2012-11-28 5&6: Glycogen; Reg. of Glycogen Metab.

Question 1

What type of linkage connect glucose molecules in the “branch” (i.e. “horizontal” components) of glycogen?

Answer 1

alpha-1,4 glycosidic linkages

Question 2

What type of linkage connects strands in glycogen together (i.e. vertical components)?

Answer 2

alpha-1,6 glycosidic linkages

Question 3

Which enzymes are needed to synth glycogen? Which is/are reg’d?

Answer 3

1) UDP-glucose pyrophosphorylase
2) glycogen synthase (REG’D)
3) branching enzyme

Question 4

Which enzymes are needed to degrade?

Answer 4

1) glycogen phosphorylase (REG’D)

2) debranching enzyme

Question 5

Why bother with glycogen?

Answer 5

allows glucose storage compactly and w/ little ∆ in intracellular osmolality (it’s just one big molecule)

Question 6

Why is glycogen branched?

Answer 6

branched to expose many non-reducing ends; therefore, many enzymes can “peel off” glucose molecules

Question 7

What form must glucose be in to be added to glyocogen? How does it get there?

Answer 7

Must be glucose-1-P

G-6-PG-1-P
**bi-directional

Question 8

If the non-reducing ends of glycogen branches are free to be “broken off” by glycogen phosphorylase, what is the “reducing end” attached to?

Answer 8

the protein, glycogenin (one per glycogen molecule); has short strand of glucosyl residues that will never be detached called the “limit dextran”

Question 9

What does UDP-glucose pyrophosphorylase do? Is it reversible?

Answer 9

—Gluc-1-Pi + UTP —UDP-glucose pyrophosphorylase—> Gluc-UDP (one P from G1P and one from UTP) + PPi

would be reversible except the PPi is rapidly degraded to 2Pi by pyrophosphatase

NOTE—This same enzyme makes the UDP-Glucose used in Galactose metabol.

Question 10

What does glycogen synthase do?

Answer 10

MAKES α(1,4) glycosidic linkages to add glucosyl residues to limit dextran

Question 11

What regulates glycogen synthase?

Answer 11

Inactivated when phosphorylated, so:

protein kinase—>inactivates
protein phosphatase—>activates

Question 12

What does branching enzyme do?

Answer 12

MAKES α(1,6) glycosidic linkages by peeling off 7 glucosyl residues and attaches them elsewhere to form a branch

—must leave at least 4 glucosyl residues between cut point and the beginning of limit dextran

—also must start the new branch at least 4 away from another strand due to steric hinderance of the enzyme

Question 13

How do you get glucose out of glycogen?

Answer 13

glycogen—glycogen phosphorylase—>G1P
—phosphorylates at the α(1,4) linkage
—the glucose released is P’ed so it cannot leave the cell in SKM b/c these cells lack glucose-6-phosphatase

Question 14

What regulates glycogen phosphorylase?

Answer 14

a) allosteric reg

b) phosphorylation and de-phos

Question 15

What vitamin co-factor does glycogen phosphorylase need?

Answer 15

b6 (pyridoxal phosphate)

Question 16

What does debranching enzyme do?

Answer 16

bi-functional:

a) after glyc. Pase removes all but last 4 glucosyl residues from the branch, debranching enzyme’s:

a) “Transferase” activity transfers 3 of those four to non-reducing end of the main branch (leaving one nub behind)
b) the nub is removed by de-branching’s α(1,6) glucosidase activity

Question 17

How does G1P get out of cell?

Answer 17

re-call, only happens in liver; SKM G1P is trapped and used to fuel contraction
—phosphoglucomutase converts G1P—>G6P
—G6P—G6Pase—>glucose (happens in lumen of ER)

Question 18

What is Von Gierke’s dz?

Answer 18

a.k.a. glycogen storage disease Type I = lack of G6Pase

Question 19

How is it possible to have a genetically inherited! Phosphorylase deficiency that affects muscle but does not affect liver?!

Answer 19

muscle and liver have diff isozymes

Question 20

What enzymes in glycogen metabolism are regulated?

Answer 20

glycogen phosphorylase

glycogen synthase

Question 21

What are the states of glycogen phosphorylase?

Answer 21

glycogen phosphorylase can be:
—[T]ense or [R]elaxed
——based on allosteric regulation
——[R] is more active
—"b" [un-P'ed] or "a" [P'ed]
——based on phosphorylation status
——"a" is more active

Question 22

How is glycogen phosphorylase allosterically regulated? (LOCATION SPECIFIC)

Answer 22

LIVER: glucose favors more active “R” state
(you don’t want to degrade glycogen when there’s plenty around)

MUSCLE: AMP allosterically activates the inactive “T” form into the active “R” form (ATP/G6P favor less ATP so favor T state)

Question 23

How does epinephrine/glucagon regulate glycogen metabolism?

Answer 23

i) activates adenylate cyclase—>incr cAMP—>activates PKA
ii) PKA P’s protein phosphatase’s reg subunit—>the 2 subunits dissociate making it less active
iii) PKA P’s inhibitor protein of PP which cause it to bind PP fully inactivating it

Now, PP, which normally activated glycogen phosphorylase and inhibited glycogen synthase can do neither

Question 24

How does glucose regulate glycogen metabolism in liver, specfically?

Answer 24

Big picture:
—glucose turns OFF glyc. phosphorylase
—turns ON glycogen synthase

Here’s how:

Normally, protein phosphatase (with its two subunits) is BOUND to glycogen phosphorylase

i) glucose binds to glycogen phosphorylase causing:
—a) ∆ to “T” state
—b) dissociation from protein phosphatase

ii)protein phosphatase is now free to:
—a) phosphorylate Glycogen phosphorylase: ∆ from “a”—> to less-active “b” form
—b) phosphorylate glycogen synthase: ∆ from “b” to more active “a”

Question 25

In the coordinate regulation of glycogen synthesis and degradation…

a. glucose allosterically activates glycogen phosphorylase a in both liver and muscle.
b. cAMP-dependent protein kinase activates glycogen synthase in both liver and muscle.
c. cAMP-dependent protein kinase activates glycogen phosphorylase in both liver and muscle.
d. protein phosphatase 1 activates glycogen phosphorylase and inactivates glycogen synthase.

Answer 25

C

Question 26

How does glucose regulate glycogen metabolism in liver, specfically?

Answer 26

In muscle:

AMP (i.e. NOT cAMP):
—allosterically activates phosphorylase b [i.e. ∆s T-state to R-state]

Ca2+:
—activates phosphorylase kinase (which will activate glycogen phosphorylase [i.e. ∆ forms b—>a] and increase glycogen breakdown)
—inhibits protein P’ase (which normally turns OFF glycogen synthase, so now it will be ON)