Glycogen Degradation

Question 1

• Understand the structure of glycogen and why relative to stored fatty acids, glucose is the more versatile energy source

Answer 1

Glycogen- highly branched homopolymer of glucose present in all tissues. (contain alpha 1,4 linkages and at every 12th residue, alpha, 1,6 linkages)
compared to FA’s, glucose released from glycogen is readily mobilized and a good source of energy for strenuous activity, supplies energy for anerobic activity (absence of O2) and maintains blood glucose [ ] between meals, supplies brain with glucose.

Question 2

*Consider the distinction between muscle and liver in terms of glycogen synthesis and degradation (energy needs of each organ) .

Answer 2

a

Question 3

*Understand what the enzymes; glycogen phosphorylase, transferase and alpha- 1, 6 glucosidase do.

Answer 3

a

Question 4

• Know what organ and know why this organ has the enzyme, glucose 6-phosphatase.
  What makes this enzyme unique?

Answer 4

LIVER has glucose-6- phosphatase, which is an enzyme that generates FREE GLUCOSE from glucose 6-phosphate.
The free glucose is released into blood for use by other tissues such as brain and red blood cells.
Glucose6-phosphatase is ABSENT in most other tissues (unique)
(glucose 6-phosphate uses H2O to form free glucose).

Question 5

*Understand the regulation of glycogen phosphorylase in liver vs muscle.

Answer 5

Liver glycogen phosphorylase- default state is A form (insensitive to AMP). Normally in R state
Allosterically regulated by glucose, as binding phosphorylase to glucose, will convert R to T state
Muscle glycogen phosphorylase- default state is B form (normally in T state) . muscle uses glucose especially during exercise.

Question 6

Where are the largest stores of glycogen in the cells?

Answer 6

in liver and skeletal muscle.

Question 7

How are glycogen stores utilized in liver compared to muscle cells?

Answer 7

The LIVER breaks down glycogen and releases glucose to blood to provide energy for brain and red blood cells during nocturnal fasts
MUSCLE glycogen stores are mobilized to provide energy for muscle contraction (selfish)

Question 8

Describe the different parts of glycogen granule or molecule. What process takes place at the core of glycogen?

Answer 8

The glycogen molecule has nonreducing ends that form surface of glycogen;
Core of glycogen molecule is the protein glycogenin, which is the site where glycogen degradation takes place.

Question 9

What makes the alpha 1,6 bonds special in glycogen?

Answer 9

alpha 1,6 glycosidic bonds cannot be cleaved by glycogen.

Question 10

What enzyme converts Glucose-1-phosphate into glucose-6-phosphate?
What intermediate is used to get product (G-6P)?

Answer 10

PHOSPHOGLUCOMUTASE. This enzyme will use 1,6 bisphosphate intermediate to convert G-1P to G-6P

Question 11

How does glycogen phosphorylase help produce glucose 1-phosphate? What makes this reaction energetically advantageous?

Answer 11

Glycogen phosphorylase degrades glycogen form nonreducing ends of glycogen molecule.
phosphorylase will catalyze phosphorolysis reactions that yields glucose-1-phosphate.
Reaction energetically advantageous, because released sugar is already phosphorylated, do not need to use ATP for phosphorylation.
Also, in muscles, there are no transporters that exist for glucose-1-phosphate.

Question 12

what are the three enzymes that are required for enzyme breakdown?

Answer 12

1. Glycogen phosphorylase- cannot cleave near branch points and can only cleave alpha 1,4 glycosidic bonds
2. Transferase- shifts a small oligosaccharide near the branch point to a nearby chain, making glucose moieties accessible to phosphorylase.
3. Debranching enzyme (alpha-1,6 glucosidase)- then cleaves the alpha-1,6 bond at branch point, releasing a free glucose.
   free glucose then phosphorylated by hexokinase to produce glucose-6-phosphate.

Question 13

Which of the three enzymes in glycogen breakdown are Michaelis Menten?

Answer 13

Transferase and glucosidase are michaelis menten enzymes.

Question 14

What is liver’s main role regarding glucose?

Answer 14

Liver’s role is to maintain a nearly constant concentration of glucose in the blood.

Question 15

What is the key regulatory enzyme for glycogen degradation? How many forms exist of this enzyme and how do they differ? What kind of equilibrium state does each form favored (relaxed or tense state)

Answer 15

The key regulatory enzyme is GLYCOGEN PHOSPHORYLASE.
The phosphorylase exists in two forms, a LESS active form B and MORE Active form a.
A form - a serine reside is phosphorylated.
B form- no phosphorylated serine form.
Both a and b form display R T equilibrium (T- relaxed T- tense)
In A form, the R (relaxed) state is favored
In B form, the T (Tense) state is favored.

Question 16

What is the equilibrium state for Liver Phosphorylase?

What is a negative regulator of liver phosphorylase and why?

Answer 16

Liver phosphorylase is in the A form (phosphorylated serine) in R state.
Liver phosphorylase is prepared to generate blood glucose unless signaled otherwise.
GLUCOSE is a negative regulator of liver phosphorylase, that will lead to transition of R state to T state.
If there are high levels of glucose, the phosphorylase enzyme will shut down.

Question 17

Differentiate between the T and R state structurally. Also describe the difference in phosphorylation level in liver and muscle.

Answer 17

In the T state, the active site is partly BLOCKED by regulatory structure.
In R state- active site NOT obstructed.
In liver, there is LARGE phosphorylation, occurs most of the time.
In the muscle, there is NO phosphorylation until hormone induces signal transduction.

Question 18

Differentiate between the T and R state structurally. Also describe the difference in phosphorylation level in liver and muscle. Which state is more active?

Answer 18

In the T state, the active site is partly BLOCKED by regulatory structure.
In R state- active site NOT obstructed.
In liver, there is LARGE phosphorylation, occurs most of the time.
In the muscle, there is NO phosphorylation until hormone induces signal transduction.
The R state is more active.

Question 19

What is the default form of phosphorylase in muscle? What is equilibrium state is muscle usually in? What must occur before muscle switches to R state?
What are the two things its phosphorylase is stabilized by?

Answer 19

In muscle, default form is phosphorylase B, in T state.
When energy change is needed, signaled by increase in concentration of AMP, the phosphorylase will bind AMP and stabilize R state.
The T state of phosphorylase b is stabilized by ATP and Glucose-6-phosphate.

Question 20

Describe phosphorylase a in terms of activation. What pushes its activation? What factors is this phosphorylase a not sensitive to?
compare this level of activation and phosphorylation to phosphorylase b? What makes it switch from b to a?

Answer 20

Phosphorylase A is fully active.
Phosphorylation pushes it to be fully active.
It is not sensitive to AMP, ATP, and glucose-6-phosphate (seen in LIVER)
Phosphorylase B is mostly INACTIVE and NOT phosphorylated (in MUSCLE).
The AMP levels push it to R state, as increasing energy demands will activate signal transductions pathways to phosphorylate b and allow it to become a.

Question 21

What happens to equilibrium state when there is a lot of ATP? a lot of AMP?

Answer 21

A lot of ATP, the more favored form is T state.

A lot of AMP, more favored form is R state

Question 22

What process converts the promotion of Phosphorylase b to phosphorylase a? How does a form differ from b.
What hormones stimulate phosphorylation and what is the result of phosphorylation.

Answer 22

PHOSPHORYLATION promotes conversion of phosphorylase b to a.
A form- Serine residue 14 is phosphorylated.
B form- not phosphorylated.
Phosphorylation is stimulated by hormones GLUCAGON and EPINEPHRINE (adrenaline)
Phosphorylation alters the active site such that Alpha-helices that partly block the active site in b, are removed.

Question 23

What enzyme is responsible for converting glycogen phosphorylation from unphosphorylated b form to a form?
How is this enzyme activated? How is Phosphorylase kinase activated and when is it most active?

Answer 23

PHOSPHORLASE KINASE - enzyme that converts Glycogen phosphorylase from b form (unphosphorylated) to a form
This enzyme is activated by both PHOSPHORYLATION and CALCIUM binding.
Phosphorylase kinase is phosphorylated by PROTEIN KINASE A.
The Delta subunit of phosphorylase kinase is the calcium sensor CALMODULIN.
Phosphorylase kinase is most active when phosphorylated and bound to calcium.

Question 24

Differentiate between the three muscle fiber types and what processes are used for gaining ATP.

Answer 24

Muscles are composed of several muscle fiber types:

• Type I- SLOW twitch fibers rely primarily on Cellular Respiration, as means of getting ATP
• Type II b (type IIx) or FAST twitch fibers rely permanently on LACTIC ACID fermentation for ATP generation. Type II b fibers are rich in GLYCOGEN PHOSPHORYLASE
• Type II a fibers- have biochemical characteristics intermediate between other fiber types.

Question 25

Describe the kind of physical activity that each of the muscle fibers are used for.

Answer 25

Type I- slow twitch used for ENDURANCE, using fatty acids/CAC and glycogen phosphorylase (low in glycogen, high in fatigue resistance, TAG and citrate synthase)
Type II b: Fast twitch like a SPRINT, where glycogen is needed and glycolysis occurs. (low in fatigue resistance, citrate synthase and TAG; high in glycogen)
Type II a: intermediate (appears to be trainable depending (oxidative/glycolytic)

Question 26

what occurs in Hers disease?

Answer 26

Hers disease- results from deficiency in liver isozyme of glycogen phosphorylase
This causes glycogen accumulation in liver (hepatomegaly) results and hypoglycemia (both manifestations are due to inability to mobilize glycogen)

Question 27

What are the three mechanisms where glycogen breakdown degradation can be turned off?

Answer 27

Glycogen degradation can be turned off:
As all HORMONE LEVELS DECREASE
1. The inherent GTPASE activity of G-protein will render proteins inactive
2. Phosphodiesterase converts cAMP into AMP, which does NOT stimulate protein kinase A.
3. Protein phosphatase 1 (PP1) removes phosphoryl groups from phosphorylase kinase and glycogen phosphorylase, and inactivates the enzymes.

Question 28

What structures transmit the signal for initiation of glycogen breakdown?

Answer 28

G proteins transmit signal for initiating glycogen breakdown.

Question 29

Which two hormones initiate G protein cascade and what is the result of this?
How is calcium released in liver vs muscle?
How are the products of these processes eventually convert glycogen phosphorylase b to a form?

Answer 29

GLUCAGON (in liver) and EPINEPHRINE (in muscle) initiate G-protein cascades. This cascade results in the production of cAMP.
Calcium is released in muscle, to stimulate contraction, and this calcium initiates the activation of phosphorylase kinase.
In liver, Calcium release is stimulated by epinephrine binding to alpha-adrenergic receptor, which will activate G protein and instigate PHOSPHOINOSITIDE CASCADE.
Cyclic AMP activates PROTEIN KINASE A, which phosphorylates and completes activation of phosphorylase kinase. phosphorylase kinase then converts glycogen phosphorylase b to a form (activate glycogen breakdown)

Question 30

How can epinephrine ultimately release Calcium?

Answer 30

Epinephrine (from muscle) can bind to alpha-adrenergic receptors and initiate phosphoinositide pathway, and release Calcium.