Glycogenolysis

• Glucose mobilization involves the breakdown of glycogen, also known as glycogenolysis.
• Glycogen storage diseases are a group of genetic diseases that result from a defect in an enzyme required for glycogen synthesis or degradation.
• Glycogen storage diseases result either in the formation of glycogen that has an abnormal structure, or in the accumulation of excessive amounts of normal glycogen in specific tissues as a result of impaired degradation.
• Glycogen phosphorylase catalyzes the breakdown of glycogen, converting glycogen into Glucose 1-phosphate and n-1 residues.
• The reaction of glycogenolysis proceeds to the right because the [Pi]/[glucose 1-phosphate ratio] is greater than 100.
• Glycogenolysis does not require investment of ATP and can enter glycolysis directly.
• The phosphorylated product (glucose 1-phosphate) from glycogenolysis cannot leave the cell.
• Glycogenolysis is specific for the a-1,4 bond.
• Two additional enzymes are required for glycogenolysis: one shifts 3 glycosyl units to the core and the other hydrolyzes the single 1,6 glucose unit to free glucose.
• In eukaryotes, the transferase activity and the α-1,6-glucosidase activity are within one bifunctional protein, the debranching enzyme.
• The glucose 1-phosphate is converted to glucose 6-phosphate by phosphoglucomutase.
• Enzymes of glycogen metabolism are bound to the surface of the glycogen particle.
• The resulting structure after glycogenolysis is called a limit dextrin, and phosphorylase cannot degrade it any further.
• Glucose 6-Phosphatase is an enzyme present in liver and kidney but not in other tissues.
• PKA can each activate many phosphorylase kinase molecules, causing the production of many active glycogen phosphorylase a molecules that can degrade glycogen.
• In general, PPP-1, a single enzyme, can remove phosphoryl groups from all three of the enzymes, phosphorylated in response to glucagon (in liver) and epinephrine (in liver and muscle): phosphorylase kinase, glycogen phosphorylase, and glycogen synthase.
• Glycogen Phosphorylase exists in two different forms: Glycogen Phosphorylase a, the Active Form (Phosphorylated), and Glycogen Phosphorylase b, the Inactive Form.
• Phosphoprotein phosphotase 1 (PPP1), removes the phosphoryl groups from phosphorylase a, converting it to the less active form, phosphorylase b.
• The phosphorylation event in glycogen phosphorylase occurs when hormones, such as glucagon or epinephrine, bind to plasma membrane G protein-coupled receptors.
• PPP-1 does not exist free in the cytosol, it’s tightly bound to its target proteins by one of a family of glycogen-targeting proteins (Gm) that bind glycogen and glycogen synthase (and other glycogen enzymes).
• Few hormone molecules binding to their receptors result in a number of PKA molecules being activated.
• Epinephrine and glucagon stimulate the breakdown of glycogen.
• Glycogen phosphorylase a is allosterically inhibited by glucose 6-phosphate and ATP.
• Activation of glycogen degradation by cAMP-directed pathway involves a large number of sequential steps to amplify the effect of the hormonal signal.
• The critical Pi substrate is bound to the active site by interactions with pyridoxal phosphate (PLP) and active site amino acids.
• B6 is required for the mobilization of glucose from glycogen.
• Pyridoxal phosphate is derived from Vitamin B6.
• A deficiency of the enzyme causes accumulation of glycogen in vacuoles in the lysosomes, resulting in the serious glycogen storage disease (Type II: Pompe disease).
• B6 is also required for other biochemical reactions such as transamination.
• Pyridoxal phosphate is the coenzyme for phosphorylase.
• The pathways of glycogen synthesis and degradation are allosterically controlled to meet the needs of a particular tissue.
• Glycogen phosphorylase uses pyridoxal phosphate (PLP) a derivative of pyridixine (vitamine B6) as a coenzyme.
• The synthesis and degradation of glycogen storage form are tightly regulated due to the importance of maintaining blood glucose levels.
• In the liver, glycogenesis accelerates during periods when the body has been well fed, whereas glycogenolysis accelerates during periods of fasting.
• In skeletal muscle, glycogenolysis occurs during active exercise, and glycogenesis begins as soon as the muscle is again at rest.
• Glycogen synthase and glycogen phosphorylase are hormonally regulated to meet the needs of the body as a whole.
• Glycogen phosphorylase is one of the first enzymes shown to be controlled by reversible phosphorylation.
• Glucose 6-Phosphatase is an integral membrane protein of the endoplasmic reticulum (ER) with the active site of the enzyme on the luminal side of the ER.
• Phosphorylase kinase is subject to covalent and allosteric regulation.
• Glucokinase (Hexokinase IV) phosphorylates glucose, stimulating glycolysis and supplying the precursor for the glycogen synthesis.