this chapter is about the synthesis and breakdown of glycogen in the liver and skeletal muscles. glycogen is a huge branched molecule which serves as a storage form for glucose. its role in the liver is to aid in regulating blood sugar levels by degradation of glycogen into free glucose, which can be used to replenish flagging blood glucose levels. in skeletal muscle, glycogen is broken down expressly for the purpose of supplying glucose 6-phosphate for anaerobic glycolysis when ATP demand is high.
glycogen itself is a large, highly branched polysaccharide made of repeating glucosyl units with alpha 1-4 bonds (elongating a given branch) and alpha 1-6 bonds (creating a new branch point). glycogen's synthesis mechanism is as follows:
1. glucose is phosphorylated to glucose 6-phosphate via glucokinase.
2. glucose 6-phosphate is isomerized to glucose 1-phosphate via phosphoglucomutase.
3. glucose 1-phosphate is activated by UTP into UDP glucose.
4. UDP glucose units are repeatedly added to a glycogen primer via glycogen synthase.
5. when a given branch is ~11 units (or "residues") long, a 6-8 residue piece is transferred via a transferase to another glucosyl unit with a alpha 1-6 bond, creating new branches.
glycogen breakdown is not the reverse of the synthesis pathway:
1. glycogen residues are phosphorylated by glycogen phosphorylase, forming molecules of glucose 1-phosphate (which can be isomerized to glucose 6-phosphate for use in glycolysis, etc)
2. when any given branch is shortened to 4 residues long, the glycogen phosphorylase can not remove any more due to steric hindrance.
3. the "debrancher" enzyme then transfers the last 3 residues to another branch, where they can be acted on by glycogen phosphorylase.
4. the last residue is hydrolyzed by alpha 1,6 glucosidase into a glucose molecule.
the regulation of glycogen synthesis and degradation is somewhat involved and is different in the liver and muscle due to the different uses of glycogen as mentioned above. in the liver, the primary factor that regulates glycogen synthesis/breakdown activity is the glucagon/insulin ratio in the blood, which reflects the liver's need to maintain blood sugar levels. in skeletal muscle the primary factor that regulates glycogen synthesis/degradation is AMP levels, which indicate relative ATP usage -- reflecting skeletal muscle's use of glycogen as a direct backup energy source for contraction. during times of stress, epinephrine is released and stimulates glycogen degradation in both liver and skeletal muscle.
the stimulation of glycogen synthesis by rising glucagon, AMP levels, or epinephrine levels occurs via an enzymatic cascade which begins with the synthesis of cAMP via adenylate cyclate. cAMP then activates protein kinase A, which phosphorylates two enzymes, glycogen synthase and phosphorylase kinase. glycogen synthase, which (as described above) synthesizes glycogen from glucose 6-phosphate, is inactivated by this phosphorylation whereas phosphorylase kinase, which begins the degradation pathway, is activated by the phosphorylation. thus, activated protein kinase A's net effect is to simultaneously shut down the synthesis of new glycogen as well as initiate glycogen breakdown. in the breakdown pathway: phosphorylase kinase activates glycogen phosphorylase, which then removes glycosyl residues from glycogen as described above.
protein kinase A's counterparts are the "protein phosphorylases" that removes the phosphates from glycogen synthase (thereby activating synthesis) and phosphorylase kinase (thereby deactivating breakdown). this stimulation of synthesis of glycogen can happen after a high carbohydrate meal, when glucose levels are high and need to be converted into glycogen for storage and lowering blood glucose levels. during a high carb meal, glucagon levels fall, and insulin levels rise -- it is thought that compared to glucagon, the level of insulin is more actively involved in the regulation of glycogen synthesis and breakdown although the exact mechanisms are not well understood. however, higher insulin levels are known to activate these protein phosphorylases, which inhibit the breakdown pathway and stimulate the synthesis pathway.
questions
1. what is the structure of glycogen?
2. describe the usage of glycogen in skeletal muscle vs. in the liver.
3. describe the synthesis pathway of glycogen.
4. what are the two enzymes involved in the breakdown of glycogen?
5. what are the two functions of the "debrancher" enzyme?
6. describe the mechanism for the breakdown of glycogen.
7. describe the three factors that regulate glycogen synthesis and breakdown in the liver.
8. describe the three factors that regulate glycogen synthesis and breakdown in skeletal muscle.
9. compare glycogenolysis and gluconeogenesis as means of replenishing blood glucose levels.
10. describe the role of phosphorylation states in the regulation of glycogen synthesis / regulation in the liver.
11. what is synergistic phosphorylation and how does it relate to glycogen degradation?
12. what is hepatic PP-1 and what does it do?
13. why is insulin considered the primary hormone that regulates glycogen synthesis / breakdown?
14. describe how glucose levels affect glycogen synthesis / breakdown.
15. describe epinephrine's actions on beta-receptors in the liver.
16. describe epinephrine's actions on alpha-receptors in the liver.
17. why is glucose 6-phosphate produced from glycogenolysis in skeletal muscle "committed" to the glycolytic pathway?
18. how does glucagon affect the regulation of skeletal muscle glycogen synthesis/degradation?
19. how does AMP affect the regulation of skeletal muscle glycogen synthesis/degradation?
20. contrast the intracellular Ca2+ production in the liver and skeletal muscle.
answers
1. glucosyl units linked by alpha 1-4 glycosidic bonds with alpha 1,6 branches every 8-10 residues.
2. in skeletal muscle, when ATP demands are high or when glucose 6-phosphate is used up by anaerobic glycolysis, glucose 6-phosphate can be replenished via glycogen breakdown in order to ultimately enter the glycolytic pathway. in the liver, glycogen breakdown produces glucose 6-phosphate, which is then converted to via glucose 6-phosphatase to glucose, which is then released into the blood.
3. glucose is converted to glucose 6-phosphate by hexokinases (or glucokinases in the liver). glucose 6-phosphate is converted to glucose 1-phosphate by phosphoglucomutase. glucose 1-phosphate is activated by UTP and converted to UDP-glucose, which can then be attached via glycogen synthase to a glycogen primer. when the chain of glycosyl is 11 residues long, amylotransferase transfers the chain back onto another glycogen branch in an alpha 1-4 bond-- this process happens repeatedly and creates a highly branched structure.
4. glycogen phosphorylase and the "debrancher enzyme"
5. it acts as a transferase and an alpha 1-6 glucosidase.
6. glycogen phosphorylase continually removes glucosyl residues by phosphorylating the terminal glycosidic bond, creating glucose 1-phosphate. however, due to steric hindrance, it can not free glucosyl residues that are closer than 4 units away from a branch point. the transferase portion of the debrancher enzyme transfers the end three residues onto another chain, where it can be acted on by the glycogen phosphorylase enzyme. the alpha-1,6 glucosidase portion of the debrancher enzyme then hydrolyzes the final glucosyl residue on the branch to glucose.
7. the liver's glycogenolytic activity is regulated by glucagon, insulin, and epinephrine levels: when fasting, glucagon is high and insulin is low, which stimulates glycogenolysis and inhibits glycogen synthesis. during a high carbohydrate meal, insulin levels are high and glucagon levels are low -- stimulating glycogen synthesis and inhibiting glycogen breakdown. during exercise, epinephrine stimulates glycogen breakdown and inhibits glycogen synthesis as well.
8. epinephrine, AMP, and Ca2+. higher levels of all three molecules signal the need for greater energy production, which stimulates glycogen degradation and inhibits glycogen synthesis.
9. while both are employed by the liver to replenish blood glucose levels, glycogenolysis is both faster and supplies more glucose.
10. glucagon and insulin regulate glycogen synthesis / breakdown via a mechanism involving phosphorylating the glycogen synthase and glycogen phosphorylase enzymes between inactive and active states. for example, during fasting, high glucagon stimulates phosphorylation of glycogen phosphorylase to the active form, beginning glycogen degradation, while also phosphorylating glycogen synthase to an inactive form, inhibiting glycogen synthesis.
11. the phosphorylation of glycogen synthase into the inactive form is much more complex than that of glycogen phosphorylase into the active form, in that it has up to 10 different phosphorylation sites. "synergistic phosphorylation" is the process by which glycogen synthase is inactivated, where phosphorylation of one site (by protein kinase A) changes the conformation of the enzyme and facilitates phosphorylation at the remaining sites. (analogous to oxygen binding to hemoglobin)
12. hepatic PP-1 is a protein phosphatase that works in opposition to the protein kinase A in that it removes the phosphates from phosphorylase kinase and glycogen phosphorylase (thereby inhibiting glycogen breakdown), and glycogen synthase (thereby stimulates glycogen synthesis).
13. because its levels change to a greater degree in response to changing blood sugar levels than glucagon.
14. high glucose levels inhibit glycogen breakdown almost immediately (faster than the effect of glucagon's cAMP and protein kinase A pathway, which takes 10-15 minutes). glucose stimulates protein phosphatases to remove the phosphates from glycogen synthase b and phosphorylase a, the net effect being inhibition of glycogen degradation.
15. when epinephrine binds to beta receptors in the liver, it stimulates adenylate cyclase to produce cAMP and activate protein kinase A in a similar fashion as glucagon.
16. when epinephrine binds to alpha receptors, it activates the PIP-Ca2+ signal transduction system which increases intracellular levels of Ca2+.
17. because skeletal muscle has no glucose 6-phosphatase to facilitate the conversion to glucose.
18. glucagon has no effect on skeletal muscle regulation of glycogen synthesis/degradation and therefore glycogen levels in skeletal muscle do not vary much depending on food intake.
19. AMP represents the usage of ATP and activates the muscle isozyme of glycogen phosphorylase.
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