Glycogen Metabolism Flashcards
What is glycogen
The storage form of glucose
Where is glycogen found
Liver and muscles
How is glycogen stored differently in the liver vs. the muscles?
Glycogen = stored in granules
- Muscles: glycogen is stored in beta granules
- Liver: beta granules combine to form alpha granules (10-15 beta granules)
Why is having glycogen beneficial to vertebrate organisms?
Some tissues (ex: brain) are in need of a constant supply of glucose. The compact structure of glycogen granules allows for glucose to easily be stored when there is excess and made available at a short notice.
Describe the structure of glycogen
- In the center there is a glycogenin homodimer surrounded by tiers of chains of about 13 glucose residues
- Inner B-chains contain two branch points
- Outer A-chains are unbranched (make up the majority of the granule)
- Reducing end: anomeric carbon (number 1 position)
- Non-reducing end (number 4 carbon)
What creates the branched structure of glycogen?
(α1→6) linkages
These linkages contribute to the branched structure of B chains
What linkages are responsible for conecting the A and B chains of glycogen?
(α1→4) linkages
What 3 enzymes are important for the breakdown of glycogen (glycogenolysis)?
- Glycogen phosphorylase
- Glycogen debranching enzyme
- Phosphoglucomutase
Describe the first step of glycogenolysis
Glycogen phosphorylase uses phosphate to convert glucose to glucose 1-phosphate breaking bonds between glucose residues at the (α1→4) linkage leaving behind another non-reducing end
When will glycogen phosphorylase stop?
When there are 4 glucose molecules left on the glycogen chain
Describe the regulation of glycogen phosphorylase
- 2 forms
- Phosphorylase B: dephosphorylated (inactive)
- Phosphorylase A: phosphorylated (active)
What is the role of phosphorylase kinase B
Regulates the activation of glycogen phosphorylase into its A form
What is the role of phosphoprotein phosphatase 1 (PP1)
Regulates the deactivation of glycogen phosphorylase into its B form
Describe the hormonal regulation of Phosphorylase B kinase
- Glucagon (liver) and epinephrin (muscle) act on GPCR’s located on the surface of the cell
- Once the receptor is activated GS-alpha subunit is activated
- GS-alpha subunit converts ATP into cyclic AMP thus raising the concentration
What role does cyclic AMP play in the hormonal regulation of phosphorylase B kinase
- Cyclic AMP activates protein kinase A which allosterically activates phosphorylase B kinase
- Phosphorylase kinase B activates glycogen phosphorylase into its A form (active)
- Glycogen breakdown is stimulated
The hormonal regulation of phosphorylase B kinase is an example of what?
Ań enzymatic cascade
Initiated by epinephrin or glucagon
Describe the allosteric regulation of glycogen phosphorylase by glucose
- Glycogen phosphorylase is a glucose sensor
- 2 allosteric sites separate from the active site will bind to glucose molecules at certain concentrations
- Glycogen phosphorylase undergoes a conformational change when glucose binds to its allosteric sites (serine residues stick out making it easier to remove phosphate groups)
- When blood glucose is low glucagon / epinephrin initiate cascade mechanism that activates glycogen phosphorylase to A form (glucose = released into the blood)
- When blood glucose is high glucose binds to inhibitory allosteric sites on glycogen phosphorylase A resulting in PP1 catalyzing the dephosphorylation of glycogen phosphorylase A into its inactive B form
Describe the second step of glycogenolysis
- The debranching enzyme (oligo (α1→6) to (α1→4) glucantransferase) catalyzes 2 successive reactions
- Transferase activity shifts three glucose residues from the branch of one chain to the nonreducing end of another chain (elongation)
- There is one single glucose residue remaining at the branch point
- The (α1→6) glucosidase activity of the debranching enzyme releases the remaining glucose residue
- The remaining unbranched (α1→4) polymer is now ready for further phosphorylation by glycogen phosphorylase
Describe the third step of glucogenolysis
Phosphoglucomutase converts glucose 1-phosphate to glucose 6-phosphate
What role does serine play in the third step of glucogenolysis?
- The serine residue located at the active site of phosphoglucomutase is what is initially phosphorylated
- The phosphate group is transferred from the number 1 position to the number 6 position leaving you with glucose 6-phosphate
How does the use of glucose 6-phosphate differ between the muscle and liver?
Muscle: glucose 6-phosphate enters glycolysis
Liver: glucose 6-phosphate enters the ER reticulum where it can be released into the bloodstream when blood glucose levels drop
Describe how glucose 6-phosphate is released into the blood stream by the liver when glucose levels drop
- Requires glucose 6-phosphatase (only present in the liver and kidney)
- Glucose 6-phosphatase = located on the endoplasmic reticulum with its active site on the lumen side of the ER
- Glucose 6-phosphate formed in the cytosol enters the ER lumen through G6P transporter (T1)
- In the lumen, the active site of glucose 6-phosphatase will remove the phosphate group from glucose
- Glucose is then transported from the lumen back into the cytosol (by transporters T2 and T3)
- Glucose can then enter the bloodstream via the plasma membrane transporter GLUT2
Describe glycogenesis by UDP glucose
- The generation of glycogen from individual glucose molecules requires UDP glucose (a sugar nucleotide)
- Anomeric carbon of the sugar is activated by attachment to a nucleotide through a phosphate ester linkage
- UDP glucose and other sugar nucleotides = important in glycogen synthesis and other carbohydrate derivatives (ex: monosaccharides, disaccharides etc)
Why is UDP glucose important?
- Easy to make (high -ΔG = irreversible pathway)
- Uracil has many groups that can undergo noncovalent interactions with enzymes; the free energy of binding can contribute to the catalytic activity of the enzyme
- Good leaving group (picks up / gives off glucose easily)
- Acts as a tag setting some hexoses with nucleotidyl groups aside for a particular purpose
Describe the formation of UDP glucose
- Generated by glucose 1-phosphate
- Start with uridine try-phosphate + glucose 1-phosphate
- Sugar enzyme will take up sugar via its phosphate group and make a phosphor-ester bond between two phosphate molecules
- The product = molecule of UDP glucose + molecule of pyrophosphate
- Pyrophosphate (2 phosphate groups) breaks down easily into other phosphate groups
- The breakdown of a pyrophosphate group into phosphate is what drives the reaction forward (large -ΔG)
What is the starting point for glycogen synthesis?
Glucose 6-phosphate
How is glucose 6-phosphate derived?
- Hexokinase I and II (muscle)
- Hexokinase IV (liver)
Glucose + ATP → glucose 6-phosphate + ADP
OR…
- Glucose = converted to lactate by glycolysis
- Lactate is taken up by the liver and converted to glucose 6-phosphate by gluconeogenesis
- Glucose 6-phosphate is converted to glucose 1-phosphate by phosphogluco-mutase
Glucose 6-phosphate ⇌ Glucose 1-phosphate
- Glucose 1-phosphate is converted to UDP-glucose by sugar enzyme
Glucose 1-phosphate + UTP → UDP-glucose + PPi
How does UDP glucose catalyze the addition of glucose to the non-reducing end of glycogen
- Catalyzed by glycogen synthase
- UDP glucose donates glucose residues which promotes the transfer of the glucose residue from UDP-glucose to a nonreducing end of a branched glycogen molecule forming an (α1→4) linkage (elongation)
Glycogen synthase CANNOT form branches
Describe glycogen synthase regulation
- 2 forms
- Phosphorylated: inactive (glycogen synthase B)
- Dephosphorylated: active (glycogen synthase A)
What is the role of GSK3 in glycogen synthase regulation?
GSK3 adds phosphoryl groups to three serine residues near the carboxyl terminus of glycogen synthase A converting it to its B form
GSK3 requires a primer
When can glycogen synthase B be activated without GSK3?
In the presence of its allosteric activator glucose 6-phosphate
What is the purpose of Casein Kinase II (CKII)?
- Primer
- Adds phosphate group to GSK3
GSK3 will then take over and add the three phosphate groups needed to inactivate glycogen synthase
Describe priming by casein kinase II (CKII)
- Long chain of serine residues that get phosphorylated or dephosphorylated
- First serine gets phosphorylated at the +4 position which is identified by casein kinase II
- Phosphorylation creates a negative patch on the glycogen synthase enzyme
- Negative patch is recognized by positive residues on GSK3 enzyme
- Following serine to get phosphorylated is at the number 0 position
- The result is a cascading effect the following serines to be phosphorylated are at the -4 and -8 positions
Describe the hormonal regulation of GSK3
- Hormonally regulated by glucagon and epinephrin
- Insulin converts glycogen synthase to its active form by blocking GSK3 activity and activating PP1
What makes the (α1→6) linkages found in glycogen?
Glycogen branching enzyme
Describe the branching of glycogen by the glycogen branching enzyme
- Acts on chain of glucose 11 monomers long
- Transfers 6 or 7 residues from the nonreducing end of glycogen branch sticking them onto the first glucose residue at a more interior position of the same glycogen chain thus creating a new branch
What is the biological effect of branching?
- Increase the number of nonreducing ends thus increasing the number of sites accessible to glycogen phosphorylase and glycogen synthase
Only act on nonreducing ends
How is the synthesis of a new glycogen molecule initiated?
- Glycogenin (homodimer)
- Glycogenin is both the primer for glycogen and the enzyme that catalyzes the assembly of new glycogen chains
Describe the synthesis of a new glycogen molecule
- Both monomers of glycogenin contain a tyrosine residue
- Glucose residue is transfered from UDP-glucose to the hydroxyl group of Tyr of glycogenin (2 step process pg. 2054)
- Glycogenin has the ability to add up to 8 glucose residues
- Once 8 residues have been added glycogen synthase will take over and extend the chain
What hormone favors the activation of glycogen synthase?
Insulin (lowers blood sugar)
Describe how insulin favors the activation of glycogen synthase
- Favors active form of glycogen synthase by blocking GSK3 activity (inhibits glycogen synthase by converting it to its inactive form)
- Activates PP1 (turns glycogen phosphorylase into its B form (no glycogen break down)
These two steps are required for activation of glycogen synthase
What hormone favors the deactivation of glycogen synthase?
Glucagon (raises blood sugar)
Does glucose 6-phosphate favor the active or inactive form of glycogen synthase?
- Active
- Binds to glycogen synthase promoting a conformation that is a good substrate for PP1
