Phosphorylation of glycogen

Phosphorylation of glycogen phosphorylase is the initiator for the coupled conformational changes, which are coimmmicated over a large distance to the active site. Similar to the allosteric mechanism of phophofructokinase, the inter-subunit contact sinfaces play a decisive role for the communication between the phosphorylation site... 

Response of enzyme to phosphorylation Depending on the specific enzyme, the phosphorylated form may be more or less active than the unphosphorylated enzyme. For example, phosphorylation of glycogen phosphorylase (an enzyme that degrades glycogen) increases activity, whereas the addition of phosphate to glycogen synthase (an enzyme that synthesizes glycogen) decreases activity (see p. 132). 

Phosphorylation also can modify an enzyme s sensi-tivity to allosteric effectors. Phosphorylation of glycogen phosphorylase reduces its sensitivity to the allosteric activator adenosine monophosphate (AMP). Thus, a covalent modification triggered by an extracellular signal can override the influence of intracellular allosteric regulators. In other cases, variations in the concentrations of intracellular effectors can modify the response to the covalent modification, depending on the metabolic state of affairs in the cell. 

The same cAMP-dependent protein kinase that is responsible for phosphorylating phosphorylase kinase also catalyzes the phosphorylation of glycogen synthase. Whereas phosphorylation of glycogen phosphorylase leads to increased activity, the phosphorylation of glycogen synthase decreases its activity. As a result when glycogen breakdown is stimulated in response to glucagon, glycogen synthesis is inhibited. In this way the simultaneous operation of both enzymes associated with pseudocycle la is prevented. 

Figure 18.14 Glycogen biosynthesis and degradation regulation. cAMP activates cAMP-dependent protein kinases. They cause the phosphorylation of glycogen synthase (inactivation), phosphorylase kinase (activation), and the inhibitory protein. The last inhibits phosphoprotein phosphatase. Activated phosphorylase kinase causes the phosphorylation of phosphorylase b, thus activating it to phosphorylase a. Phosphoprotein phosphatase is inhibited by the phosphorylated inhibitor protein. Such inhibition is released when the inhibitor protein is dephosphorylated. The phosphatase then reactivates glycogen synthase and inactivates phosphorylase kinase and phosphorylase a.

Activated PKB (Akt) phosphorylates the following proteins with the indicated anabolic consequences Bad phosphorylation yields P-Bad which then dissociates from a Bcl-2-Bcl-X] complex in the mitochondrial outer membrane and is sequestered by 14.3.3 proteins. Mitochondrial pore blockage by the Bad-free Bcl-2-Bcl-xL complex successively prevents cytochrome c release from mitochondria, blocks procaspase activation by cytochrome c and thus inhibits apoptosis and increases cell survival. Phosphorylation of p70S6 kinase by PKB results in activation of this PK, phosphorylation of ribosomal small subunit protein S6 and enhancement of translation (protein synthesis). Phosphorylation of glycogen synthase (GS) kinase 3 (GSK3) by PKB results in an inactive P-GSK3, a consequent increase in the amount of the active non-phosphorylated form of GS and increased glycogen synthesis. 

Glycogen synthase is a tetrameric enzyme consisting of four identical snbnnits. Its activity is regulated by phosphorylation of serine residnes in the subunit proteins. Phosphorylation of glycogen synthase rednces its activity towards UDP-glucose in the non-phosphorylated state (synthase a, active), glycogen synthase does not require glucose-6-phosphate as an allosteric activator, but when phosphorylated (synthase b, inactive), it does. 

Phosphorylation is another very common way of regulating enzymes, especially in signalling cascades. It requires ATP. A frequently quoted example is glycogen phosphorylase, an enzyme that phosphorylates glycogen, and is itself most active when phosphorylated. Phosphorylation of glycogen phosphorylase is reversible and controlled by the phosphorylase kinase and a phosphatase, (kinases add phosphate groups to proteins, phosphatases remove them). The phosphorylase kinase is itself regulated by phosphorylation (Fig. 6.19). 

Cyclic AMP promotes neuronal survival by phosphorylation of glycogen synthase kinase 3beta. Mol Cell Biol 20 9356-9363. 

Insulin triggers a cascade that leads to the phosphorylation and inactivation of glycogen synthase kinase and prevents the phosphorylation of glycogen synthase. Protein phosphatase 1 (PPl) removes the phosphates from glycogen synthase, thereby activating the enzyme and allowing glycogen synthesis, IRS. insulin-receptor substrate. 

Figure 3 Phosphorylation of glycogen synthase by glycogen synthase kinase 3 (GSK-3). (a) In vitro, phosphorylation occurs first at site 5 by casein kinase II. Then GSK-3 phosphorylates in sequence site 4, then 3c, 3b, and last, 3a. (b) Phosphorylation of sites 3a and 3b by different protein kinases, PK and PKy. In vivo, these kinases can phosphorylate sites 3a and 3b independent of prior phosphorylation of sites 3c, 4, and 5. PAS kinase has been shown to phosphorylate site 3a (S640). ...

Phosphorylation of glycogen synthase, converting it to a form dependent on glucose-6-phosphate. 

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