Glycogen Metabolism Notes

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Glycogen Breakdown:

• In muscle, the need for ATP results in the conversion of glycogen to glucose-6-phosphate for entry into glycolysis.

• Glycogen's branched structure is important: it permits glycogen's rapid degradation through the simultaneous release of the glucose units at the end of every branch.

• Plants store glucose as starch; animals store glucose as glycogen.

• Glycogen is considered a quick energy for the body because it is metabolized rapidly, it can be metabolized anaerobically, and glycogen can be used to alter blood glucose level.

• Stored body fats produce higher quality energy than glycogen does.

• Liver and muscle are two main storage areas for glycogen.

Enzymes Required for Glycogen breakdown:

Glycogen phosphorylase:

• This is a dimer that catalyzes the controlling step in glycogen breakdown. The phosphorylase reaction results in the cleavage of the C1-O1 bond from a nonreducing terminal glucosyl unit of glycogen, yielding G1P.

Phosphoglucomutase:

• When G1P is formed, it is converted to glucose-6-phosphate either for entry into glycolysis in muscle or hydrolysis to glucose in liver.

Glycogen debranching enzyme:

• This enzyme acts as an alpha (1->4) transglycosylase (glycosyl transferase) by transferring an alpha (1->4)-linked trisaccharide unit from a limit branch of glycogen to the nonreducing end of another branch.

Glycogen Synthesis:

• As obvious from the cause of McAdrle's disease, glycogen synthesis and breakdown occur in separate pathways.

Enzymes of Glycogen Synthesis:

UDP-glucose pyrophosphorylase:

• This enzyme catalyzes the reaction of UTP and G1P to yield UDP-Glucose and release PPi. The formation of PPi releases free energy that can be used nucleoside triphosphate hydrolysis to drive an otherwise endergonic reaction to completion.

Glycogen synthase:

• This enzyme transfers the C4-OH group on one of glycogen's nonreducing ends to form alpha (1->4)-glycosidic bond. Note: For each molecule of G1P that is converted to glycogen and then regenerated, one molecule of UTP is hydrolyzed to UDP and Pi. The cyclic synthesis and breakdown of glycogen is not a perpetual motion machine, but rather an engine that is powered by UTP hydrolysis.

Glycogen branching enzyme:

• Branching to form glycogen is accomplished by an enzyme called amylo-(1,4 -> 1,6) transglycosylase (branching enzyme). Branches are created by transfer of terminal chain segments consisting of about 7 glucosyl residues to C6-OH groups of glucose residues on the same or another glycogen chain.

Control of Glycogen Metabolism:

• Various types of process control glycogen synthesis; processes such as allosteric control and enzyme-catalyzed covalent modifications of both glycogen synthase and glycogen phosphorylase.

• There is direct allosteric control of glycogen phosphorylase and glycogen synthase. Some effectors include ATP, G6P, and AMP.

• When there is high demand of ATP, glycogen phosphorylase is stimulated and glycogen synthase is inhibited.

• When ATP and G6P are high, the reverse is true and glycogen synthesis is favored.

• In muscle, glycogen phosphorylase is activated by AMP, and inhibited by G6P and ATP.

Covalent modification of Enzymes by Cyclic Cascades:

• Effector "Signal" Modification.

• Glycogen phosphorylase and glycogen synthase can each be interconverted between two forms with different kinetic and allosteric properties through reactions known as cyclic cascade.

• This way, glycogen phosphorylase and glycogen synthase can respond to a greater number of allosteric stimuli, exhibit greater flexibility in their control patterns, and possess enormous amplification potential in their responses to variation in effector concentrations.

• Thus, a small change in concentration of an allosteric effector causes a large change in concentration of an active, modified target enzyme.

Glycogen Phosphorylase Bicyclic Cascade:

• Glycogen phosphorylase exists in two forms: a and b.

• A form is active without AMP; b form requires AMP for activation.

• A form is Ser 14 enzymatically phosphorylated; form b is Ser 14 enzymatically dephosphorylated.

• It should be mentioned that the activity of glycogen phosphorylase is also allosterically controlled by enzymatic interconversion through bicyclic cascade involving actions of 3 enzymes.

Glycogen Phosphorylase Activity Control:

Phosphorylase kinase:

• It specifically phosphorylates Ser 14 of glycogen phosphorylase b.

Protein kinase A:

• It phosphorylates/activates phosphorylase kinase.

Phosphoprotein phosphatase-1:

• It dephosphorylates/deactivates both glycogen phosphorylase a form and phosphorylase kinase.

Glycogen Breakdown Control:

• In resting cells, the concentrations of ATP and G6P are high enough to inhibit phosphorylase b. The level of phosphorylase activity is therefore largely determined by the fraction of the enzyme present as phosphorylase a.

• This cascade controls the rate of glycogen breakdown.

cAMP-dependent Protein Kinase:

• Phosphorylase kinase, which converts phosphorylase b to phosphorylase a, is itself subject to covalent modification. For phosphorylase kinase to be fully active, Ca2+ must be present and the protein must be phosphorylated.

• cAMP is required for the activity of protein kinase A, an enzyme that phosphorylates specific Ser and/or Thr residues of numerous cellular proteins, including phosphorylase kinase and glycogen synthase.

Phosphorylase kinase:

• Coordination of enzyme activation with Ca2+

• Phosphorylase kinase is activated by Ca2+ concentrations as well as by covalent modification.

• Activation results in nerve impulses triggering muscle contractions through release of Ca2+.

• This also results in glycogen breakdown that supplies glycolysis.

Phosphoprotein phosphatase-1:

• The phosphatase involved in cyclic cascades controlling glycogen metabolism is phosphoprotein phosphatase-1.

• This enzyme hydrolyzes the phosphoryl groups from m-glycogen phosphorylase a, both alpha and beta subunits of phosphorylase kinase, and two other proteins involved in glycogen metabolism.

Glycogen Synthase Bicyclic Cascade:

• Glycogen synthase also exists in two enzymatically interconvertible forms.

• The b-form (phosphorylated) that is inactive under physiological conditions and the a-form (de phosphorylated) that is active.

• b-form is under allosteric control and is inhibited by ATP, ADP and Pi, so the enzyme is almost inactive in vivo.

• This cascade controls the rate of glycogen synthesis.

Integration of Glycogen Metabolism Control Mechanism:

• Net synthesis and degradation of glycogen depends upon the relative balance of glycogen synthase and glycogen phosphorylase.

• This, in turn, depends upon the rates of phosphorylation and dephosphorylation of the two bicyclic cascades.

• The two cascades are intimately related.

• They are linked by protein kinase A, phosphorylase kinase, and phosphoprotein phosphatase-1.

More Glycogen Metabolism Facts:

• Glycogen metabolism is regulated by peptide hormone insulin acting opposite to glucagon.

• This is done together with epinephrine and norepinephrine.

• Glucagon and norepinephrine initiate glycogen breakdown.

• Low blood glucose causes alpha-pancreatic cells to secrete glucagon.

Glycogen is converted to G6P and the following reaction occurs:

• G6P + H2O = glucose + Pi

• If the above reaction can't occur, a type I glycogen storage disease occurs (eg., von Gierke's Disease).

• When blood glucose level rises after a mean, insulin is released and insulin-dependent glucose transport system is activated (GLUT4).

• The machinery of glycogen synthesis is activated.

Additional Readings:

Basic Biochemistry

1. Nucleic Acid Structure and Organization
2. DNA Replication and Repair
3. Transcription and RNA Processing
4. Genetic Code, Mutations, and Translation
5. Genetic Regulation
6. Recombinant DNA
7. Amino Acids, Proteins, Enzymes
8. Hormones
9. Vitamins
10. Energy Metabolism
11. Glycolysis and Pyruvate Dehydrogenase
12. Citric Acid Cycle and Oxidative Phosphorylation
13. Glycogen, Gluconeogenesis, and Hexose Monophosphate Shunt
14. Lipid Synthesis and Storage
15. Lipid Mobilization and Catabolism
16. Amino Acid Metabolism Disorders
17. Purine and Pyrimidine Metabolism
18. Electron Transport
19. Citric Acid Cycle and Glyoxylate Cycle
20. Glycolysis
21. Pyruvate Metabolism
22. Mitochondrial ATP formation
23. Gluconeogenesis
24. Glycogen Metabolism
25. Nitrogen Fixation (Metabolism) reactions, and Heme Metabolism
26. Amino Acid Metabolism
27. What is Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)?

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