11-26 Glycogen Turco

Front 1

A few review points of glycogen:
bond types
What % of the glc are terminal ones?
The ___ __ that can be added to has a protein cap called ____.

Back 1

α1,4 and at branches α1,6

8-10%

Reducing end has glycogenin

Front 2

Why do polymerize glucose since it takes all this effort and enzymes instead of just shoving it in a storage container?

Back 2

Glycogen is less osmotic to preserve water balance

Front 3

About how much glycogen do we have at a time?

Where is it?

What is the implication for glycogen storage diseases?

Back 3

1 lb-> still osmotic, so upper limit exists

In muscles and liver primarily, but it's in virtually every cell.

hepatomegaly and cardiomegaly are common symptoms

Front 4

So where does excess glucose go if glycogen is capped?

Back 4

GLUT2 transporter to liver, insulin tells liver to make triglycerides which are anhydrous, shipped out as LDL to adipose tissues for storage

Front 5

Why do we branch glucose instead of keeping it linear?

Back 5

More soluble in water
More free ends to depolymerize faster and get glc faster (In danger, need muscles -> need ATP -> need glc and need it fast -> branched you get a bunch of ends to take off. If it were linear, you'd only get one glc at a time)

Front 6

What is the glycogen in the liver used for?
What about in muscles?

Back 6

Liver uses stores to maintain blood [glc] especially between meals

Muscles, especially during exercise, use glycogen to act as readily available source for glycolysis within the muscle.

Front 7

How to make glycogen:
Prepping the glc pieces

Back 7

G6P <---phosphoglucomutase--->G1P (cytoplasm)
G1P + UTP <---UDP-Glc pyrophosphorylase-->UDP-Glc + PPi
PPi --inorganic pyrophosphatase--> 2Pi

Front 8

Why is the PPi --> 2Pi step during UDP-Glc formation so important?

Back 8

PPi is actually toxic
Makes reaction irreversible
Le Chatlier principle says if product is removed, it drives the reaction forward

Front 9

How to make glycogen:
Adding glc to the glycogen

Back 9

UDP-Glc + C4 of glycogen ----glycogen synthase--> Glycogen + UDP

Front 10

Rando Where all do you see pyrophosphate

Back 10

DNA/RNA replication
protein synthesis with aminoacyl tRNA

Front 11

glycogen synthase
What all bonds does it catalyze?
What size range of glycogen can GS work on?
How tightly is this regulate?

Back 11

α1,4 only
all sorts of different sizes
highly regulated

Front 12

How to make glycogen:
Making branches in your glycogen

Back 12

Branching enzyme takes 6-7 glc chain off a growing chain of 11-14 and makes an α1,6 linkage

Front 13

What is the process of building glycogen called?
And the process of breaking it down?

Back 13

glycogenesis
glycogenolysis

Front 14

How do you start picking off glc from the ends of glycogen? What reaction is used?

Back 14

use phosphorylase to cleave the α1,4 bonds until a chain of 4 glc remain, popping off G1P's (-phosphoglucomutase-> G6P-> glycolysis)

Cleave by phosphorolysis as opposed to hydrolysis since you use a Pi

Front 15

What are all the phosphorolysis reactions we've learned?

Back 15

purine nucleotide phosphorylase PNP
phosphorylase for glycogenolysis

Front 16

After phosphorylase eats glycogen branches to 4, what happens?

Back 16

Debranching enzyme takes all but one and moves it to a nearby terminal end. Then cleaves the α1,6 link between that last branch stub and the rest of the glycogen. This one is NOT phosphorylated.

Front 17

What percent of glc released from glycogen is free glc instead of G1P?

Back 17

8-10%

Front 18

Where does glc activation happen?
Where does the actual glycogen building happen?
Where does glycogen breakdown happen?
Which specific membranes does glycogen go through?

Back 18

cytoplasm
cytoplasm
cytoplasm
None that we learned about. Too polar to traverse a lipid bilayer.

Front 19

Why is glycogenesis and glycogenolysis so important to regulate?

So where is it regulated?

Back 19

Otherwise the net reaction of pyrophosphorylase, inorg. pyrophosphatase, glycogen synthase, and phosphorylase would be UTP --> UDP + Pi = futile.

glycogen synthase and phosphorylase: the dominant enzyme of each pathway

Front 20

Describe the active and inactive forms of glycogen synthase.

Back 20

Glycogen synthase I (active)
PKA for a specific Ser changing it to
glycogen synthase D (inactive, PO4'd)
phosphatase changes it back

This is the opposite of phosphorylase.

Front 21

Describe the active and inactive forms of phosphorylase.

Back 21

Phosphorylase b (inactive)
phosphorylase kinase acts on specific Ser changing it to
Phosphorylase a (active, PO4'd)
phosphatase changes it back

This is the opposite of glycogen synthase.

Front 22

So net for glycogen synthase and phosphorylase: What does the presence/absence of PO4 mean for the breakdown/synthesis?

Back 22

Protein phosphorylation: ups breakdown, downs synthesis.

Protein dephosphorylation: downs breakdown, ups synthesis

Front 23

What are target organs of epinephrine in terms of glycogen effects?

What receptor does epinephrine use?

What does it do there?

Back 23

(results in phosphorylation)
Liver: ups glycogen breakdown for anaerobic muscular work
Muscle: ups glycogen breakdown for glycolytic ATP formation

These two are Cori Cycle.

adrenergic receptor

Front 24

G-proteins are never ever ever ever a __

Back 24

receptor. It can be coupled with a receptor. There can be G-protein coupled receptor.

Front 25

What does glucagon do to regulate glycogen metabolism? Why is it doing this?

Back 25

Liver: (results in phosphorylation) ups glycogen breakdown and gluconeogenesis (concurrently, not sequentially)

Glycogen will run out (12 hours at rest), so gluconeogenesis is important

Front 26

What does insulin do to regulate glycogen metabolism? Why is it doing this?

Back 26

End result is phosphoprotein phosphatases which lower breakdown of glycogen and ups synthesis

Front 27

Outline insulin pathway.

Back 27

Tyr kinase class of receptor -> dimerizes -> autophosph on certain Tyr -> IRS docs -> other proteins like PI3K and RAS can dock and a phosphatase downstream turned on to change

Front 28

Outline epinephrine/glucagon pathway to get to second messenger

Back 28

Use adrenergic receptors- transmembrane, serpentine coupled to a G-:protein: Gs-GDP via α subunit

When hormone bound, GDP -swap-> GTP = Gs-GTP

Gs αβγ-GTP drops βγ and Gs α-GTP goes to activate->

Adenylate cyclase. Membrane bound on internal side, this ATP -> cAMP + PPi (cAMP is the second messenger)

Gs-GTP hydrolyzes itself after a certain time -> Gs-GDP hooks back up with βγ.

Front 29

What does cAMP do?

Back 29

activates protein kinase A which acts on glycogen synthase I to change it to GS D

Phosphorylase kinase needs both [Ca2+ (SR) binds to calmodulin] (partially activates) and PKA to PO4 it (fully active)

So "phosphorylated phosphorylase kinase is active and catalyzes phosphorylation of phosphorylase b to phosphorylase a (active form)" Easier to understand in a diagram than words.

Front 30

So, hormonal regulation of the enzymes ___ and ___ makes the hormones the ___ regulation of glycogen metabolism.

You can also ___ stimulate the one enzyme (_[name it]__) in ___ tissue only.

Back 30

glycogen synthase I/D and phosphorylase a/b
primary

allosterically stimulate phosphorylase b in muscle tissue only

Front 31

Outline the allosteric regulation of phosphorylase.
Include location, the allosteric effector, and why it makes sense.

Back 31

In muscle only, high [AMP] makes higher phosphorylase b activity which makes sense because if [AMP] is high, you're obvi low on energy and need more glucose free-- works to activate PL b that was missed by phosphorylase kinase

Also-- [AMP] being high stimulates PFK1 to drive glycolysis.

Front 32

Shutting off glycogen breakdown:
What all do you need to modify?

Back 32

Hormones switch from epi, glucagon, cortisol to insulin
Gs-GTP -auto cleave-> Gs-GDP plus get beta gamma back.
cAMP --phosphodiesterase-> AMP
phosphoprotein phosphatase: phosphorylase kinase, phosphorylase a, glycogen synthase (activates)

Front 33

Describe the regulation of cAMP's phosphodiesterase.

Back 33

It is not actually regulated but constitutively active. cAMP can work because it goes up in concentration enough to overcome it

Front 34

Draw out the whole pathway that happens with glucagon/epinephrine signal.

Then modify after insulin signal received.

Back 34

be sure to mark the locations where the hormones act.

Note: epinephrine's receptor is specifically deemed adrenergic (epi is catecholamine) Gs protein coupled receptor but receptors are the same.

Hormone hitting receptor induces Gs-GDP -> Gs-GTP

Add glycogen synthase being PO4'd to inactive by PKA (later with insulin phosphatase takes off)

The glycogen that's released is G1P --phosphoglucomutase-> G6P -- LIVER ONLY G6phosphatase--> Glc
(obviously muscle wouldn't want to do this)

Add insulin's:
Tyr kinase class of receptor -> dimerizes -> autophosph on certain Tyr residues-> IRS (insulin receptor substrate) docs -> other proteins like PI3K and RAS signaled to and phosphatase downstream turned on.

cAMP cleaved by phophodiesterase (and it being inhibited by methyl xanthines: theophylline and caffeine)

Mark where diseases interfere.

Add actual glycogen building:
G6P <---phosphoglucomutase--->G1P (cytoplasm)
G1P + UTP <---UDP-Glc pyrophosphorylase-->UDP-Glc + PPi
PPi --inorganic pyrophosphatase--> 2Pi

branching enzyme. all of that.