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124 Cards in this Set

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Why do we maintain blood glucose levels by using glycogen stores, when fat is the most efficient?
Because fat metabolism is SLOW and it can't be converted to glucose!!!
What is glycogen, and where is it mostly found?
A branched polymer of glucose; most in skeletal muscle/liver.
In terms of %by mass, what has a higher [glycogen]; sk musc or liver?
Liver - 10%

Skeletal muscle only = 1-2%
Which tissue STORES more glycogen?
Skeletal muscle - by nature of the fact that there is just that much more tissue in the body.
When does muscle glycogen decr?
When does liver glycogen decr?
Muscle: during exercise
Liver: during fasting
What molecule represents a major branch point in carb metabolism?
What 4 pathways are available to the G6P branchpoint?
1. Glycogen synthesis
2. Pentose Phosph Pathway (HMP)
3. Glycolysis
4. Gluconeogenesis (liver)
How is the futile cycling of glycogenesis and glycogenolysis avoided?
By having one unique set of enzymes for each direction - not the same. That makes regulation easier and more precise.
What 3 hormones regulate glycogen metabolism?
How do Insulin/Epi/Glucagon regulate glycogen metabolism?
Insulin: stim glycogen formatn
Epineph: stim glycogen breakdown in muscle and liver
Glucagn: stim glycogen breakdown in liver only
How do the tissues use the G-1-P product of glycogen breakdown?
Muscle - for energy

Liver - to maintain blood glucose levels.
What enzymes are affected by the hormones regulating glycogen metabolism
Insulin: glycogen SYNTHASE

Epi/Glucagon: Glycogen PHOSPHORYLASE
What is the blood's normal glucose range? Concentration?
70-100 mg/dL
3.9-5.6 mM
What are signs of hypoglycemia w/ a level lower than 60?
Hunger, sweating, trembling
What are signs of hypoglycemia w/ a level lower than 40?
Lethargy, convulsions, coma
What is the result of a very hypoglycemic state for a long period of time?
Perm. brain damage and death.
What diagnostic tool is used to indicate long-term excessive hyperglycemia?
What specific tissues are HIGHLY DEPENDENT on maintaining blood glucose levels, and why?
-Renal medulla
-They have little/no mitochondria
Can RBCs use ketone bodies like the brain? Why?
No; they have no mitochondria, where fat metabolism occurs.
So the 3 sources of glucose in the body are:
1. Diet
2. Glycogenolysis
3. Gluconeogenesis
What is required for Glucose to traverse cell plasma membranes?
Facilitated transport - no energy, but transporters b/c glucose is so large.
What cells have GLUT 1 and 3? What is the function of GLUT1/3?
Nearly all cells; allows for basal glucose uptake.
Why are GLUT 1/3 good for basal uptake?
Because they have a low Km (1mM) so they're nearly always saturated and operate well even at low blood glucose conc.
Why is it good that Brain and RBCs have Glut 1/3?
Because they always need glucose; you wouldn't want their function match the daily blood glucose fluctuations.
What 3 tissues have GLUT2?
-LIVER (v. important)
-Pancreatic B-cells
-Enterocytes - basolateral side
How does GLUT2 operate when:
-Blood [Glu] is normal
-Blood [Glu] is low
Normal: don't operate efficiently

Low: low operation
High: high operation
So how is the operation of GLUT2 in the liver affected by blood glucose levels?
They are directly proportional - the liver only takes up glucose after a meal when levels are high.
What allows for the liver to only take up glu at high blood concentrations?
Its HIGH Km = 15-20 mM
What tissues have GLUT 4?
Skeletal muscle
Fat cells
Why do we want muscles/fat to have GLUT4?
B/c it is insulin responsive - they only take up glucose to store it when there is extra.
What is the Km of GLUT4?
Intermediate - 5 mM
What is insulin's effect on GLUT4?
It increases its microvesicular transport to the plasma membrane of muscle/fat.
So what GLUT transporters will be functioning when the blood is at 5 mM?
Glut 1/3 (brain/RBCs)
Glut 4 (sk. muscle/fat)
-B/c 5 is on the high end
-But not high enough for liver
What tissues have GLUT5 and for what?
Apical side of enterocytes - for FRUCTOSE uptake
What is the sodium glucose transporter related to GLUTs?
Where is SLGT-1 located? What is its function?
-On apical side of enterocytes
-Functions for Glucose and Galactose uptake from the intestines into enterocytes.
How is SLGT-1 distinct from the other GLUT transporters?
It requires energy and transport is irreversible.
What makes the transport of Glucose/Galactose thru SLGT-1 favorable?
Na gradient establishd by ATP pump
So what transporters are on enterocytes?
SLGT-1 -> Apical
GLUT-5 -> Apical
GLUT-2 -> Basolateral
When would GLUT2 on enterocytes be functional?
After a meal b/c its Km is so high!! (same as in liver)
What is expressed by tumors as they outgrow their blood supply?
HIF-1 (hypoxia-inducible transcription factor)
What does HIF-1 do?
Induces GLUT1 and GLUT3 so the tumor cells get a basal glucose uptake (more efficient)
What is the metabolically active form of glucose? Why?
Glucose-6-phosphate -> this is the only kind that stays within cells; plain glucose is freely reversible and equilibrated across cell membranes.
What 2 enzymes achieve G6P?
Where is HEXOKINASE found?

Where is GLUCOKINASE found?
Hexo = all cells

Gluco = liver & pancreatic Bcell
Why is it good for all cells to have Hexokinase?
B/c it has a VERY LOW KM -> traps glucose very efficiently
What does Hexokinase require for function? What inhibits it?
-Requires Mg-ATP
-G6P (its product) inhibits it
Why is it good that only liver and pancreatic B-cells have GLUCOKINASE?
B/c Glucokinase has a much HIGHER KM -> ~10mM; only traps glucose when levels are high.
What are the 3 important differenes between glucokinase and hexokinase?
Glucokinase has
1. Higher Km
2. Cooperative binding curve
3. No product inhibition
How does glucokinase behave?
When liver glu levels high, it traps glucose continuously until levels decrease - regardless of how much G6P builds up.
Recap; why is it good for SLGT-1 to be dependnt on ATP?
Because if ATP in the body is high, there will be less glucose uptake - no need for it!
..thats a stretch...
Fates of G6P; what will it do
-After a meal?
-Between meals?
After a meal G6P -> glycogen

Between meals G6P goes to
a. PPP pathway -> NADPH
b. Gluconogenesis -> LIVER
c. Glycolysis -> sk muscle
Describe glycogen again:
Branched polymer of glucose with 1. a-1,4 linear glycosidic bonds
2. B-1,6 branchpoint linkages
How much glucose does 0.01 uM of glycogen equal?
400 mM -> provides a great advantage of storing LOTS of glucose w/out osmolar signific.
Are there reducing ends on glycogen?
1 - tied up with glycogenin
What is the major storage tissue for glycogen?
how many steps are involved in glycogen breakdown? What are they?
Four steps:
1. Phosphorylation
2. Mutation
3. Hydrolysis
4. Debranching
What are the four enzymes in glycolysis?
1. Glycogen phosphorylase
2. Phosphoglucomutase
3. Glucose-6-Phosphatase
4. Debranching enzyme
What occurs in the phosphorylation step one?
Phosphoryltic cleavage to produce Glu-1-PO4 and Glycogen (minus one residue)
What is the active site residue of Glycogen phosphorylase, adn how does it act?
PLP - pyridoxal phosphate; acts as a general acid/base catalyst, which is an atypical use of PLP.
Where on glycogen can Glycogen Phosphorylase act?
-ONLY at residues at least 4 away from branchpoints
-only at a-1,4 linkages
So what is the cofactor of Glycogen Phosphorylase?
What happens to Glucose-1-PO4 in step 2?
Phosphoglucomutase converts it to G6P so it can be further metabolized.
What happens in the mechanism of mutation of G1P?
Exchange of PO4 from enzyme to G1P to make G1,6-bisphosphate; then it gives a PO4 back to the enzyme to result in G6P
What cell compartment contains phosphoglucomutase?
What is the enzyme for Step 3 and where is it found?
G6Phosphatase -> only in LIVER lumenal side of ER membrane.
What happens to G6P during step 3 of glycogenolysis? (3 steps)
1. G6P transport to ER
2. Hydrolysis produes Glucose + Phosphate
3. Glucose transported back to cytosol, then bloodstream.
What must you remember about Step 3's enzyme Glucose-6-Phosphatase?
Why is a debranching enzyme needed for glycogenolysis?
Because Glycogen Phosphorylase only acts on a-1,4 linkages, not the B-1,6 linkages at branchpoints.
What is the name of the product resulting after Glycogen Phosphorylase cleaves all the outermost residues of glycogen?
Limit Dextrin
What is the mechanism of Debranching Enzyme?
1. Move 3 residues from a-1,6 branchpoint to main chain.
2. Cleave remaining a-1,6 residue.
Now normal processing can go.
When G6Phosphatase releases free glucose into the cytosol (step 3), how does it not just get rephosphorylated and trapped?
Liver cells only have glucokinase - it only traps it when the Glu concentration is high. (not the case when breaking DOWN glycogen)
In general what do we call debranching enzyme?
1. Transferase
2. a(1-6)-Glucosidase
Is glycogen synthesis just the reverse of breakdown? Why/why not?
In VITRO, yes.
In VIVO, No; b/c the ratio of Phosphate to G1P is normally HIGH; favors glycogenolysis
Are ALL the enzymes of glycogen synthesis different from glycogen breakdown?
No; both processes use the same phosphoglucomutase.
How many enzymes are used in glycogen synthesis? What are they?
1. Phosphoglucomutase
2. UDP-Glucose Pyrophosphorylase
3. Glycogen synthase
4. Glycogenin
5. Branching Enzyme
What is the first step of glycogen synthesis?
mutation - phosphoglucomutase converts G6P -> G1P
What is the 2nd step of glycogen synthesis?
Conversion of G1P to an activated glucose
How is Glucose activated for glycogen synthesis?
By UDP-Glucose Pyrophosphorylase which adds a PO4 to G1P, and subsequent PPi hydrolysis to drive the reaction forward.
What happens to Activated Glucose (UDP-Glucose)?
Glycogen synthase adds them to pre-existing glycogen chains at least 4 residues long. Prevents adding to free glucose.
When UDP is released from activated glucose during glycogen synthesis, what follows?
It is immediately converted to UTP by ATP (if the cell's energy charge is high, which it should be if you're STORING glycogen)
What enzyme catalyzes conversion of UDP to UTP?
Nucleoside Diphosphate Kinase (NiDiKi)
What is glycogenin and why is it important?
An enzyme that has Tyr residues linked to glucose; it catalyzes addition of 7 more glu to itself, providing the substrate w/ >4 residues for Glycogen synthase.
What is the glucose source for Glycogenin when it builds itself up?
Activated glucose (UDP-glucose), same as for glycogen synthase.
When does branching enzyme operate on glycogen synthesis?
When linear polymers are at least 11 residues long; Moves a 7-unit chain to a C6 position if it's at least 4 residues away from a previous branchpoint.
What regulates liver glycogen metabolism - determining whether synth or degradation occurs?
Blood glucose levels.
What factors stimulate glycogen synthesis?
-Plentiful glucose
What factosr stimulate glycogen degradation?
How do these factors alter rates of glycogen synth/degradation?
By regulating the ENZYMES:
-Glycogen synthase
-Glycogen phosphorylase
How is Glycogen phosphorylase regulated? (2 ways)
1. Allosteric regulation via metabolites
2. Covalent regulation via phosphorylation
What are the states that Glycogen phosphorylase can exist in?
T (inactive) vs. R (active)

b (inactive) vs. a (active)
What are the b/a forms used to signify?
Unphosphorylated = b

Phosphorylated = a
What controls whether glycogen phosphorylase is b or a?
Hormones - they act through phosphorylase kinase and phosphoprotein phosphatase 1.
What allosteric regulators in muscle turn on Glycogen phosphorylase by causing conform change from T->R?
What allosteric regulators have the opposite effect and inactivate glycogen phosphorylase?
ATP and G6P
What mechanism is mostly regulating Glyc. phosph in
-Skeletal muscle?
Skeletal muscle = allosteric regulation by metabolites (fast)

Liver = phosphorylation controlled by hormones.
What 2 enzymes are responsible for regulating the phosphorylated state of glycogen phosphorylase?
1. Phosphorylase kinase
2. Protein phosphatase 1
What does Phosphorylase kinase do? What stimulates it?
Phosphorylates Glycogen phosphorylase; stim by Glucagon/Epi (need glucose);
inhibited by glucose/insulin
How is Phosphorylase KINASE regulated?
By cAMP-dependent protein kinase (PKA)
What is the role of Phosphoprotein Phosphatase 1?
It dephosphorylates both Phosphorylase Kinase, and Glycogen phosphorylase, to inactivate them.
How does Glycogen degradation get stimulated by hormones?
Epinephrine starts the PKA cascade; PKA phosphorylates Phosphorylase b -> a; degradation is turned on.
How is the simultaneous degradation and synthesis of glycogen prevented?
When PKA phosphorylates Glycogen synthase it converts from a->b which is its inactive form.
What is required of Glycogen Phosphorylase for it to be phosphorylated by PKA?
It must be in the T - inactive state.
What form does Glycogen Phosphorylase tend to be in in the liver?
R state (active); because glucose is low (unless you just ate a meal).
What happens to Glycogen Phosphorylase when glucose is high in the liver?
It will be in the T (inactive) state, which can be dephosphorylated.
Why is it good that the modified form of Glycogen phosphorylase (the phosphorylated a form) predominates in liver?
Allows it to ignore the cell's energy status (ATP/GTP) and be regulated mainly by glucose levels.
What is the mechanism of PKA's actn on Glycogen phosphorylase?
1. Phosphorylates B-subunit
2. Binds Ca2+ to delta subunit
Why does PKA phosphorylate Glycogen Phosphorylate w/ 2 steps?
Because they're both needed for max enzyme activity.
What protein is responsible for activating PKA via Cortisol or stress hormones?
cAMP (cyclic AMP dependent protein kinase)
What enzyme dephosphorylates both cAMP and Glycogen phosph.?
Phosphoprotein phosphatase 1
What is the effect of Epi and stress hormones on PP1?
-PKA phosphorylatn of a molecule connecting PP1 to glycogen makes PP1 dissociate (partly inactive)
-PKA also phosphorylts an Inhibitor molecule, which binds PP1 to fully inactivate it.
What is the net effect of inhibiting PP1?
Both Glycogen phosphatase and Glycogen synthase are phosphorylated, so active and inactive respectively.
How does INSULIN alter the activity of PP1?
1. Activates Receptor Tyrosine Kinase
2. Phosphorylates PP1's glycogen connector at a different site activates Pp1.
What is the net effect of activating PP1?
It dephosphorylates Glycogen Phosphatase (inactive) and Glycogen synthase (ACTIVE).
What 2 factors cause PP1 to dissociate from Glycogen and be activated?
1. Insulin
2. GLUCOSE binding
How does Epi/Cortisol stimulation of glycogenolysis differ in liver vs sk. muscle?
Liver: HAS G6Pase; inhibits glycolysis, favors gluconeogen.

Sk. muscle: no G6Pase; favors glycolysis for energy.
How does Insulin's effect on glycogenesis differ in liver vs. sk. muscle?
It doesn't, still uses the same Receptor Tyrosine Kinase; BUT
GLUT2= liver glucose transportr
GLUT4= muscle transporter
What does Ca2+ release from nerve impulse stimulation do to glycogen metabolism?
Turns on PKA -> turns on Glycogen Phosphorylase -> turns on glycogen breakdown.
What are the 4 most common glycogen storage diseases?
1. Von Gierke's
2. Pompe's
3. Cori's
4. McArdle's
Which one doesn't belong? why?
Pompe's - caused by enzyme deficiency of pathway not discussed in lecture (hydrolysis of glycogen, not phosphorylase)
Which storage disease is most common? What enzyme deficient?
Von Gierke's - Glucose 6-Phosphatase
What is the effect on liver glycogen storage in Von Gierke's?
Normal glycogen structure, but storage in very high amounts.
What are symptoms of Von Gierke's?
-Failure to thrive
-Severely enlarged liver
What enzyme is deficient in Cori's disease? What is the pathologic effect?
Debranching enzyme; increased glycogen storage with shorter branches. Milder than Von Gierke's.