Control of glycogen phosphorylase

Figure 6.40 Reciprocal control of glycogen phosphorylase and glycogen synthase...

The control of glycogen phosphorylase by the phosphorylation-dephosphorylation cycle was discovered in 1955 by Edmond Fischer and Edwin Krebs50 and was at first regarded as peculiar to glycogen breakdown. However, it is now abundantly clear that similar reactions control most aspects of metabolism.51 Phosphorylation of proteins is involved in control of carbohydrate, lipid, and amino acid metabolism in control of muscular contraction, regulation of photosynthesis in plants,52 transcription of genes,51 protein syntheses,53 and cell division and in mediating most effects of hormones. 

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. 

In a second class of regulatory enzymes the active and inactive forms are inter-converted by covalent modifications of their structures by enzymes. The classic example of this type of control is the use of glycogen phosphorylase from animal tissues to catalyse the breakdown of the polysaccharide glycogen yielding glucose-1-phosphate, as illustrated in Fig. 5.37. 

Two key regulatory enzymes involved in the control of glycogen metabolism were first recognized as targets of cAMP and cAMP-dependent protein kinase in liver and skeletal muscle. These are phosphorylase b kinase and glycogen synthase. The molecular details of the phosphorylation and regulation of these enzymes are better understood in muscle than in liver since the liver enzymes have only recently been purified to homogeneity in the native form. However, it appears that they share many key features in common. 

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). 

Regulation of glycogen phosphorylase in muscle is accomplished by many of the same enzymes that control glycogen synthesis. Phosphorylase kinase converts the dimeric phosphorylase from the inactive to the active form by Mg + and ATP-dependent phosphorylation of two identical serine residues. The principal enzyme that removes this phosphate may be protein phosphatase-1 (phosphorylase phosphatase). 

Whether glycogen synthase is a substrate for phosphorylase kinase in vivo is unclear. [Modified and reproduced with permission from P. Cohen, Protein phosphorylation and the control of glycogen metabolism in skeletal muscle. Philos. Trans. R. Soc. Land. (Biol.) 302, 13 (1983).]... 

Skeletal muscle cells lack glucagon receptors. Hormonal control of glycogen degradation is achieved by epinephrine via P-adrenergic activation of adenylate cyclase, resulting in enhanced cytoplasmic cyclic AMP levels. Neural activation of skeletal muscle cells considerably increases the cytoplasmic Ca level. Cyclic AMP and Ca " act in a synergistic fashion to fully express the activity of glycogen phosphorylase in the process described above (Devlin, 1992). 

ATP + glycogen phosphorylase <1> (conversion to an AMP-independent form, key enzyme of neural and hormonal control of glycogen metabolism) [29]... 

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