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LET'S TALK LIFE-SCIENCE BIOCHEMISTRY

Suraj Prakash Sharma | Ekta Chotia

GLYCOGENOLYSIS
119

17.          GLYCOGENOLYSIS

Glycogenolysis is the breakdown of glycogen (n) to glucose-6-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase.

Glycogen is synthsized of \alpha - 1, 4 and \alpha, 1, 6 glycosidic bonds. It is the storage form of glucose when body supplied with high glucose diet. In low glucose levels glycogen is reversed back to the form of glucose by the process glycogenolysis. This process is under highly control of hormonal responses in adrenaline-induced fight-or-flight response.

17.1.      Steps of Glycogenolysis

17.1.1.   Degradation of Glycogen to Glucose 1 phosphate

Glycogen is cleaved to the glucose 1 phosphate by the glycogen phosphorylase. Glycogen phosphorylase was the first allosteric enzyme to be discovered. It is present in the form of homodimer. It is regulated allosterically by the structural change in phosphorylation at the Serine residue and with the conversion of phosphorylase b to phosphorylase a. It is inhibited by ATP, G6P and glucose and activated by AMP.

A long cleft in the phosphorylase connects with the glycogen which covers around 5 glucose residues so there by phosphorylase cleaves 5 residue away  from branch point. In mammals muscle, liver, and brain have the major isozymes of glycogen phosphorylase.

Glycogen Phosphorylase binds with the cofactor pyridoxal 5’ phosphate at its active site which is a vitamin B6 derivative and form a schiff base between its aldehyde group and E amino group of Lys.

The reaction catalyzed by this enzyme is -

Glycogen (n res) + Pi \leftarrow------\rightarrow  Glycogen (n-1 res) + G1P

The overall reaction for the breakdown of glycogen to glucose-1-phosphate is:

glycogen(n residues) + Pi \leftrightharpoons glycogen(n-1 residues) + glucose-1-phosphate

Here, glycogen phosphorylase cleaves the bond linking a terminal glucose residue to a glycogen branch by substitution of a phosphoryl group for the α[1→4] linkage.

17.1.2.   Importance of Glycogen Phosphorylase -

  1. Target for the treatment of type 2 diabetes by inhibiting the release of glucose from the glycogen storage of liver.
  2. Mutation in glycogen phosphorylase causes McArdle’s disease showing symptoms of muscle weakness and muscle pain (myalgia).
  3. Mutation in liver isoform of glycogen phosphorylase causes Hers’ disease which shows symptoms of hypoglycaemia.
  4. The brain isoform of glycogen phosphorylase (PYGLB) has been proposed as a biomarker for gastric cancer.

17.1.3.   Debranching enzyme

Debranching phosphorolysis occurs till the 5 residues from the \alpha (1-6 ) branch point. Glycogen debranching enzyme act as an \alpha (1-4) transglycosylase which transfers the \alpha (1-4) trisacharide chain to the non reducing of another branch. So normally the first glucosyl residue connected with \alpha (1-6) residue is simply hydrolysed and rest of the \alpha (1-4) attached glucosyl residues converted to G1P. Debranching enzyme have two separate active site for transferring and for hydrolysis of \alpha 1-6 residue.

17.1.4.   Activity of Debranching Enzyme

So normally glycogen phosphorylase works in body on glucose requirement in body which catalyzes its reaction fast. If the further requirement is beyond this point then debranching enzyme comes in action which is relatively slower reaction. 

17.1.5.   Fate of Glucose -1- Phosphate

Glucose 1 Phosphate formed by the phosphorylase has two fates according to the requirement of body-In muscles – Glucose -1- Phosphate is converted to Glucose -6- Phosphate by the enzyme phosphoglucomutase. This Glucose -6- Phosphate is redirected towards the glycolysis and provides energy. Hereby it bypasses the activation step of glucose to glucose 6 phosphate hence save one molecule of ATP. In high working muscles net yield of ATP per glucose to lactate is 3 rather than 2.

17.2.      The overall equation is

Glycogen(n glucose residues) + 3 ADP + 3 Pi → glycogen + 2 lactate + 3 ATP(n-1 glucose residues)

In liver – Glucose -6- Phosphate formed from Glucose -1- Phosphate, is dephosphorylated by the enzyme glucose -6- phosphatase and free glucose is released in blood for uptake by other cells by the glucose transporters present in cell membrane.

Glucose-6-phosphate + H2O → Glucose + Pi

17.3.      Regulation of glycogen metabolism

This enzyme is allosterically regulated by AMP, ATP And Glucose-6-phosphate. ATP and glucose-6-phosphate produce a negative effect on the cooperativity of substrate binding. While AMP has positive effect.

The enzyme exist in only two conformations designated R and T. These conformations are in equilibrium R  \leftrightarrow  T.  The substrates bind when the enzyme is in the R state. Positive allosteric effectors bind to the R state and stabilize it shifting the equilibrium to the left. Negative allosteric effectors bind to the T state and stabilize it shifting the equilibrium to the right.

This enzyme binds inorganic phosphate cooperatively. This allows the enzyme’s activity to increase by great amounts over a narrow range of substrate concentrations.

17.3.1.   Regulation of glycogenolysis is by the phosphorylation cascades

The conversion of inactive glycogen phosphorylase ‘b’ to active glycogen phosphorylase ‘a’ is dependent upon the phosphorylation cascade through cyclic AMP-dependant Protein Kinase A (PKA) which is a Ser/Thr kinase which in turn is activated by cyclic AMP.

Both hormones Adrenaline (epinephrine, which is released in response to a threat or stress - the ‘fight-or-flight’ response) and glucagon, (which is released by pancreatic alpha cells in response to low blood glucose levels), stimulate glycogenolysis by binding to their respective receptors (both of which are G-protein coupled receptors) which activates membrane localized protein adenyl cyclase. Adenyl cyclase forms cAMP from ATP then activates PKA. Which stimulates glycogen phosphorylase and inhibits glycogen synthase.

Insulin have counter effect on glycogenolysis. It inhibits glycogenolysis by activating protein phosphatase 1 (PP1) and the enzyme phosphodiesterase which both contribute to the inactivation of glycogen phosphorylase.

Calcium ions

Calcium ions or cyclic AMP (cAMP) act as secondary messengers which is an example of negative control. The calcium ions activate phosphorylase kinase which activates glycogen phosphorylase and inhibits glycogen synthase.

Page no. 119