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Biochem > Glycogen Metabolism > Flashcards

Glycogen Metabolism Flashcards

1
Q

What is glycogen

A

The storage form of glucose

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2
Q

Where is glycogen found

A

Liver and muscles

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3
Q

How is glycogen stored differently in the liver vs. the muscles?

A

Glycogen = stored in granules
- Muscles: glycogen is stored in beta granules
- Liver: beta granules combine to form alpha granules (10-15 beta granules)

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4
Q

Why is having glycogen beneficial to vertebrate organisms?

A

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.

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5
Q

Describe the structure of glycogen

A
  • 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)
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6
Q

What creates the branched structure of glycogen?

A

(α1→6) linkages
These linkages contribute to the branched structure of B chains

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7
Q

What linkages are responsible for conecting the A and B chains of glycogen?

A

(α1→4) linkages

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8
Q

What 3 enzymes are important for the breakdown of glycogen (glycogenolysis)?

A
  1. Glycogen phosphorylase
  2. Glycogen debranching enzyme
  3. Phosphoglucomutase
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9
Q

Describe the first step of glycogenolysis

A

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

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10
Q

When will glycogen phosphorylase stop?

A

When there are 4 glucose molecules left on the glycogen chain

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11
Q

Describe the regulation of glycogen phosphorylase

A
  • 2 forms
  • Phosphorylase B: dephosphorylated (inactive)
  • Phosphorylase A: phosphorylated (active)
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12
Q

What is the role of phosphorylase kinase B

A

Regulates the activation of glycogen phosphorylase into its A form

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13
Q

What is the role of phosphoprotein phosphatase 1 (PP1)

A

Regulates the deactivation of glycogen phosphorylase into its B form

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14
Q

Describe the hormonal regulation of Phosphorylase B kinase

A
  • 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
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15
Q

What role does cyclic AMP play in the hormonal regulation of phosphorylase B kinase

A
  • 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
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16
Q

The hormonal regulation of phosphorylase B kinase is an example of what?

A

Ań enzymatic cascade
Initiated by epinephrin or glucagon

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17
Q

Describe the allosteric regulation of glycogen phosphorylase by glucose

A
  • 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
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18
Q

Describe the second step of glycogenolysis

A
  • 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
19
Q

Describe the third step of glucogenolysis

A

Phosphoglucomutase converts glucose 1-phosphate to glucose 6-phosphate

20
Q

What role does serine play in the third step of glucogenolysis?

A
  • 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
21
Q

How does the use of glucose 6-phosphate differ between the muscle and liver?

A

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

22
Q

Describe how glucose 6-phosphate is released into the blood stream by the liver when glucose levels drop

A
  • 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
23
Q

Describe glycogenesis by UDP glucose

A
  • 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)
24
Q

Why is UDP glucose important?

A
  • 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
25
Q

Describe the formation of UDP glucose

A
  • 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)
26
Q

What is the starting point for glycogen synthesis?

A

Glucose 6-phosphate

27
Q

How is glucose 6-phosphate derived?

A
  • 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

28
Q

How does UDP glucose catalyze the addition of glucose to the non-reducing end of glycogen

A
  • 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
29
Q

Describe glycogen synthase regulation

A
  • 2 forms
  • Phosphorylated: inactive (glycogen synthase B)
  • Dephosphorylated: active (glycogen synthase A)
30
Q

What is the role of GSK3 in glycogen synthase regulation?

A

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

31
Q

When can glycogen synthase B be activated without GSK3?

A

In the presence of its allosteric activator glucose 6-phosphate

32
Q

What is the purpose of Casein Kinase II (CKII)?

A
  • Primer
  • Adds phosphate group to GSK3
    GSK3 will then take over and add the three phosphate groups needed to inactivate glycogen synthase
33
Q

Describe priming by casein kinase II (CKII)

A
  • 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
34
Q

Describe the hormonal regulation of GSK3

A
  • Hormonally regulated by glucagon and epinephrin
  • Insulin converts glycogen synthase to its active form by blocking GSK3 activity and activating PP1
35
Q

What makes the (α1→6) linkages found in glycogen?

A

Glycogen branching enzyme

36
Q

Describe the branching of glycogen by the glycogen branching enzyme

A
  • 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
37
Q

What is the biological effect of branching?

A
  • Increase the number of nonreducing ends thus increasing the number of sites accessible to glycogen phosphorylase and glycogen synthase
    Only act on nonreducing ends
38
Q

How is the synthesis of a new glycogen molecule initiated?

A
  • Glycogenin (homodimer)
  • Glycogenin is both the primer for glycogen and the enzyme that catalyzes the assembly of new glycogen chains
39
Q

Describe the synthesis of a new glycogen molecule

A
  • 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
40
Q

What hormone favors the activation of glycogen synthase?

A

Insulin (lowers blood sugar)

41
Q

Describe how insulin favors the activation of glycogen synthase

A
  • 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
42
Q

What hormone favors the deactivation of glycogen synthase?

A

Glucagon (raises blood sugar)

43
Q

Does glucose 6-phosphate favor the active or inactive form of glycogen synthase?

A
  • Active
  • Binds to glycogen synthase promoting a conformation that is a good substrate for PP1

Biochem (22 decks)

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