Phosphorylases Phosphorylation

Phosphorylase phosphorylation is catalyzed by phosphorylase kinase. Phosphorylase kinase is inactive in a nonphosphorylated state and active when phosphorylated. Phosphorylase kinase phosphorylation is catalyzed by the cAMP-dependent protein kinase. 

Silver PJ, Stull JT (1982) Regulation of myosin light chain and phosphorylase phosphorylation in tracheal smooth muscle. J Biol Chem 257 6145-6150... 

Showdomycin. Showdomycin (2-p-D-ribofuranosyhnaleimide) (7) is a maleimide C-nucleoside antibiotic synthesi2ed by S. showdoensis-, isoshowdomycin (8) and maleimycin (9) have also been isolated (1—6). Showdomycin is not phosphorylated by nucleoside kinase and is not a substrate for nucleoside phosphorylase. Once (7) enters the cell, it blocks the uptake of glucose and other nutrients. 

B. Ca -calmodnlin (CaM)-dependent Phosphorylase kinase (PhK) —krk qis vrgl— phosphorylation by PKA... 

Muscle glycogen phosphorylase is a dimer of two identical subunits (842 residues, 97.44 kD). Each subunit contains a pyridoxal phosphate cofactor, covalently linked as a Schiff base to Lys °. Each subunit contains an active site (at the center of the subunit) and an allosteric effector site near the subunit interface (Eigure 15.15). In addition, a regulatory phosphorylation site is located at Ser on each subunit. A glycogen-binding site on each subunit facilitates prior association of glycogen phosphorylase with its substrate and also exerts regulatory control on the enzymatic reaction. 

As early as 1938, it was known that glycogen phosphorylase existed in two forms the less active phosphorylase b and the more active phosphorylase a. In 1956, Edwin Krebs and Edmond Eischer reported that a converting enzyme could convert phosphorylase b to phosphorylase a. Three years later, Krebs and Eischer demonstrated that the conversion of phosphorylase b to phosphorylase a involved covalent phosphorylation, as in Eigure 15.17. 

Johnson, L. N., 1992. Glycogen phosphorylase Control by phosphorylation and allosteric effectors. FASEB Journal 6 2274-2282. 

The principal enzymes controlling glycogen metabolism—glycogen phosphorylase and glycogen synthase— are regulated by allosteric mechanisms and covalent modifications due to reversible phosphorylation and... 

In hver, one of the serine hydroxyl groups of active phosphorylase a is phosphorylated. It is inactivated by hydrolytic removal of the phosphate by protein phos-phatase-1 to form ph osphorylase h. Reactivation requires rephosphorylation catalyzed by phosphorylase kinase. 

Muscle phosphorylase is distinct from that of Hver. It is a dimer, each monomer containing 1 mol of pyridoxal phosphate (vitamin Bg). It is present in two forms phos-phoiylase a, which is phosphorylated and active in either the presence or absence of 5 -AMP (its allosteric modifier) and phosphorylase h, which is dephosphorylated and active only in the presence of 5 -AMP. This occurs during exercise when the level of 5 -AMP rises, providing, by this mechanism, fuel for the muscle. Phosphorylase a is the normal physiologically active form of the enzyme. 

Both phosphorylase a and phosphorylase kinase a are dephosphorylated and inactivated by protein phos-phatase-1. Protein phosphatase-1 is inhibited by a protein, inhibitor-1, which is active only after it has been phosphorylated by cAMP-dependent protein kinase. Thus, cAMP controls both the activation and inactivation of phosphorylase (Figure 18-6). Insulin reinforces this effect by inhibiting the activation of phosphorylase b. It does this indirectly by increasing uptake of glucose, leading to increased formation of glucose 6-phosphate, which is an inhibitor of phosphorylase kinase. 

Like phosphorylase, glycogen synthase exists in either a phosphorylated or nonphosphorylated state. However, unlike phosphorylase, the active form is dephosphorylated (glycogen synthase a) and may be inactivated to... 

Protein phosphorylation Calmodulin kinase I ATI Elongation factor-2 kinase Phosphorylase kinase Myosin Light Chain kinase... 

SIGNAL INTEGRATION by phosphorylase kinase. Phosphorylase kinase eventually phosphorylates and activates glycogen phosphorylase. Either (or both) phosphorylation and calcium signaling pathways converge at phosphorylase kinase. 

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