Glycogen Metabolism Flashcards Preview

Week 8- SHANE > Glycogen Metabolism > Flashcards

Flashcards in Glycogen Metabolism Deck (51):
1

What is a primary reason for converting glucose to glycogen?

linking many glucose residues together reduces osmotic pressure in the cell

residues liked by a-1,4 and a-1,6

2

Where is glycogen primarily found?

liver and muscle

3

the glucose residue at the reducing end of glycogen is bound to what?

a protein called glucogenin

4

What advantage does the branching nature of glycogen offer?

Multiple rxns can be occurring at different points of the glycogen at the same time

5

What is the primary role of glycogenolysis in the liver?

glycogen is broken down to maintain BG levels

6

What is the primary role of glycogenolysis in skeletal muscle?

glycogen is broken down for ATP generation as needed (i.e. doesn't respond to the feed-fast cycle)- the only fate is glycolysis

7

What allows the liver to move broken down glycogen out of the cell to maintain BG?

the liver has glu-6-phosphatase to change glu-6-p into glucose (BG lowers about 2 hrs after a meal)

8

After 24 hrs, how do you get glucose?

glycogen stores are depleted, so the body uses gluconeogenesis

9

What are the intermediates from glucose to glycogen?

glucose -> glu-6-p -> glu-1-p -> glycogen

10

What converts glu-6-p to glu-1-p?

phosphoglucomutase

11

What is the first step from glu-1-p to glycogen?

UTP changes glu-1-p into uridine diphosphate glucose (UDP-glucose)

12

What are the steps of adding UDP-glucose to a growing glycogen chain?

1) glycogen synthase adds a glucose residue from the UDP-glucose (i.e. it takes glucose, leaving UDP) and adds it to the chain by a 1,4 linkage

2) when the branches of the glycogen get too big, Amylo-4,6-transferase (branching enzyme) moves a portion of a 1,4 branch and re-attaches it to another spot on the glycogen polymer by a 1,6 linkage (cleaves 1,4- generates 1,6)

13

What does glycogen synthase need to synthesize glycogen?

a primer

14

Where does glycogen synthase get a primer from?

glycogenin

15

How does glycogenin make a primer for de novo glycogen synthesis (using glycogen synthase)?

Glycogenin catalyzes the addition of the gluosyl residue from UDP-glucose to a tyrosine residue within the protein. Then glycogenic can extend the chain until its long enough to act as a primer

16

What is the first step in glucogenolysis?

glycogen phosphorylase successively removes glucosyl residues from the glycogen chain (one at a time) and releases them as glu-1-phosphates- break 1,4 linkages

this step is regulated

17

What does debranching enzyme do?

two actions/'activities': (note that it has both of the following activities- these are not alternative names of the enzyme)

1) 4:4 transferase activity:
can act as a 4:4 transferase (i.e. moves a 1,4 linked residue to another spot on the chain in a 1,4 manner

2) a-1,6-glucosidase activity:
completely breaks 1,6 bonds on terminal glucosyl resides on a branch and releases it as GLUCOSE not glu-1-p (important distinction!!)- remember, glycogen phosphorylase will remove sucessive glucosyl resides as GLU-1-P

18

Does glycogenesis and glycogenolysis occur at the same time ever within a cell?

No. the cell ensures that only one or the other is occurring

19

How long do BG levels stay elevated after a meal?

2 hrs. After this is reservoir is gone, liver will breakdown glycogen for energy (will muscle start to break down glycogen for use in the bloodstream?). What happens after the glycogen is gone?

20

Assuming that both liver and muscle have deb ranching enzymes with a-1,6-glucosidase activity, what stops glucose residues from leaving muscle cells once cleaved from glycogen?

Hexokinase has an extremely low Km (~0.1mM), so any 'free' glucose will be rapidly phosphorylated in the cell before intracellular glucose concentrations have a chance to rise enough to be transported out of the cell by facilitated movement (using GLUT)

21

Which organs have glu-6-phosphatase?

liver and kidney

22

Which of these three increase after a meal: glucagon, insulin, BG

BG and insulin. Note that although glucagon decreases, it never decreases a lot in relation to insulin. In fact, it never changes that much at all. It is the RATIO of insulin to glucagon that decides which pathway (glycogenesis or glycogenolysis) is occurring

23

Does the level of glucagon ever really vary that much in a cell in relation to how much insulin changes (say in the presence of high BG)?

No. again, it is the RATIO that determines what is happening at a given time in the cell.

24

If the insulin to glucagon ratio in the cell is low, what is happening, glycogenesis or glycogenolysis?

glycogenolysis

25

If the insulin to glucagon ratio in the cell is high, what is happening, glycogenesis or glycogenolysis?

glycogenesis

26

Dealing with glycogenolysis, when the insulin/glucagon ratio is low (aka when glucagon levels are high), how is the production of glucagon regulated?

phosphorylation of glycogen phosphorylase occurs and activates it (to degrade glycogen)

phosphorylation of glycogen syntheses also occurs (which INACTIVATES it) and leads to decreased synthesis

***They are phosphorylated by the same machinery at the same time!****

27

Does phosphoylation of glycogen phosphorylase and glycogen synthesase occur at the same time and by the same machinery?

Yes

28

Where are glucagon receptors present in the body?

only liver and kidney (another reason why muscle is affected by changes in BG levels)

29

How does glucagon activate PKA?

1) Gluagon binds to a GCPR receptor on the cell surface,

2) A G protein becomes bound to GTP upon ineraction with the GCPR and activates adenylyl cyclase which releases cAMP,

3) cAMP then attaches to the regulatory subunit of inactive PKA, activating it

30

What are the two roles of PKA in glucagon-mediated BG regulation?

1) it directly phosphorylates glycogen synthase, inactivating it

2) it phosphorylates a protein called phosphorylate kinase, which activates it. The activated phosphorylate kinase phosphorylates glycogen phosphorylase, activating it (and thus causing continued glycogen breakdown)

Thus, we are using PKA to both turn off production of glycogen and increase degradation.

31

What is the consequence of glycogen synthase and glycogen phosphorylase being regulated by the same enzyme (PKA)?

It ensures that glycogenesis and glycogenolysis never occur at the same time

32

Why doesn't muscle respond to BG level changes again?

Two reasons:

no glu-6-phosphatase and no glucagon receptors

33

What enzyme is responsible for turning back on the glycogen synthase that has been turned off by PKA (and also responsible for turning off glycogen phosphorylase that has been turned by PKA)?

Hepatic protein phosphatase I (hepatic pp-1)

34

How does hepatic protein phosphatase (hepatic pp-1) work?

it works to reverse the effects of PKA by de-phosphorylating the phosphorylated glycogen synthase (thus, reactivating it) and glycogen phosphorylase (thus, deactivating it)

35

When is hepatic pp-1 activated?

When the insulin/glucagon ratio begins to rise and/or is high.

It is activated directly by INSULIN

36

Would hepatic pp-1 be activate or inactive during a fasting state?

inactive.

(PKA would be active)

37

What kind of receptor does insulin have?

TKR (classic type that dimerizes upon ligand binding, has SH2 and SH3, etc)

38

Where is epinephrine secreted by?

the adrenal medulla

39

What two ways can epinephrine work in the liver?

1) stimulation through B adrenergic receptors that work identical to how glucagon works (i.e. binds to GCPR, activates G protein, cAMP release, PKA activation, etc).

2) stimulation through a receptors stimulates glycogenolysis in the liver by increasing Ca2+ levels

40

How does epinephrine interact with a receptors to stimulate glycogenolysis in the liver? Steps?

1) Epinephrine binds to a GCPR on the cell surface and activates a G protein

2) the activated G protein activates phospholipase C (which creates diacylglycerol (DAG) and IP3)

3) DAG (along with Ca2+--see below) activates PKC in the membrane, which can directly phosphorylate the glycogen synthase, inactivating it

4) IP3 binds to IP3 receptors in the ER membrane, stimulating the release of large amounts of Ca2+ in the cytoplasm

Ca2+ has two roles once released:
1) helps DAG activate PKC

2) binds to calmodulin, which in turn does two things:
A) can bind to phosphorylase kinase and activate it. The activated phosphorylase kinase can then phosphorylate either glycogen synthase (and deactivate it further) or glycogen phosphorylase (thus activating it)

B) can bind to calmodulin-dependent protein kinase which can then phosphorylate glycogen synthase, deactivating it

41

regulation of glycogen metabolism in skeletal muscle is solely dependent on what?

the availability of ATP (only degraded when ATP demand is high, and vice-versa)

42

What activates muscle glycogen phosphorylase?

AMP binding (high AMP means low ATP)

43

Describe GSD Type 1 (Von Gierke's Disease)

glc-6-phosphatase deficiency

increased glycogen in liver and kidneys
causes severe fasting hypoglycemia
primary organ affected: liver
glycogen still has a normal structure

44

Describe GSD Type 2 (Pompe's disease)

lysosomal a-1,4 glucosidase deficiency

causes accumulation of glycogen in lysosomes in heart, muscle, liver, etc.

causes cardiomegaly (usually before 1y/o)

45

Describe GSD Type 3 (Cori's disease)

debranching enzyme deficiency causing elevated glycogen levels in the liverand skeletal muscle

results in hypoglycemia

46

Describe GSD Type 4

branching enzyme deficiency leading to abnormally branched glycogen

effects seen mostly in liver and muscle

47

Describe GSD Type 5 (McArdle's disease)

muscle phosphorylase deficiency elading to reduced ability to degrade muscle glycogen

can't turn the muscle glycogen degrader on

48

Describe GSD Type 6 (Her's disease)

liver phosphorylase deficiency (thus can't turn glycogen phosphoylase to break down glycogen)

normal glycogen struture

49

Describe GSD Type 7

muscle PFK-1 deficiency

causes fatigue after exercise (only fatigue after exercise because muscle has mitochondria (FA oxidation) for normal circumstances but the lack of the ability to do glycolysis makes it difficult following exercise when ATP demands are higher

50

Describe GSD Type 9

affects liver phosphorylase kinase (causing the inability to turn on glycogen phosphorylase)

affects liver

51

Describe GSD Type 10

PKA (cAMP dependent) deficiency

affects liver. Why? signaling in the liver is primarily through the glucagon receptor (and the cAMP pathway). Muscle has nerve stimulation pathways (epinephrine, Ca2+ release, nerve stimulation, AMP stimulation) so it's not entirely dependent on PKA