Glycogen Flashcards
If there is lots of energy available under the form of ATP and lots of glucose had been consumed. What is converted to make glycogen?
G6P (glucose-6-phosphate)
Excess glucose is stored under the form of _______ in the ______ and _______.
glycogen
muscles
liver
Other than being converted to glycogen, what other routes can glucose go through?
Glycolyis
Pentose-phosphate pathway
The emergency stock of glycogen is only sufficient for ___-___ hours.
20-24 hours
If glycogen stores are exhausted, what mechanism can be used to generate more glucose?
Neoglucogenesis
What is neoglucogenesis?
generation of glucose from non-carbohydrate sources: proteins, fats.
Plants store excess glucose as ______, humans store excess glucose as _______.
starch
glycogen
What are the links between glucose molecules in glycogen. What are the links between branches?
Links between glucose = alpha(1-4) glycoside links.
Branches = alpha(1-6) glycoside links
Starch has _____ branches than glycogen.
fewer
What is the only difference between starch and glycogen?
The amount of branching
How is cellulose different from glycogen and starch.
Beta links rather than alpha links.
This is the reason we cannot digest cellulose.
Undigested cellulose is ________.
Cellulose is a major component of the plant ____ _____.
fibre
cell wall
What are the reasons we store glucose as glycogen rather than just glucose?
If we were to store energy in the free glucose form, we would reach over 400mM (or 0.4M) and over 0.5M in the liver and muscle cells. This would cause hyperosmolarity and lead to cell lysis.
When stored under the form of glycogen, the heavy branching allows for the molecule to achieve a very high molecular weight and thus barely affect osmolarity (10nM).
Molarity is based on the number of particles. Glucose would be 1 000 000+, glycogen just 1.
What are the two purposes for storage of glycogen in the muscles and liver?
1 - In the muscles, glycogen is stored for emergency purposes when exercising and blood glucose is not sufficient.
2 - Live glycogen is used to maintain blood glucose around the body.
Why do we store emergency fuel under the form of glycogen instead of fat?
1 - Glycogen can be rapidly converted to glucose
2- During an emergency, we use glycolysis and lactic acid fermentation to generate energy anaerobically. However, fat cannot be catabolized aneorabically, glycogen can.
3 - Animals cannot convert fatty acids to glucose.
- glycogen is the only substances that can be converted to glucose to maintain blood glucose.
- fat cannot maintain blood glucose
4 - Large amounts of glucose can be stored under the form of glycogen without affecting the osmolarity of cells
- cells wont burst
What is the most important reason for extensive branching in glycogen?
So that multiple glycogen phosphorylases can act at several non-reducing ends of glycogen chains to generate large amounts of G1P for glycolysis or, to release glucose in the blood very quickly.
Every branch that is created in glycogen will have a ________ end tail.
non-reducing
What is a non-reducing end?
Cannot be oxidized.
Why can’t a non-reducing end be oxidized?
In the non-reducing end, carbon with H and OH is not near the oxygen, harder to get rid of Hydrogen.
In the reducing end, H-OH present near oxygen, easier to get rid of hydrogen.
What are the advantages of multiple branches?
1 - Increased solubility
- more branching means more soluble
- when fully solvated, not recognized by immunity as foreign
2 - More branching allows more glycogen phosphorylases to function simultaneously
What 3 enzymes participate in glycogen breakdown?
1 - Glycogen phosphorylase
2 - Debranching enzyme
3 - Phosphoglucomutase
Describe glycogen phosphorylase.
Produces glycogen and G1P. Works at reducing ends, stops at branches. Two forms: Phosphorylase a Phosphorylse b. Dimer of two identical subunits. Co-factor = PLP
Where does glycogen phosphorylse get phosphorylated? Can it be active without phosphorylation?
Phosphorylated at serine-14 to become phosphorylase b, super-active.
Can be slightly active by presence of AMP.
What are the inhibitors of glycogen phosphorylase. Activators?
Activators: AMP (dominant allosteric activator)
Inhibitors: ATP, G6P, glucose
Serine-14 is located at which terminus?
Amino
What is the co-factor for glycogen phosphorylase.
PLP - vitamin B6
What does the amino terminal domain contain in glycogen phosphorylase?
Interface subdomain - contains serine 14 and allosteric effector site
Glycogen binding subdomain
- glycogen binding/storage site
What is an effector?
Both an inhibitor and activator
What is the key player in PLP?
Phosphate
Describe 1,5-gluconolactone. What evidence does it provide?
Imitates the same structure as the oxonium intermediate.
It binds to the active site of glycogen phosphorylase but inhibits the reaction.
Provides evidence for oxonium ion and SN1 reaction in the glycogen phosphorylase mechanism.
The glycogen phoshorylase mechanism is an SN_ mechanism.
1
How is G1P converted to G6P?
Phosphoglucomutase.
Describe the transient labelling of phosphoglucomutase.
Take G1P during glycogen breakdown and add radiolabeled phosphate.
Enzyme gets labeled until it exchanges its phosphate for a new G1P.
Only labeled transiently.
What are the two activities of glycogen debranching enzyme?
1 - a(1-4) transglycosidase or glycosyltransferase
- transfers an alpha(1-4)-linked trisaccharide unit from the limit branch to the non-reducing end of another branch
2 - a(1-6)glucosidase activity
- hydrolyses the remaining glucose of the branch linked by a alpha(1-6) link to the main chain, releasing free glucose instead of G1P
Approximately how much glucose from glycogen is pure glucose and not G1P?
10%
Glcyogen synthesis is achieved by what three enzymes?
1 - UDP-glucose phosphorylase
2 - Glycogen synthase
3 - Branching enzyme
Glycogen metabolism is regulated both by different _________ present in the cells as well as by _______ through signal transduction cascades.
metabolites
hormones
What two enzymes are regulated to afford control in glycogen metabolism?
Glycogen phosphorylase
Glycogen synthase
How are glycogen phosphorylase and glycogen synthase controlled?
1 - Increase or decrease amount of substrate/product
2 - Allosteric activators or inhibitors
3 - Phoshorylation
Glycogen is broken down by _________ _______ to make ____. This is then converted to _____ to go into glycolysis. Both the _________ enzyme and _________ _______ are necessary.
From G1P, through ____, glucose loaded onto ________ and pyrophosphate comes out.
This last step is accomplished by UDP-glucose __________.
UDP-glucose taken as substrate by ______ _____ which adds it to glycogen chain with UDP coming out.
glycogen phosphorylase; G1P G6P branching enzyme; phosphoglucose mutase UDP; UDP Phosphorylase glycogen synthase
Glycogen phosphorylase is activated by what?
Allosterically activated by AMP and by phosphorylation.
Glycogen phosphorylase is inactivated/inhibited by what?
Removal of phosphate, ATP, (glucose), G6P
What are the different forms for glycogen phosphorylase?
a, b, T
T is inactive
a is super active (phosphorylated)
b is less active (AMP)
Why is the phosphorylated form independent of the activity of the allosteric activators/inhibitors?
During an emergency, the enzyme should not be inhibited by what is already present/lacking, we want to create more ATP and G6P to run away and thus inhibition would make no sense.
The phosphorylation of glycogen phosphorylase only occurs on the ______ enzyme.
inactive
Why does phosphorylation of glycogen phosphorylase only occur to the inactive enzyme?
This is because we already have active enzyme to produce G6P as needed, we want to further amplify that response so, focus on inactive pool to make superactive.
What is another term to describe phosphorylation?
Covalent modification
Glycogen phosphorylsae is controlled by mane enzymes, these are?
1 - Phosphorylase kinase
2 - cAMP-dependent protein kinase (PKA)
3 - PP1 (phosphoprotein phosphatase 1)
How does phosphorylase kinase get super-activated?
Glycogen phosphorylase?
What is the purpose of PP1?
PKA phosphorylates phosphorylase kinase (when cAMP increases during emergency) to get superactivated.
phosphorylase kinase phosphorylates glycogen phosphorylase to get super activated.
PP1 removes the phosphorylations post-emergency to inactivate these enzymes.
PP1 removes phosphates from multiple enzymes including: _______ _______, ________ ________ and ________ _______.
phosphorylase kinase
glycogen phosphorylase
glycogen synthase
cAMP is a ________-messenger.
second
Describe PKA’s structure.
Two regulatory subunits and two catalytic units.
When bound, catalytic units are off.
How does cAMP activate PKA?
4 cAMP bind to the two regulatory units to cause them to release the catalytic units, now active.
Describe the structure of phosphorylase kinase.
Has four subunits, alpha, beta, delta, gamma.
Gamma unit has the active site.
Alpha and beta have phosphorylation sites.
delta is calmodulin, binds to calcium
How does calcium factor into activation of phosphorylase kinase?
Calcium can activate phosphorylase kinase on its own if its of sufficient concentration (mM).
However, if phosphorylated, the amount of calcium needed is drastically reduced (uM concentrations of calcium)
In most cells, calcium is not sufficiently abundant. In some cells, like muscles, there is.
Calcium binding changes the conformation of the enzyme to make it more active. Phosphorylation also changes the conformation.
Calcium will bind to the the delta subunit of phosphorylase kinase, a calmodulin-like protein. This will cause it to relieve inhibition of the gamma subunit, active site.
What enzymes converts ATP to cAMP?
Adnylate cyclase
After the emergency is done, what happens to cAMP?
Cyclic nucleotide phosphodiesterase breaks cAMP to AMP, bringing levels back down to normal.
What are inhibitors of cyclic nucleotide phosphodiesterase?
Caffeine, theophylline
How does adnylate cyclase get activated?
Epinephrine activates it indirectly.
Epinephrine will bind to a hormone receptor (transmembrane, serpentine receptor).
This receptor is bound to a G-protein that, once epinephrine is bound to the receptor will cause the Gs unit to dissociate from the beta and gamma units.
Gs unit moves to adnylate cyclase and activates it.
Describe the amplification of the signal?
From a tiny amount of epineprhine, during an emergency, we release millions of glucose molecules.
What is the advantage of having multiple control points in this signal transduction pathway?
Signal amplification. Only need a tiny amount of hormone/neurotransmitter.
How can PP1 be covalently modified?
Phosphorylation on the top of its G-unit by insulin-dependent protein kinase. (superactivated)
Phosphorylation on the bottom of the G-unit by PKA. (dominant, inactivating response)
Describe a situation in which PP1 would be phosphorylated on the top and bottom, what occurs?
Just ate so blood glucose is high, insulin secreted leading to insulin-dependent protein kinase phosphorylating PP1 on the top.
Suddenly, a tiger jumps in the room, emergency, need to run. Epineprhine released leading to PKA phosphorylation of PP1 on the bottom, inactivating it. This is the dominant response.
What are the substrates of PKA?
Phosphorylase kinase - activates it
PP1 inhibitor - activates it (can be considered phosphorylation of PP1 on the bottom)
Bottom part of PP1 Gm subunit - inactivates it
Glycogen synthase - inactivates it
What is the general purpose of PKA?
Purpose of PKA is to block glycogen synthesis and promote its catabolism.
What are the substrates of PP1?
Glycogen synthase - activates it
Phosphorylase kinase - inactivates it
Glycogen phosphorylase - inactivates it
PP1 inhibitor - inactivates it
Insulin stimulates the __________ system.
dephosphorylation
What phosphorylates glycogen synthase?
PKA, phosphorylase kinase, other kinases
When is glycogen synthase active?
when insulin is present, PP1 is active, removes the phosphate and activates it.
What is an emergency we face everyday?
Low blood glucose
What is the hormone secreted to face low blood glucose?
Glucagon
Describe glucagon.
Opposite to insulin
Acts on liver cells to make sure glycogen is degrade to glucose to maintain blood glucose.
What is similar between epinephrine and glucagon, what is different?
Epinephrine is only released during emergencies, glucagon is secreted when blood glucose is low.
Epinephrine has alpha and beta receptors.
Glucagon uses the same beta receptor as epinephrine so, the signal transduction cascade is the exact same from there on.
What is the purpose of the alpha receptor of epinephrine?
Cause release of calcium as a fail-safe to force activation of phosphorylase kinase.
What is the purpose of the beta receptor of epinephrine?
initiate the signal transduction cascade including the G-protein receptor downwards.
In an emergency, the liver ______.
In an emergency, the muscles ______.
Increase blood glucose
Make you run
Phosphate is removed in the liver for maintenance of blood glucose, why?
All G1P is converted to glucose to allow transport out of the liver and into the blood.
With this negative charge, it is impossible to transport out of the liver.
Describe what would occur to a person with Glucose-6-phosphatase deficiency.
What tissue is affected? What are the symptoms?
What are treatments?
In this case, the phosphate on G6P cannot be removed. This would only be an issue in the liver.
This means that the phosphate cannot be removed and glucose cannot be transported into the blood, leading to hypoglycemia and hepatomegaly.
Treatments include frequent feeding or a liver transplant.
Describe what would occur to a person with liver phosphorylase deficiency.
What tissue is affected? What are the symptoms?
What are treatments?
Glycogen phosphorylase is necessary for glycogen breakdown. In the liver, this would mean that we cannot breakdown glycogen stores and thus maintenance of blood glucose would not occur.
Thus, the symptoms would be hypoglycemia and hepatomegaly.
Treatment would be frequent feeding or a liver transplant.
Describe what would occur to a person with branching enzyme deficiency.
What tissue is affected? What are the symptoms?
What are treatments?
This would affect both the liver and muscles.
Without the branching enzyme, we cannot form glycogen but instead a starch-like molecule.
This means that the stores are not soluble and will be attacked by the immune response of the body leading to liver inflammation.
Deadly.
Symptoms are serious liver pain and malfunction, early death.
The only treatment is a liver transplant.
Is starch that bad? We eat it…
When we eat it, we digest it so, only glucose is absorbed in our system.
Starch is fine through the oral route but bad in the blood or liver.
Describe what would occur to a person with liver glycogen synthase deficiency.
What tissue is affected? What are the symptoms?
What are treatments?
This means that the liver cannot synthesize glycogen.
This means that the person is very sensitive to glucose intake from food and will be hyperglycemic after a meal, and hypoglycemic before a meal.
Describe what would occur to a person with muscle phosphorylase deficiency.
What tissue is affected? What are the symptoms?
What are treatments?
This means that the person cannot break down glycogen in their muscles.
This means that there are no emergency stores in the muscles leading to frequent cramps due to lack of energy reserves.
