Glycogen phosphorylase covalent modification

Glycogen Phosphorylase Allosteric Regulation and Covalent Modification 473... 

FIGURE 15.17 The mechanism of covalent modification and allosteric regnlation of glycogen phosphorylase. The T states are bine and the R states bine-green. 

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

As indicated in Section 6.3.3 and Table 6.2 the key control step is mediated by glycogen phosphorylase, a homodimeric enzyme which requires vitamin B6 (pyridoxal phosphate) for maximum activity, and like glycogen synthase (Section 6.2) is subject to both allosteric modulation and covalent modification. 

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. 

Many enzymes are regulated by covalent modification, most frequently by the addition or removal of phosphate groups from specific serine, threonine, or tyrosine residues of the enzyme. In the fed state, most of the enzymes regulated by covalent modification are in Ihe dephosphorylated form and are active (see Figure 24.2). Three exceptions are glycogen phosphorylase (see p. 129), fructose bis-phosphate phosphatase-2 (see p. 98), and hormone-sensitive lipase of adipose tissue (see p. 187), which are inactive in their dephosphorylated state. 

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. 

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. 

Fig. 2. Regulation of (a) glycogen phosphorylase activity and (b) glycogen synthase activity by phosphorylation (covalent modification).

Glycogen synthase is also regulated by covalent modification and allosteric interactions. The enzyme exists as an active glycogen synthase a and a normally inactive glycogen synthase b. However, in contrast to phosphorylase, it is the active form of glycogen synthase (synthase a) that is dephosphorylated whereas the inactive synthase b form is the phosphorylated form (Fig. 2b). 

Compare the glycogen phosphorylase activity between the reactions in tubes FI and I. What effect does phosphorylation of Ser 14 have on the activity of glycogen phosphorylase b Can you estimate how much the activity of the enzyme is increased or decreased with this type of covalent modification ... 

What do you think is the advantage of having an enzyme such as glycogen phosphorylase b controlled both by an allosteric effector and by covalent modification ... 

The catalytic activity of enzymes is controlled in several ways. Reversible allosteric control is especially important. For example, the first reaction in many biosynthetic pathways is allosterically inhibited by the ultimate product of the pathway. The inhibition of aspartate trans carbamoyl as e by cytidine triphosphate (Section 10.1) is a well-understood example offeedback inhibition. This type of control can be almost instantaneous. Another recurring mechanism is reversible covalent modification. For example, glycogen phosphorylase, the enzyme catalyzing the breakdovm of glycogen, a storage form of sugar, is activated by phosphorylation of a particular serine residue when glucose is scarce (Section 21.2.1). 

During exercise, [ATP] falls and [AMP] rises. Recall that AMP is an allosteric activator of glycogen phosphorylase b. Thus, even in the absence of covalent modification by phosphorylase kinase, glycogen is degraded. 

Enzyme activity can be regulated by covalent modification or by noncovalent (allosteric) modification. A few enzymes can undergo both forms of modification (e.g., glycogen phosphorylase and glutamine synthetase). Some covalent chemical modifications are phosphorylation and dephosphorylation, acetylation and deacetylation, adeny-lylation and deadenylylation, uridylylation and deuridyly-lation, and methylation and demethylation. In mammalian systems, phosphorylation and dephosphorylation are most commonly used as means of metabolic control. Phosphorylation is catalyzed by protein kinases and occurs at specific seryl (or threonyl) residues and occasionally at tyrosyl residues these amino acid residues are not usually part of the catalytic site of the enzyme. Dephosphorylation is accomplished by phosphoprotein phosphatases ... 

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