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30 Cards in this Set

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What is the polymer structure of glycogen?
--Glycogen is a polymer of glucose.
--Arranged in alpha-1,4 glycosidic linkages and alpha-1,6 glycosidic linkages. This helps store glycogen, so it's not so bulky.
1,4--side-by-side
1,6--up-and-down

--Has a "reducing" end (with free carbon 4) and "nonreducing" end.

--Glycogen is stored in cytoplasm of liver, muscle in GRANULES.
What is the role of glycogenin in the glycogen molecule?
--Glycogenin is a little protein in the middle of the glycogen polymer.
--The "primer" in glycogen sythesis--accepts glucose residues.
--OH of the tyrosine on glucogenin is attached to carbon 1 of first glucose (uses UDP-Glucose)
--Glycogenin adds several more residues to the initial glucose (that its attached to), then glycogen synthase takes over.
What is the word for glycogen formation?
What is the word for glycogen breakdown?
--Glycogenesis
Glucose-->Glycogen

--Glycogenolysis
Glycogen-->Glucose
What is glycogenolysis used for?
--Glycogen stored and broken down in liver (and muscle) to provide glucose during times where it is scarce.

Basic overview

GLYCOGEN--(Glycogen phosphorylase)-->G-1-P--(Phosphoglucomutase)-->G-6-P

G-6-P can be used for tons of stuff..
What is fate of G-6-P released from liver, muscle, and brain glycogen?
After glycogenolysis, G-6-P has several paths it can take..


LIVER--
G-6-P--(G-6-phosphatase)-->GLUCOSE-->RELEASE

MUSCLE/BRAIN
G-6-P--(glycolysis)-->PYRUVATE-->LACTATE and CO2+H20

PPP can convert G-6-P-->RIBOSE+NADPH
What are the steps in glycogen synthesis (glycogenesis) reaction?
--Uses UDP-glucose to add the glucose residue to the growing chain in an alpha-1,4 linkage.

1) G-6-P--(phosphoglucomutase)-->G-1-P

UDP-Glucose Phosphorylase Reaction
2) G-1-P + UTP--(UDP-glucose phosphorylase)-->UDP-GLUCOSE

Glycogen Synthase Reaction
3) UDP-GLUCOSE + GLYCOGEN (n residues)--(GLYCOGEN SYNTHASE)-->GLYCOGEN (n+1 residues)+ URIDINE
--UDP-glucose carries glucose residues to the chain

Branching Enzyme Reaction--formation of alpha-1,6 linkages.
--After chain is 11 residues long, branching enzyme breaks an alpha-1,4 bond and transfers a bunch of residues to the carbon 6 of an internal rsidue, forming an alpha-1,6 bond. Causes BRANCHING.
What are the steps in glycogen breakdown (glycogenolysis) reaction?
Glycogen Phosphorylase Reaction
Glycogen (n)--(Glycogen phosphorylase)-->G-1-P + Glycogen (n-1)
-->uses phosphate to break alpha-1,4 bonds in the glycogen molecule, decreasing by ONE residue each time.

Debranching enzyme reaction
-->Glycogen phosphorylase STOPS when it reaches glucose fourth down from a branch point due to steric hindrance--debranching enzyme takes over.

-->Debranching enzyme has two activities:

Transferase-->removes three glucose residues nearest to non-reducing end by breaking an internal alpha-1,4 glycosidic bon--leaves one glucose residue.

Alpha-1,6 glucosidase-->breaks the alpha-1,6 glycosidic bond--releases last ("branch point") glucose residue-->leaves as free glucose.
What is the fate of G-1-P and glucose in liver, after glycogenolysis?
G-1-P--(phosphoglucomutase)-->G-6-P--(G-6-phosphatase)-->Glucose

Can release glucose to other cells during a fast
What is the fate of G-1-P and glucose in muscle, after glycogenolysis?
G-1-P--(phosphoglucomutase)-->G-6-P

-->Muscle has no G-6-phosphatase, so it can only break G-1-P down into G-6-P
How do glucagon/epinephrine regulate glycogenolysis in the liver?
Glucagon/Epinephrine are active during FAST-->want to release glucose from liver.
--Want to STIMULATE GLYCOGENOLYSIS and INHIBIT GLYCOGEN SYNTHESIS.

Bind to receptor-->activate Gas-->activate adenylate cyclase-->increase cAMP-->activates PKA-->wants to PHOSPHORYLATE.

Activates..glycogenolysis.
Inhibits...glycogenesis, glycolysis (by phosphorylating PFK-2)
How do glucagon/epinephrine regulate glycogenolysis in the muscle?
NO GLUCAGON RECEPTORS IN THE MUSCLE!

--Epinephrine wants to STIMULATE glycogenolysis, glycolysis and INHIBIT glycogenesis.

Binds to receptor like always-->activates PKA-->wants to PHOSPHORYLATE things.

Similar to liver--only difference: phosphorylation of PFK-2 ACTIVATES it-->get INCREASED GLYCOLYSIS.
How does insulin regulate glycogenolysis in the liver/muscle?
--Stimulates liver and muscle glycogenesis and inhibits glycogenolysis.

--Stimulates cascade that DEPHOSPHORYLATES things.
--Also, increases GLUT-4 transporters in muscle-->increase glucose uptake.
How do Glucagon/Epinephrine regulate glycogen phosphorylase?
Glucagon/Epinephrine are active during a fast, so they want to STIMULATE glycogenolysis and INHIBIT glycogen synthesis.

-->Glycogen phosphorylase CATALYZES GLYCOGENOLYSIS--so, they want to turn it on.
-->Glycogen phosphorylase is ACTIVATED by a phosphorylase kinase and INHIBITED by phosphoprotein phosphatase.
-->In BOTH glycogen phosphorylase AND phosphorylase kinase, the active form is A (PHOSPHORYLATED) and the inactive form is B (DEPHOSPHORYLATED)
-->The phosphoprotein phosphatase is INHIBITED by cAMP and ACTIVATED by insulin.

--Glucagon and epinephrine love to PHOSPHORYLATE things, so it's easy for them to ACTIVATE this enzyme and STIMULATE glycogenolysis.
--Also, their pathway generates cAMP, which INHIBITS phosphoprotein phosphatase, so ACTIVE phosphorylase can be made.

So...

Glucagon/Epinephrine bind to receptor-->elicit pathway that generates cAMP-->activates protein kinase A (PKA)

cAMP-->INHIBITS phosphoprotein phosphatase (phosphorylase A can be made)

PKA-->phosphorylates KINASE (B-->A) which phosphorylates PHOSPHORYLASE (B-->A)

-->ALSO inhibits phosphoprotein phosphatase

BOTH of these steps will help Glycogenolysis happen!
How does insulin regulate glycogen phosphorylase?
Remember--

Glycogen phosphorylase is converted to active form by a kinase. BOTH forms are ACTIVATED by PHOSPHORYLATION (B form-->A form).

Phosphoprotein phosphatase REMOVES phosphate from phosphorylase, making it inactive. This enzyme is ACTIVATED by insulin.

--Insulin loves to DEPHOSPHORYLATE things, so this is also a perfect scenario.

So...

Insulin binds to its receptor and ACTIVATES phosphoprotein phosphatase.

phosphoprotein phosphatase--> DEPHOSPHORYLATE KINASE (A-->B)-->can no longer phosphorylate phosphorylase-->no more glycogenolysis!
Overall, what are the activators/inhibitors of glycogen phosphorylase kinase?
ACTIVATED (B-->A) by...Calcium, PHOSPHORYLATION by protein kinase A
INHIBITED (A-->B) by..DEPHOSPHORYLATION by phosphoprotein kinase.

During muscle contraction, calcium will activate whatever it can..this leads to a better chance of obtaining energy.
Overall, what are the activators/inhibitors of phosphoprotein phosphatase?
ACTIVATED by..Insulin

INHIBITED by...cAMP
Overall, what are the activators/inhibitors of glycogen phosphorylase?
ACTIVATED (B-->A) by..AMP, PHOSPHORYLATION by phosphorylase kinase.

INHIBITED (A-->B) by...Glucose, ATP, DEPHOSPHORYLATION by phosphoprotein phosphatase.
What are the hormone regulators of glycogenolysis?
1) Glucagon-->increase cAMP-->activates protein kinase A-->phosphorylates kinase (B-->A)-->phosphorylates phosphorylase (B-->A)-->glycogenolysis!

**Protein kinase A also inhibits phosphoprotein phosphatase, which keeps phosphorylase active.

2) Epinephrine--same.
3) Insulin--activates phosphatase-->inhibits kinase AND phosphorylase.
What are the allosteric controls on glycogenolysis?
1) Calcium-->activates phosphorylase kinase.
2) AMP-->activates glycogen phosphorylase.
3) Glucose-->inhibits glycogen phosphorylase.
How do glucagon/epinephrine regulate glycogen synthase?
-Glucagon/Epinephrine are high during a FAST, so want to INHIBIT glycogen synthase.

--Glycogen synthase is opposite of glycogen phosphorylase.

Active form-->DEPHOSPHORYLATED (A)
Inactive form-->PHOSPHORYLATED (B)

So..glucagon/epinephrine begin the phosphorylation extravaganza..
Bind-->increase cAMP-->activate PKA-->activates PHOSPHORYLASE KINASE-->PHOSPHORYLATES glycogen synthase-->INHIBITS glycogen synthase-->stops glycogenesis.

Also, there is a protein phosphatase present--want to keep synthase phosphorylated, so phosphatase is INHIBITED by cAMP.
How does insulin regulate glycogen synthase?
--Insulin wants to ACTIVATE glycogen synthesis.

--Binds to receptor-->INHIBITS glycogen synthase kinase-->can not phosphorylate glycogen synthase-->keeps it active!

--Also, phosphatase is ACTIVATED by insulin-->so, it will DEPHOSPHORYLATE the synthase, so it is ACTIVE and can allow glycogenesis.
What are hormone regulators of glycogenesis?
1) Glucagon-->increase PHOSPHORYLATION of GLYCOGEN SYNTHASE (inhibits it) and inhibits phosphatase
2) Epinephrine--same.
3) Insulin--ACTIVATES phosphatase and INHIBITS glycogen synthase kinase (GSK)
What are allosteric regulators of glycogenesis?
1) Calcium activates calmodulin kinase-->phosphorylates glycogen synthase-->INHIBITS it.
2) G-6-P can ACTIVATE glycogen synthase, directly.
How does insulin/glucagon/epinephrine inhibit phospoprotein phosphatase?
-->Phosphoprotein Phosphatase is phosphatase present in both glycogenolysis and glycogen synthesis--tries to de-phosphorylate glycogen synthase and glycogen phosphorylase

Gluca/Epi--PKA phosphorylates a glycogen regulatory protein (G)-->causes phosphatase to dissociate from G and lose activity.
-->PKA also phosphorylates the inhibitor protein (I), which binds and FULLY inactivates phosphatase.

Insulin--
Stimulates dephosphorylation of G-->phosphatase re-joins with G-->active enzyme!
How does glucose allosterically activate glycogen synthesis?
--Allows liver to shut off glycogenolysis quickly, once new glucose is introduced.
--Liver contains Glut 2, which has high Km-->glucose enters liver cells-->binds to glycogen phosphorylase and inhibits it (converts it to B form)--also makes it a better substrate for phosphatase.
--phosphorylase B does not inhibit phosphatase (like A) and allows phosphatase to dephosphorylate and activate the glycogen synthase.

--Only a temporary fix--need insulin to maintain this inhibition.
What is type I glycogen storage disease?
--Von gierke disease.
--No G-6-phosphatase or transport system.
--Affects liver and kidney.
--High glycogen.

Sx's--hypoglycemia (liver/kidney can't release glucose), hyperlipemia and ketosis (B-oxidation is increased), high pyruvate/lactate (tons of G-6-P-->tons of glycolysis)
What is type II glycogen storage disease?
--Pompe disease
--Defect in lysosomal enzyme
--Affects all organs.
--Glycogen gets into lysosomes-->is not degraded-->lysosomes ENGORGED with glyogen-->toxicity.

Sx's--cardiorespiratory failure, death.
What is type III glycogen storage disease?
--Cori disease
--Defect in debranching enzyme (glucosidase)
--Affects muscle, liver
--Glycogen can't be broken down completely--get tons of short, little, half-digested glycogens in the system.
What is type IV glycogen storage disease?
--Andersen disease
--Defect in branching enzyme.
--Affects liver, spleen.
--Can't make glycogen correctly-->generate huge glycogen chains w/no branches-->can build up in the liver-->cause cirrhosis.
What is type V glycogen storage disease?
--McArdle disease.
--defect in phosphorylase.
--affects muscle.
--Initial exercise is inhibited, because you are not generating ATP efficiently (crappy glycogenolysis).
--However, get a "second wind" when blood-borne glucose and FA can supply ATP.