number 15 Done by BaraaAyed Corrected by Mamoon Alqtamin Doctor Nayef Karadsheh 1 P a g e
Regulation of glycogen synthesis and degradation Regulation of glycogen synthesis and degradation involves two aspects: Allosteric regulation Quick response within the cell due to allosteric regulation of the enzymes:glycogen phosphorylase and glycogen synthase by effector molecules to meet the demand of particular tissue (non-covalent regulation). Hormonal regulation A hormone binds to a certain receptor to transmit a signal inside the cell. This mechanism involves modification of the enzymes:glycogen phosphorylase and glycogen synthaseby phosphorylation and dephosphorylation of the enzymes(covalent regulation). Now, we will discuss these 2 mechanisms in details: Allosteric regulation We studied in glycogen synthesis that we have glycogen synthase under regulation, and in glycogen degradation we have glycogen phosphorylase. During well fed state, we have high concentrations ofglucose, G6P, and ATP. In boththeliver and muscle, glucose 6 phosphate is considered to be anallosteric inhibitor for the enzyme glycogen phosphorylase. Note that G6P is a product of glycogen degradation by glycogen phosphorylase. So, high concentration of G6P means that the enzyme must be inhibited. Also,high concentration of ATP inhibits the enzyme glycogen phosphorylase; because the energy inside the cell is already high, andglycogen is broken down into glucose in order to produce energy. In both the liver and muscle, G6P is the allosteric activator for the enzyme glycogen synthase (when G6P level is high, this indicates that it should be stored). In theliver only, glucose is an allosteric inhibitor for glycogen phosphorylase. 2 P a g e
Remember: muscles lack the enzyme glucose 6 phosphatase, so there is no glucose to inhibit glycogen phosphorylase. Only G6P and ATP can inhibit it. In muscles only,high concentration of AMP means that the energy charge is low. So, it will activate glycogen phosphorylase to produce more glucose 6 phosphate that enters aerobic and anaerobic pathways to produce more ATP. Remember that AMP also activates phosphofructokinase in glycolysis pathway. Ca++ which is producedby neuron stimulation is an indirect activator for glycogen phosphorylase. (The last two points will be discussed in detail in the end of this sheet) Note: during fasting, degradation is activated and synthesis is inhibited whereas during well fed state, degradation is inhibited and synthesis is activated. 3 P a g e
Hormonal regulation It has a powerful effect but slower than allosteric regulation, because it triggers a signal by neurotransmitters or hormones. Glucagon and epinephrine are secreted in response to low blood sugar. Glucagon binds to G protein coupled receptors in the liver only. Muscles don t have receptors for glucagon, so glucagon gives a response in liver cells only. Whereas epinephrine binds to adrenergic receptorsβ/α and epinephrine gives a response in both liver cells and muscles. Mechanism: (this example is in the liver) Low blood sugar leads to the secretion ofepinephrine and glucagon, then glucagon binds to G protein coupled receptorsand epinephrine binds to β adrenergic receptors on liver cells. As we said that these receptors are GPCRs, this binding stimulates α subunit to bind to GTP rather than GDP. This will lead to releasing the α subunit that binds to GTP. Activated α subunit binds to adenylyl cyclase which converts ATP to camp. camp activates protein kinase A which is a tetramer that has 2 regulatory subunits and 2 catalytic subunits. camp binds to the regulatory subunits, releasing catalytic subunits that are now active. Active PKA phosphorylatesglycogen phosphorylase kinaseb(inactive form)at serine or threonine residue to become in the active form. Glycogen phosphorylase is activated by the addition of a phosphate group (due to the active enzyme glycogen phosphorylase kinase a) Remember: some enzymes exist in two forms: active form "a" and inactive form "b". Now, glycogen phosphorylase kinase phosphorylates glycogen phosphorylase b to become active in the form of glycogenphosphorylase a. Glycogen phosphorylase starts glycogen degradation. 4 P a g e
Also, protein kinase A phosphorylates glycogen synthase a (active form) to become inactive in the form of glycogen synthase b (inactive form). It meanswhen glycogen synthase is phosphorylated, it will be in the inactive form. Note: glycogen phosphorylase becomesactive by phosphorylation and glycogen synthase becomesinactive by phosphorylation (it is activated by dephosphorylation). This long cascade happens to amplify the signaland therefore, amplify the effect. 5 P a g e
Note: there is an enzyme called protein phosphatase 1(PP1) which functions to make glycogen phosphorylase kinase a andglycogen phosphorylase ain their inactive forms by dephosphorylation. BUT through epinephrine/glucagon action, this enzyme becomes inactive. HOW? PP1 is bound to an inhibitor protein. This inhibitor protein is activated through phosphorylationby the active protein kinase A and PP1 is inhibited. So we maintain the phosphorylated state of glycogen phosphorylase kinase a andglycogen phosphorylase a (we maintained the active forms for these enzymes). When blood sugar returns to normal, glycogen phosphorylase kinase a and glycogen phosphorylase a must return to their inactive forms. However, phosphorylation is covalent modification so, it is anirreversible reaction. But there should be a way to reverse this regulation by: 1. Phosphodiesterase enzyme When blood sugar becomes normal, the signal by glucagon and epinephrine is inhibited and camp production will be inhibited. The camp that was within the cell is converted to 5 AMP by phosphodiesterase enzyme. PKA stays inactive and it will not phosphorylate glycogen phosphorylase kinase b. 2. Protein phosphatase 1(PP1) 6 P a g e
Increasing blood sugar leads to insulin secretion and it binds to its receptors inhibiting the production of camp (by activating the phosphodiesterase), protein kinase A is inactive. Now, the protein inhibitor that linked to PP1 is not phosphorylated (it becomes inactive) so it cannot inhibit PP1 and PP1 is now active. PP1 converts glycogen phosphorylase kinase A toglycogen phosphorylase kinase b,and glycogen phosphorylase a to glycogen phosphorylase b(converting these enzymes to their inactive forms). So, glycogen degradation will be inhibited. Also, PP1 activates glycogen synthase by dephphosphorylation. The role of AMP in the muscles Muscles can sometimes suffer from hypoxia (low oxygen level) that leads to the decrease of ATP production and the increase of AMP concentration. Because muscles need to survive, AMP activates glycogen phosphorylase b without being phosphorylated (allosteric regulation). So, degradation of glycogen happens, which leads to glucose generation. Also, AMP activates PFK1 in the glycolysis pathway so muscles produce some energy to survive until the oxygen concentration is restored. The role of calcium in muscle contraction (duringexercise) Muscles contract through nerve impulses; when the nerve impulse reaches the cell it stimulates the release of Ca++ from the sarcoplasmic reticulum leading to an increase in the concentration of Ca++ in the cytoplasm. Ca++that isreleased from the SR binds to a protein called calmodulincam(the most abundant calcium protein),four ions of Ca++ bind to calmodulin. After binding, Ca++ -CaM complex binds to glycogen phosphorylase kinase b and it is activated without phosphorylation. During excessive muscle contraction, ATP is highly reduced leading to the accumulation of ADP. When there is high concentration of ADP, this equation happens: ADP+ADP ATP +AMP. Then AMP activates glycogen phosphorylase b without phosphorylation. 7 P a g e
Differences in glycogen degradation between the liver and muscle Glucagon has no effect on muscles. AMP is an allosteric activator of muscle glycogen phosphorylase only (not the liver). Neural stimulation increases calcium concentration. Glucose is not an allosteric inhibitor of glycogen phosphorylase in muscles. Muscle glycogen is a stronger feedback inhibitor of glycogen synthase than in the liver becauseglycogen in the musclesis made at less concentration than inthe liver. We know that the amount of glycogen in muscles is higher because of the mass of muscles, but it is less concentrated per gram of tissue than the liver. This mechanism is not understood well. The role of calcium in the liver 8 P a g e
We know that calcium is released in muscles by nerve impulses but how is it released in the liver? During stress, epinephrine is secreted, and it bindsto α adrenergic receptors in liver cells. Remember: we said previously that epinephrine binds to two types of receptors: β adrenergic receptors and α adrenergic receptors. We discussed the mechanism of binding to β adrenergic receptors and they are GPCR that work on adenylyl cyclase. α adrenergic receptors are also GPCR but work on phospholipase C. Binding of epinephrine at β adrenergic receptors activates α subunit to bind to PLC and activate it. PLC starts breaking down PIP2,it will dissociate to DAG and IP3. IP3 triggers endoplasmic reticulum to release calcium. Four Calcium ions bind to calmodulin. Calcium and DAG activate protein kinase C which phosphorylatesglycogen synthase a to become in the inactive form. Ca++ - CaM complex activates glycogen phosphorylase kinase b to become in the active form(it phosphorylatesglycogen synthase a to become inactive). Also, Ca++ - CaM complex activatescalcium calmodulin dependent protein kinasewhich phosphorylatesglycogen synthase a to become inactive. So, glycogen synthase isphosphorylated at several sites, and it becomestotally inactive. 9 P a g e
The End A lion doesn t concern itself with the opinion of sheep LordTywinLannister. 10 P a g e