17.1.2. Importance of Glycogen Phosphorylase -
- Target for the treatment of type 2 diabetes by inhibiting the release of glucose from the glycogen storage of liver.
- Mutation in glycogen phosphorylase causes McArdle’s disease showing symptoms of muscle weakness and muscle pain (myalgia).
- Mutation in liver isoform of glycogen phosphorylase causes Hers’ disease which shows symptoms of hypoglycaemia.
- 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 (1-6 ) branch point. Glycogen debranching enzyme act as an (1-4) transglycosylase which transfers the (1-4) trisacharide chain to the non reducing of another branch. So normally the first glucosyl residue connected with (1-6) residue is simply hydrolysed and rest of the (1-4) attached glucosyl residues converted to G1P. Debranching enzyme have two separate active site for transferring and for hydrolysis of 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 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 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.