Glycogen phosphorylase allosteric control

Allosteric Enzymes Typically Exhibit a Sigmoidal Dependence on Substrate Concentration The Symmetry Model Provides a Useful Framework for Relating Conformational Transitions to Allosteric Activation or Inhibition Phosphofructokinase Allosteric Control of Glycolysis Is Consistent with the Symmetry Model Aspartate Carbamoyl Transferase Allosteric Control of Pyrimidine Biosynthesis Glycogen Phosphorylase Combined Control by Allosteric Effectors and Phosphorylation... 

Glycogen Phosphorylase Combined Control by Allosteric Effectors and Phosphorylation... 

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 ... 

Reflect and Apply Explain how glycogen phosphorylase is controlled allosterically and by covalent modification. 

Glycogen phosphorylase is controlled allosterically by several molecules. In the muscle, AMP is an allosteric activator. In the liver, glucose is an allosteric inhibitor. Glycogen phosphorylase also exists in a phosphorylated form and an unphosphorylated form, with the phosphorylated form being more active. 

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. 

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... 

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. 

Muscle glycogen phosphorylase is one of the most well studied enzymes and was also one of the first enzymes discovered to be controlled by reversible phosphorylation (by E.G. Krebs and E. Fischer in 1956). Phosphorylase is also controlled allosterically by ATP, AMP, glucose and glucose-6-phosphate. Structurally, muscle glycogen phosphorylase is similar to its hepatic isoenzyme counterpart composed of identical subunits each with a molecular mass of approximately 110 kDa. To achieve full activity, the enzyme requires the binding of one molecule of pyridoxal phosphate, the active form of vitamin B6, to each subunit. 

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 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). 

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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