The figure shows the actions of phosphorylase and debranching enzyme. The first glucose residue in each branch is released as free glucose; all other residues are released as glucose 1-phosphate.
The latter molecule can be converted to glucose 6-phosphate in a step shared with other pathways Villar-Palasi and Larner ; Hers Glycogen can also be taken up into lysosomes, where it is normally broken done by the action of a single enzyme, lysosomal alpha-glucosidase GAA.
Villar-Palasi, C , Larner, J. Hers, HG. Toggle navigation. About What is Reactome? Glycogen breakdown glycogenolysis Stable Identifier. Homo sapiens. Locations in the PathwayBrowser Expand all.
Metabolism Homo sapiens Metabolism of carbohydrates Homo sapiens Glycogen metabolism Homo sapiens Glycogen breakdown glycogenolysis Homo sapiens. Click the image above or here to open this pathway in the Pathway Browser. Glycogen metabolism Homo sapiens.
Go Biological Process. Glycogen breakdown glycogenolysis Bos taurus. Glycogen breakdown glycogenolysis Caenorhabditis elegans. Glycogen breakdown glycogenolysis Canis familiaris. Glycogen breakdown glycogenolysis Danio rerio. It acts as a calcium sensor, that is, it responds to changes in intracellular calcium concentration, influencing the activity of proteins with which it interacts see below.
One of the target proteins of the phosphorylase kinase is glycogen phosphorylase. This enzyme exists as isoenzymes in different tissues, and in two conformational states in dynamic equilibrium, referred to as:. The kinase phosphorylates a single serine residue Ser in each of the two subunits of glycogen phosphorylase, which is almost entirely in the T state, converting it to the active form, which, conversely, is almost entirely in the R state, and therefore triggering the breakdown of glycogen.
The phosphorylated enzyme is the more active form of the enzyme and is referred to as glycogen phosphorylase a; the non-phosphorylated enzyme is the less active form of the enzyme, and is referred to as glycogen phosphorylase b.
The two enzymatic forms can be inhibited or activated allosterically see below. In the muscle , glycogenolysis releases glucose 1-phosphate which, as previously seen, is metabolized in the muscle itself to produce energy for muscle contraction, and therefore for the fight-or-flight response triggered by adrenaline. In the liver , glucagon triggers the release of glucose into the circulation to counteract hypoglycemia. Once the stressful situation ends, phosphorylase a phosphatase, also called phosphoprotein phosphatase 1 or PP1 EC 3.
PP1 is made up of a catalytic subunit, which has low catalytic efficiency and low affinity for glycogen, and the aforementioned G-subunit, which belongs to a family of proteins that bind other proteins to glycogen, known as glycogen-targeting proteins also phosphorylase kinase, glycogen phosphorylase, and glycogen synthase are bound to glycogen particles by proteins of this family. PP1 is also inhibited by another protein called inhibitor 1 of PP1.
As previously seen, PKA phosphorylates:. Therefore, the binding of the hormone to its receptor triggers a cascade reaction that, among other things, leads to the inhibition of PP1 activity. This maintains phosphorylated both glycogen phosphorylase and glycogen synthase: the first enzyme is activated whereas the latter is inhibited. In this way, carbohydrate metabolism is optimized. Glycogenolysis is also regulated by both positive and negative allosteric effectors. They act on three enzymes: muscle phosphorylase kinase, hepatic and muscle glycogen phosphorylase, and PP1.
Enzyme activity is regulated by two positive allosteric effectors, calcium ion and AMP, and one negative allosteric effector, ATP. AMP accumulates in the muscle during intense contraction, due to the consumption of ATP, and binds to and activates the enzyme.
Conversely, when the ATP concentration is high, that is, the muscle is not contracting, it binds to the allosteric site for AMP inactivating the kinase. Some hormones can act both by triggering covalent modifications of target proteins and by causing the release of calcium ions from the endoplasmic reticulum. In the liver, phosphorylase kinase is regulated by hormones that cause release of calcium ions. Inositol 1,4,5-triphosphate causes the release of calcium ions from the endoplasmic reticulum.
Muscle glycogen phosphorylase b is activated in the presence of high concentrations of AMP , which, binding to a specific nucleotide binding site, changes the quaternary structure of the enzyme, shifting the allosteric equilibrium toward the active R state of the b form.
Conversely, ATP and glucosephosphate , which compete with AMP for the same nucleotide-binding site, act as negative allosteric effectors, shifting the allosteric equilibrium toward the inactive T state of the b form. In resting muscle, nearly all the glycogen phosphorylase is in the inactive b form.
In fact, the covalent and allosteric regulation of the enzyme ensures that intracellular glucose levels are finely regulated. PP1 is allosterically activated by glucosephosphate , therefore when the cellular energy charge is low. In the liver, the purpose of glycogenolysis is to provide glucose to other tissues when the blood glucose level is low. When blood glucose level is back to normal, its concentration in hepatocytes increases and it binds to glycogen phosphorylase a , inducing a conformational change that exposes the phosphorylated serine residues to PP1 activity, which inactivates the enzyme through dephosphorylation.
Therefore, the allosteric site for glucose of hepatic glycogen phosphorylase allows the enzyme to act as a blood glucose sensor , responding appropriately to changes in blood glucose level. Ultimately, the hepatic isoenzyme responds only to glucose, not to AMP, that is, to the cellular energy charge, and this is noteworthy because fatty acids , and not glucose, are the primary energy source for the liver.
Nelson D. Principles of biochemistry. Freeman and Company, Roach P.
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