Glycogen metabolism. UNIT II: Intermediary Metabolism. Figure 11.1. Glycogen synthesis and degradation shown as a part of the essential reactions of energy metabolism (see Figure 8.2, p. 90, for a more detailed view of the overall reactions of metabolism). Overview.
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Figure 11.1. Glycogen synthesis and degradation shown as a part of the essential reactions of energy metabolism (see Figure 8.2, p. 90, for a more detailed view of
the overall reactions of metabolism)..
II. Structure and function of glycogen
A. Amounts of liver and muscle glycogen
Figure 10.2. Functions of muscle and liver glycogen.
B. Structure of glycogen
Figure 11.3. Branched structure of glycogen, showing a-1,4 and a-1,6 linkages.
C. Fluctuation of glycogen stores
Note: synthesis & degradation of glycogen are processes that go on continuously. Differences b/w rates of these 2 processes determine levels of stored glycogen during specific physiologic states
- Glycogen is synthesized from molecules of α-D-glucose. The process occurs in cytosol, and requires energy supplied by ATP (for phosphorylation of gluc) & uridine triphosphate (UTP)
A. Synthesis of UDP-glucose
Note: G-6-P is converted to G-1-P by phosphoglucomutase. G-1,6-BP is an obligatory intermediate in this reaction
Figure 11.4. The structure of UDP-glucose.
B. Synthesis of a primer to initiate glycogen synthesis
Note: glycogenin stays associated with & is found in center of completed glycogen molecule
Figure 11.5. Glycogen synthesis.
C. Elongation of glycogen chain by glycogen synthase
- Elongation of glycogen chain involves transfer of gluc from UDP-gluc to the non-reducing end of growing chain, forming a new glycosidic bond b/w the anomeric hydroxyl of C-1 of activated gluc & C-4 of accepting glucosyl residue
Note: “non-reducing end” of a CHO chain is one in which anomeric C of terminal sugar is linked by a glycosidic bond to another cpd, making terminal sugar “non-reducing”.
- The enz responsible for making α (1→4) linkages in glycogen is glycogen synthase
Note: UDP released when the new α (1→4) glycosidic bond is made can be converted back to UTP by nucleoside diphosphate kinase (UDP + ATP ↔ UTP + ADP)
Figure 11.6. Interconversion of glucose 6-phosphate and glucose 1-phosphate by phosphoglucomutase.
D. Formation of branches in glycogen
1. Synthesis of branches:
2. Synthesis of additional branches:
- After elongation of these two ends has been accomplished by glycogen synthase, their terminal 5 to 8 glucosyl residues can be removed & used to make further branches
A. Shortening of chains
Note: this enz contains a molecule of covalently bound pyridoxal phosphate that is required as a coenzyme
- Resulting structure is called a limit dextrin, & phosphorylase can’t degrade it any further
Cleavage of an α (1→ 4)-glycosidic bond.
B. Removal of branches
Note: both the transferase & glucosidase are domains of a single polyp molecule, the ‘debranching enzyme”.
- The glucosyl chain is now available for degradation by glycogen phosphorylase until 4 glucosyl units from next branch are reached
Glycogen degradation, showing some of the glycogen storage diseases. (Continued on
Figure 11.8 (Continued )
C. Conversion of G-1-P to G-6-P
Note: in muscle, G-6-P can’t be dephosphorylated because of a lack of glucose-6-phosphatase. Instead, it enters glycolysis, providing energy needed for muscle contraction
D. Lysosomal degradation of glycogen
Note: regulation of glycogen synthesis & degradation is extremely complex, involving many enz’s (e.g., protein kinases & phosphatases), calcium, & enz inhibitors, among others
A. Allosteric regulation of glycogen synthesis & degradation
1. Regulation of glycogen synthesis & degradation in the well fed state:
Note: in liver, gluc also serves as an allosteric inhibitor of glycogen phosphorylase
Figure 11.9. Allosteric regulation of glycogen synthesis and degradation in A. Liver, and B. Muscle.
2. Activation of glycogen degradation in muscle by calcium
Note: calmodulin is the most widely distributed of these proteins, & is present in virtually all cells
- Binding of 4 molecules of Ca2+ to calmodulin triggers conformational change such that activated Ca2+-calmodulin complex binds to & activates protein molecules, often enz’s, that are inactive in absence of this complex
Note: phosphorylase kinase is maximally active in exercising muscle when it is both phosphorylated & bound to Ca2+
Figure 11.10. Calmodulin mediates many
effects of intracellular calcium.
3. Activation of glycogen degradation in muscle by AMP
B. Activation of glycogen degradation by cAMP-directed pathway
1. Activation of protein kinase:
Note: when cAMP removed, inactive tetramer R2C2, is again formed
2. Activation of phosphorylase kinase:
Note: phosphorylated enz can be inactivated by hydrolytic removal of its P by protein phosphatase 1. This enz is activated by a kinase-mediated signal cascade initiated by insulin
3. Activation of glycogen phosphorylase:
-Phosphorylase a is converted to phosphorylase b by hydrolysis of its P by protein phosphatase 1.
-when gluc is bound to glycogen phosphorylase a, thus signaling that glycogen degradation is no longer required, the complex becomes a better substrate for protein phosphatase 1.
Figure 11.11. Stimulation and inhibition of glycogen degradation.
4. Summary of regulation of glycogen degradation:
C. Inhibition of glycogen synthesis by a cAMP-directed pathway
Note: protein kinase C, a Ca2+ & phospholipid-dependent protein kinase, also phosphorylates glycogen synthase. Neither protein kinase A nor C directly phosphorylates glycogen phosphorylase
- Binding of glucagon or epinephrine to hepatocyte receptors, or of epinephrine to muscle cell receptors, results in the activation of adenylyl cyclase, mediated by G-protein
Figure 11.12. Hormonal regulation of glycogen synthesis. [Note: In contrast to
glycogen phosphorylase, glycogen synthase is inactive if phosphorylated.]
VI. Glycogen storage diseases
Figure 11.13. Key concept map for glycogen metabolism in liver.