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102411 Glycogen Metabolism
UC MED 2015
53
Medical
Graduate
10/26/2011

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Term
What is the storage form of glucose?
Definition
glycogen
Term
Where is glycogen primarily synthesized?
Definition
liver(highest concentration) and muscle(greatest amount overall)
Term
Muscle uses glycogen for?
Definition
energy
Term
Liver uses glycogen for?
Definition
raising blood glucose levels in response to glucagon
Term
Glycogen synthesis will occur in direct response to?
Definition
insulin release
Term
Why are the branches in glycogen, a(1,6), so important?
Definition
-They increase the overall solubility of glycogen.(W/o direct damage to our muscle and liver will occur.)
-Allow for rapid synthesis and degradation
Term
What side are glucose residues added to?
Definition
4' hydroxyl end
Term
Muscle has no glucagon receptors, so it has no response to its release. Does muscle,however, respond to insulin release?
Definition
Yes, it responds by taking glucose from the blood and it will also synthesize glucagon under these conditions.
Term
What two enzymes degrade glycogen?
Definition
1) glycogen phosphorylase (only can work up to 4 residues away from a branch point)
2) debranching enzyme
Term
What two enzymes synthesize glycogen?
Definition
1) glycogen synthase
2) branching enzyme
Term
What enzyme regulates glycogen phosphorylase activity?
Definition
(Glycogen) Phosphorylase kinase
Term
What are the regulatory enzymes of importance to glycogen metabolism?
Definition
1) Glycogen Phosphorylase Kinase
2) cAMP dependent protein kinase
3) Protein phosphatase I- dephosphorylates proteins
4) Protein Inhibitor- regulates the phosphatase
Term
What enzyme uses ATP to make G6P from glucose?
Definition
hexokinase or glucokinase
Term
What enzyme is reversible and can make Glucose-1-Phosphate from G6P?
Definition
Phosphoglucomutase
Term
What enzyme does the irreversible reaction of making UDPG from G1P?
Definition
UDP-Glucose Pyrophosphorylase
Or glucose 1-phosphate
uridylyltransferae
Term
Where do the phosphates comes from in UDPG?
Definition
One phosphate in UDP-glucose is from G-1-P; the other is the a phosphate of UTP.
Term
What is the role of glycogenin?
Definition
-It is the initiator of glycogen synthesis.
-Glycogen Initiator Synthetase, an activity of glycogenin adds the first six glucose residues to itself (glycogenin). Glycogen synthase and branching enzyme can then use this as a primer to fully synthesize glycogen.
Term
How much ATP is required to add a glucose residue starting from glucose to an existing glycogen chain.
Definition
2 ATP or 1 ATP if you start from G6P
Term
What cofactor does Glycogen Phosphorylase require?
Definition
Vit B6 aka pyridoxal phosphate
Term
What adds one glucose residue from UDP-glu to non-reducing end of existing glycogen chain?
Definition
glycogen synthase
Term
What transfers residues from one chain to create an a (1,6) bond and a new non-reducing end. Increases glycogen solubility and enzyme access rate to the ends?
Definition
branching enzyme
Term
What degrades glycogen at non-reducing ends one residue at a time via a phosphorolysis reaction? Will only work up to four residues of a branch point.
Definition
glycogen phosphorylase
Term
What removes 3 glucosyl residues from a non-reducing end and adds to another chain? Removes a (1,6) linkages by a hydrolysis reaction.
Definition
Debranching enzyme
Term
cAMP Dependent Protein Kinase does what in terms of glycogen metabolism?
Definition
It Phosphorylates both
1) Glycogen synthase- goes from a/I(active to b/D(inactive
2) Phosphorylase Kinase- goes from inactive to active form
then this phosphorylates- Phosphorylase(inactive) b to Phosphorylase a(active)
Term
What can active Glycogen Synthase after it has been phosphorylated and this inactivated?
Definition
Protein Phosphatase 1
Term
What can allosterically activate Glycogen Synthase D?
Definition
1) G6P
Term
What can G6P regulate?
Definition
1) Glycogen Synthase D- activates
2) UDP-glucose D form (decreases Km and Vmax)-activates
3) Hexokinase- inactivates
Term
What inhibits Phosphorylase a(active) in the liver and muscle?
Definition
Phosphorylase(liver)- Glucose

Phosphorylase(muscle)- Creatine-phosphate
Term
Thus Phosphorylase b in the liver have any allosteric modifiers? If yes what?
Definition
No
Term
Thus Phosphorylase b in the muscle have any allosteric modifiers? If yes what?
Definition
Activator- AMP
Inhibitor- ATP, G6P
Term
Phosphorylase kinase which is activated by PKA, also can be activated partially by what?
Definition
Ca2+ (it binds to the delta subunit)
Term
What is the delta subunit in Phosphorylase Kinase also called?
Definition
calmodulin subunit
Term
What regulates Protein Phosphatase I? And what activates this?
Definition
Protein phosphatase inhibitor I- regulated by PKA(activated via phosphorylation)- when activated it binds to and blocks Protein Phosphatase I
Term
What else regulates Phosphtase I?
Definition
glycogen particles
Term
What happens when glucagon is released?
Definition
1) Glucagon binds to receptors on the cell
2) Gs activated, binds GTP
3) Adenylate cyclase activated, cAMP levels increase, the cascade is initiated
4) PKA(cAMP dependent protein kinase activity increases)
5) Phosphorylase kinase is phosphorylated and activated
6) Protein inhibitor-1 phosphorylated, activated, and binds to protein phosphatase 1 to block phosphatase activity
7) Phosphorylase kinase activates phosphorylase, converting it from the b to the a form
8) Phosphorylase a converts glycogen to G-1-P, which is isomerized(by Phosphoglucomutase) to G-6-P, and then exported as glucose
9) Glucose is exported because glycogen synthase has been phosphorylated and inactivated by the cAMP dependent protein kinase (or phosphorylase kinase, or a calcium activated kinase)
10) As G-6-P levels increase, G6Pase produces glucose, which is in levels below the Km for glucokinase, so rephosphorylation does not occur
11) Protein kinase A has also inhibited PFK-2 and PK in the liver, stopping glycolysis
12) This aids liver glucose export
Term
Epinephrine has two receptors alpha and Beta, when it binds to this receptor the same cascade occurs as when glucagon binds?
Definition
Beta receptor for epinephrine
Term
What happen epinephrine binds to the alpha receptor?
Definition
1) Generates second messengers based on phosphatidylinositol
a- Diacylglycerol(DAG) and IP3 are released
b- DAG activated Protein Kinase C
c- IP3 stimulates calcium entry into the hepatocyte
2) The calcium binds to, and activates, phosphorylase kinase (also another calcium dependant kinase, via calmodulin)
3) PKC also phosphorylates, and inactivates, glycogen synthase
Term
Glycogen Storage Disease: Type 0

What is lacking and what are the symptoms?
Definition
Lacks: liver glycogen synthase

Symptoms: Fasting hypoglycemia. Liver has very low, if any, glycogen.

Treatment- frequent small meals
Term
Glycogen Storage Disease: Type I (von Gierke's disease)

What is lacking and what are the symptoms?
Definition
Lacks- glucose-6-phosphatase

Symptoms- Enlargement of liver, severe hypoglycemia. Increased glycogen in liver, of a normal structure.

Treatment- frequent small meals
Term
Type I Glycogen Storage Disorder is also known as?
Definition
von Gierke's disease
Term
Glycogen Storage Disease: Type IV (Anderson's disease)

What is lacking and what are the symptoms?
Definition
Lacks- branching enzyme

Symptoms- Fatal disease. Liver has low levels of non-branched glycogen, which presents solubility problems. Cirrhosis develops.

Treatment- liver transplant
Term
Type IV Glycogen Storage Disease is also known as
Definition
Anderson's Disease
Term
Glycogen Storage Disease: Type V (McArdle's disease)

What is lacking and what are the symptoms?
Definition
Lacks- muscle phosphorylase

Symptoms- Weakness and cramping after exercise; inability to use muscle glycogen as energy source.

Treatment- pt can still makes ATP from fatty acids, more of an inconvenience
Term
Type V Glycogen Storage Disease is also called?
Definition
McArdle's disease
Term
What does MODY stand for?
Definition
Maturity onset diabetes of the young
Term
How do you get MODY and what problems are associated with it?
Definition
-Inheritable(in one case, mapped to glucokinase/other case transcription factors are mutated)

- Glucokinase is only expressed in liver and pancreatic B-cels
-Normally B-cells release insulin in response to glucose
-MODY pt doesn't release insulin properly
-this suggests that a metabolite of glucose signals the b-cell to release insulin, since glucokinase is the defective enzyme
Term
What makes Glucokinase an effective glucose sensor for the pancreatic B-cells as apposed to Hexokinase?
Definition
Glucokinase has a higher Km than Hexokinase, so it will only work when glucose levels are high
Hexokinase with its lower Km will always be sensitive to glucose even low levels
Term
What drug is given to type II diabetics? They bind to and close the potassium channels on the surface of the beta cells. This increases calcium movement into the beta cell, leading to insulin release.
Definition
Sulfonylurea-based drugs (Glipizide)
Term
What is the critical metabolite for releasing insulin from the B-cell?
Definition
ATP (it inhibits the K+ channel/ Ca2+ keeps flowing in and then once a critical level is hit- insulin goes out)
Term
What is the influence of these factors on insulin release?
1) glucose
2) amino acids
3) neural input
4) gut hormones
5) epinephrine
Definition
1) positive
2) minor- positive
3) minor- positive
4) minor- positive
5) negative
Term
Are neural signals(vagus nerve) required for insulin release?
Definition
no
Term
What released after food ingestion also stimulates insulin release(minor)?
Definition
Gastric Inhibitory Peptide
Term
Does a MODY pt develop the same longterm problems that a Type I diabetic has?
Definition
No, because insulin is still being produced, GK has been altered and is not making G6P as well and not enough ATP to stimulate proper release of insulin.
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