9-glycogen - Biochemistry of Metabolism Glycogen Metabolism...

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Glycogen Metabolism Copyright © 1999-2007 by Joyce J. Diwan. All rights reserved. Biochemistry of Metabolism
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Glycogen is a polymer of glucose residues linked by α (1 4) glycosidic bonds, mainly α (1 6) glycosidic bonds, at branch points. Glucose is stored as glycogen predominantly in liver and muscle cells. H O OH H OH H OH CH 2 OH H O H H OH H OH CH 2 OH H O H H H O O H OH H OH CH 2 H H H O H OH H OH CH 2 OH H OH H H O O H OH H OH CH 2 OH H O H O 1 4 6 H O H OH H OH CH 2 OH H H H O H OH H OH CH 2 OH H H O 1 OH 3 4 5 2 glycogen
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Glycogen Phosphorylase catalyzes phosphorolytic cleavage of the α (1 4) glycosidic linkages of glycogen, releasing glucose-1-phosphate as reaction product. glycogen (n residues) + P i glycogen (n–1 residues) + glucose-1- phosphate This phosphorolysis may be compared to hydrolysis: Hydrolysis: R-O-R' + HOH R-OH + R'-OH Phosphorolysis: R-O-R' + HO-PO 3 2- R-OH + R'-O- glucose-1-phosphate H O OH H OH H OH CH 2 OH H O PO 3 2 - H Glycogen catabolism (breakdown):
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Pyridoxal phosphate ( PLP ), a derivative of vitamin B 6 , serves as prosthetic group for Glycogen Phosphorylase. pyridoxal phosphate (PLP) N H C O P O - O O OH CH 3 C H O - + H 2
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Pyridoxal phosphate (PLP) is held at the active site by a Schiff base linkage, formed by reaction of the aldehyde of PLP with the ε -amino group of a lysine residue. In contrast to its role in other enzymes, the phosphate of PLP is involved in acid/base catalysis by Phosphorylase. N H C O P O - O O O - CH 3 HC - + H 2 N (CH 2 ) 4 Enz H + Enzyme (Lys)-PLP Schiff base H 3 N + C COO - CH 2 CH 2 CH 2 CH 2 NH 3 H + lysine
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The P i substrate binds between the phosphate of PLP and the glycosidic O linking the terminal glucose residue of the glycogen. N H C O P O - O O O - CH 3 HC - + H 2 N (CH 2 ) 4 Enz H + Enzyme (Lys)-PLP Schiff base After the phosphate substrate donates H + during cleavage of the glycosidic bond, it receives H + from the phosphate moiety of PLP. PLP then takes back the H + as the phosphate O attacks C1 of the cleaved glucose to yield glucose-1-phosphate.
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A glucose analog , N -acetylglucosamine (GlcNAc), is adjacent to pyridoxal phosphate at the active site in the crystal structure shown. Glycogen Phosphorylase : a homodimeric enzyme, subject to allosteric control. It transitions between relaxed ” (active) & tense ” (inhibited) conformations. Diagram comparing relaxed and tense conformations. PLP PLP GlcNAc GlcNAc inhibitor Human Liver Glycogen Phosphorylase PDB 1EM6
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Question: Why would an inhibitor of Glycogen Phosphorylase be a suitable treatment for diabetes? A class of drugs developed for treating the hyperglycemia of diabetes (chloroindole- carboxamides), inhibit liver Phosphorylase allosterically. These
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This note was uploaded on 12/28/2011 for the course STEP 1 taught by Professor Dr.aslam during the Fall '11 term at Montgomery College.

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9-glycogen - Biochemistry of Metabolism Glycogen Metabolism...

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