limited by the need for physical association between glycogenin and glycogen synthase. When the granule grows too large, the synthase stops working.

• Formation of branches is catalyzed by "branching enzyme",( amylo (α-1,4ـــα1,6) transglycosylase).

• This enzyme breaks off a chain of about 5 to 8 glucose residues from the growing end of glycogen by hydrolyzing an( α 1,4 glycosidic linkage), and transfers the short chain to another residue in the same glycogen molecule that is at least four residues away from the cleavage point, forming an( α 1,6 glycosidic linkage)

After the transfer, both the old C4 end and the newly exposed C4 end can be elongated by glycogen synthase.

As soon as the new ends are long enough, they can again be branched. A mature glycogen granule may have seven layers of

branches.

• Branching gives glycogen two advantages over starch as a storage form of glucose.

• First, it is more soluble than its unbranched cousin.

• Second, the exposure of more C4 (nonreducing) ends means that glycogen can be both sythesized and degraded more quickly than a single starch chain with the same number of residues.

Control and regulations Epinephrine (Adrenaline)

• 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 deactivated by phosphoprotein phosphatase-1. 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 adenosine monophosphate AMP from Adenosine triphosphate (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. 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.

Insulin• Insulin has an antagonistic effect to adrenaline. • When insulin binds on the G protein-coupled receptor, the

alpha subunit of Guanosine diphosphate GDP in the G protein changes to Guanosine-triphosphate GTP and dissociates from the inhibitory beta and gamma subunits.

• The alpha subunit binds on adenylyl cyclase to inhibit its activity.

• As a result, less cyclic AMP then less protein kinase A will be produced. Thus, glycogen synthase, one of the targets of protein kinase A, will be in non-phosphorylated form, which is the active form of glycogen synthase.

Calcium ions• Calcium ions or cyclic AMP (cAMP) act as

secondary messengers.

• This is an example of negative control. The calcium ions activate phosphorylase kinase. This activates glycogen phosphorylase and inhibits glycogen synthase.

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Glycogenolysis • is the Breakdown of glycogen to glucose-

1-phosphate and glucose

Regulation

• Glycogenolysis is regulated hormonally in response to blood sugar levels by glucagon and insulin, and stimulated by epinephrine during the fight-or-flight response.

• In myocytes, glycogen degradation may also be stimulated by neural signals.