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.
the overall reactions of metabolism)..
A. Amounts of liver and muscle glycogen
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
Note: glycogenin stays associated with & is found in center of completed glycogen molecule
- 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)
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
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
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
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
Note: regulation of glycogen synthesis & degradation is extremely complex, involving many enz’s (e.g., protein kinases & phosphatases), calcium, & enz inhibitors, among others
1. Regulation of glycogen synthesis & degradation in the well fed state:
Note: in liver, gluc also serves as an allosteric inhibitor of glycogen phosphorylase
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+
effects of intracellular calcium.
1. Activation of protein kinase:
Note: when cAMP removed, inactive tetramer R2C2, is again formed
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:
- 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.
Note: protein kinase C, a Ca2+ & phospholipid-dependent protein kinase, also phosphorylates glycogen synthase. Neither protein kinase A nor C directly phosphorylates glycogen phosphorylase
glycogen phosphorylase, glycogen synthase is inactive if phosphorylated.]