Glycogen phosphorylase regulation

Increasing sophistication of glycogen phosphorylase regulation Section 21,3.3 The a-amylase family Section 21,4.3... 

Glycogen Phosphorylase Allosteric Regulation and Covalent Modification 473... 

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

A well-known example, indeed the first enzyme that was shown to be regulated by the phosphorylation/ dephosphorylation mechanism, is glycogen phosphorylase, which catalyses the breakdown of glycogen (Box 3.7). 

Figure 3.29 Control of an enzyme activity by multiple allosteric regulators. The enzyme glycogen phosphorylase b in muscle is regulated by changes in the concentrations of AMP and inosine monophosphate (IMP) (which are activators) and ATP and glucose 6-phosphate (G6P), which are inhibitors.

The glucose concentration is the major factor regulating glycogen synthesis in liver. Glucose activates glucokinase directly as a substrate and indirectly via an increase in the concentration of fructose 6-phosphate. It also activates glycogen synthase but it inhibits glycogen phosphorylase (see text). 

Covalent interconversion of enzymes is well established as a fundamental theme in metabolic regulation. The prototypic reversible interconverting systems include the sequence of phosphorylation/dephosphorylation steps in the activation of mammalian glycogen phosphorylase and pyruvate dehydrogenase as well as the nucleotidyla-tion/denucleotidylation using UTP and ATP in the bacterial glutamine synthetase cascade (see Fig. 1.). 

Glycogen phosphorylase was the first enzyme shown to be regulated via protein phosphorylation (Krebs, 1959). In recognition of their trad-blazing work, Edwin Krebs and Edmond Fisher were rewarded the Nobel prize for Chemistry in 1992. 

Fig. 7.18. Regulation of glycogen metabolism in muscle. Phosphorylase kinase stands at the center of regulation of glycogen metabolism. Phosphorylase kinase may exist in an active, phosphorylated form and an inactive, unphosphorylated form. Phosphorylation of phosphorylase kinase is triggered by hormonal signals (e.g. adrenahne) and takes place via an activation of protein kinase A in the cAMP pathway. In the absence of hormonal stimulation, phosphorylase kinase can also be activated by an increase in cytosolic Ca. The active phosphorylase kinase stimulates glycogen degradation and inhibits glycogen synthesis, in that, on the one side, it activates glycogen phosphorylase by phosphorylation, and on the other side, it inactivates glycogen synthase by phosphorylation.

An important example of regulation by phosphorylation is seen in glycogen phosphorylase (Afr 94,500) of muscle and liver (Chapter 15), which catalyzes the reaction... 

FIGURE 6-31 Regulation of glycogen phosphorylase activity by covalent modification. In the more active form of the enzyme, phosphorylase a, specific Ser residues, one on each subunit, are phosphorylated. Phosphorylase a is converted to the less active phosphorylase b by enzymatic loss of these phosphoryl groups, promoted by phosphorylase phosphatase. Phosphorylase b can be reconverted (reactivated) to phosphorylase a by the action of phosphorylase kinase. 

The breakdown of glycogen in skeletal muscles and the liver is regulated by variations in the ratio of the two forms of glycogen phosphorylase. The a and b forms differ in their secondary, tertiary, and quaternary structures the active site undergoes changes in structure and, consequently, changes in catalytic activity as the two forms are interconverted. 

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