glycogenreg - Regulation of Glycogen Metabolism Bryant...

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Regulation of Glycogen Metabolism Bryant Miles I. Glycogen Phosphorylase Glycogen phoshorylase catalyzes the following reaction: Glycogen n + Pi Glucose-1-phosphate + glycogen n-1 Glycogen phosphorylase is dimer of two identical subunits. Each subunit has an active site which contains a pyridoxal cofactor covalently attached via a Schiff base. The active sites are located in the center of each subunit. This enzyme is allosterically regulated. AMP ± ATP ² Glucose-6-phosphate ² The binding sites for these allosteric effectors is located near the subunit interfaces. This enzyme binds inorganic phosphate cooperatively. This allows the enzyme’s activity to increase by great amounts over a narrow range of substrate concentrations. Glycogen phosphorylase generates glucose-1-phosphate which is isomerized into glucose-6-phosphate and enters the glycolytic pathway to produce ATP. This end product ATP is a feed back inhibitor of glycogen phosphorylase. Glucose-6-phosphate is an allosteric inhibitor of the enzyme. ATP and glucose- 6-phosphate produce a negative effect on the cooperativity of substrate binding. As shown above the substrate saturation curve is shifted to the right by ATP requiring a lot higher concentration of Pi to produce half of the maximal velocity.
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AMP is also an allosteric effector of glycogen phosphorylase. It competes for the same allosteric binding site as ATP but stimulates glycogen phosphorylase by having a positive effect on the cooperativity of substrate binding. Increase in the cellular concentration of AMP is an indicator that the energy status of the cell is low and more ATP via glycolysis needs to be produced. The reciprocal changes of ATP and AMP concentrations combined with their competition for the allosteric binding site with opposite effects provide a mechanism for rapid and reversible control over glycogenolysis. Glycogen phosphorylase is a typical allosteric enzyme. It is composed of 2 identical subunits (multiple subunits) The dimer has symmetry The enzyme exist in only two conformations designated R and T. These conformations are in equilibrium R T The substrates bind when the enzyme is in the R state. Positive allosteric effectors bind to the R state and stabilize it shifting the equilibrium to the left. Negative allosteric effectors bind to the T state and stabilize it shifting the equilibrium to the right. In the T-state, the active site is buried which lows the affinity of the enzyme for the substrates. In addition, Asp-283 faces the active site so that there is electrostatic repulsion between this residue and the substrate inorganic phosphate. In the R-state, the active site is exposed to the solvent facilitating substrate binding. In addition, Asp-283 is displaced from the active site and replaced by Arg-569 which produces favorable electrostatic interactions between the negatively charged inorganic phosphate.
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This note was uploaded on 04/11/2010 for the course BICH bich 411 taught by Professor Bryantmiles during the Spring '10 term at Texas A&M.

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glycogenreg - Regulation of Glycogen Metabolism Bryant...

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