Glycogenolysis

Hepatic Glycogenolysis regulated by hypoglycemic signals phosphorylase b Phosphoglucomutase

Glycogen phosphorylase use inorganic phosphate to attack nonreducing ends phosphorolysis

Glycogenolysis To mobilizing glycogen, three enzymes are required: glycogen phosphorylase, debranching enzyme, and phosphoglucomutase. The end product of glycogenolysis is glucose 6-phosphate.

Glycogenolysis Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase. Glycogenolysis is the degradation of glycogen by removal of a glucose monomer through cleavage with inorganic phosphate to produce glucose-1-phosphate. This derivative of glucose is then converted to glucose-6-phosphate, an intermediate in glycolysis Glycogen phosphorylase catalyzes the reaction in which an (α 14) glycosidic linkage between two glucose residues at a nonreducing end of glycogen undergoes attack by inorganic phosphate (Pi), removing the terminal glucose residue as glucose 1-phosphate Pyridoxal phosphate is an essential cofactor in the glycogen phosphorylase reaction.

Glucose 6-phosphate has 3 fates.

Mechanism 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. Glucose-1-phosphate is converted to glucose-6-phosphate by the enzyme phosphoglucomutase. Glucose residues are phosphorolysed from branches of glycogen until four residues before a glucose that is branched with a α[1→6] linkage. Glycogen debranching enzyme then transfers three of the remaining four glucose units to the end of another glycogen branch. This exposes the α[1→6] branching point, which is hydrolysed by α[1→6] glucosidase, removing the final glucose residue of the branch as a molecule of glucose and eliminating the branch. This is the only case in which a glycogen metabolite is not glucose-1- phosphate. The glucose is subsequently phosphorylated to glucose-6-phosphate by hexokinase.

- – It is a highly branched –chain homopolysaccharide made from α-D glucose . Structure of Glycogen

1- Shortening of glycogen chain: phosphorylase Cleaving of a(1-4) bonds of the glycogen chain producing glucose 1-phosphate Glucose 1-phosphate is converted to glucose 6-phosphate (by mutase enzyme) Pyridoxal phosphate (vit -B6

2- Removal of branches : by debranching enzymes Cleaving of a(1-6) bonds of the glycogen chain producing free glucose (few) 3- Fate of glucose 6-phosphate (G-6-P): - G-6-P is not converted to free glucose - It is used as a source of energy for skeletal muscles during muscular exercise (by anaerobic glycolysis starting from G-6-P step) ( in case of liver glucose-6-phosphatase converts G6P to glucose

Debranching enzyme Debranching enzyme transfer the  as whole from the branch to the main chain, then it will use its (a16) glucosidase activity to hydrolyze the  from glycogen for glycogen phosphorylase.

* Glycogen phosphorylase sequentially degrades the glycogen chains at their non-reducing ends until 4 glucosyl units remain on each chain before a branch poin, it is called limit dextrin, phosphorylase cannot degrade it. Removal of branches Branches are removed by two enzymic activities: The outer three of four glucosyl residues attached at a branch and transferrs them to the non-reducing end at another chain, thus the new chain is subjected to glycogen phosphorylase. The enzyme Glycosyl (4:4) transferase Remaining single glucose residue attached in an α- 1,6 – linkage is removed by amylo α –(1,6)–glucosidase releasing free glucose

Phosphoglucomutase Phosphoglucomutase use its phosphorylated Ser residue to convert G-1-P to G-6-P.

Glucose 6-phosphatase Glucose 6-phosphatase converted T1 transported G-6-P to glucose and Pi. Then glucose and Pi are transported to cytosol by T2 and T3, and glucose leave the hepatocyte by GLUT2 transporter.

Glycogen phosphorylase acts repetitively on the nonreducing ends of glycogen branches until it reaches a point, four glucose residues away from an (α 14) branch point , where its action stops. Glucose residues near a branch are removed in a two-step process that requires a bifunctional “debranching enzyme.” First, the transferase activity of the enzyme shifts a block of three glucose residues from the branch to a nearby nonreducing end, to which they are reattached in (α 14) linkage. The single glucose residue remaining at the branch point, in ( α 16) linkage, is then released as free glucose by the enzyme’s glucosidase activity.

Function Glycogenolysis takes place in the cells of the muscle and liver tissues in response to hormonal and neural signals. In particular, glycogenolysis plays an important role in the fight-or-flight response and the regulation of glucose levels in the blood. In myocytes (muscle cells), glycogen degradation serves to provide an immediate source of glucose-6-phosphate for glycolysis, to provide energy for muscle contraction. In hepatocytes (liver cells), the main purpose of the breakdown of glycogen is for the release of glucose into the bloodstream for uptake by other cells. The phosphate group of glucose-6-phosphate is removed by the enzyme glucose-6-phosphatase, which is not present in myocytes, and the free glucose exits the cell via GLUT2 facilitated diffusion channels in the hepatocyte cell membrane.

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. Clinical significance Parenteral (intravenous) administration of glucagon is a common human medical intervention in diabetic emergencies when sugar cannot be given orally. It can also be administered intramuscularly.