PPP_glycogen_metabolism

Part 2 الفريق الطبي األكاديمي

لكــية الطب البرشي

البلقاء التطبيقية / املركز

6102/6166أ حياها و من

Done By: - Shady Soghayr

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**How we get glucose-1-phosphate from glucose (source of glucose-1-

phosphate)?

From glucose-6-phosphate by phosphoglucomutase

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**From where we get glucose-6-phosphate?

Glucose is converted to glucose-6-phosphate by hexokinase

**glucose-1-phosphate is not used directly to be incorporated into glycogen by

glycogen synthase, it must be converted to activated intermediate.

**the active intermediate of glucose-1-phosphate is synthesized by the reaction

of glucose-1-phosphate with UTP (Uridinile Tri Phosphate)

**UTP is a high energy compound

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**activated intermediate is going to be used by glycogen synthase in order to

incorporate glucose units to the growing chain of glycogen

**Why we use this activated intermediate (activated intermediate)?

In order to make α(1-4) glycosidic bonds for the incorporation of glucose into the

growing chain of glycogen (this intermediate has very high energy bond that when

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hydrolyzed it will be able to incorporate glucose and forming α(1-4) glycosidic

bond

**the energy of the activated intermediate is stronger than the energy of α (1-4)

glycosidic bond

**the activated intermediate is UDP-glucose

**glycogen synthase will incorporate the glucose molecule to the glycogen chain

+UDP

**how to make the α (1-6) glycosidic bond?

The (branching enzyme) and it works by carrying a bunch of glucose units

breaking the α(1-4)glycosidic bond and forming the

α(1-6)glycosidic bond

**the energy needed to make the α(1-6) glycosidic bond is taken from the

hydrolysis of the α(1-4) glycosidic bond

**the body depends on glucose that comes from glycogen because it comes very

fast and it comes when needed

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**the body will activate glycogen degradation and in the same time inhibits

glycogen synthesis

** function of glycogen phosphorylase?

Degradation of glycogen by phosphorolases

**how phosphorolyses of glycogen will take place?

By adding a phosphate group (in the presence of phosphate and glycogen

phosphorylase ,phosphate will be added to glucose giving a glucose-1-phosphate)

**glycogen phosphorylase is regulated by 2 different mechanisms the first is

covalent modification (include phosphorylation and DE phosphorylation) and the

second is allosteric regulation

**in the pic from right to left or from left to right is covalent modification and

what is involved in it is the phosphorylation of glycogen by an enzyme called

phosphorylase kinase

**phosphorylate kinase will phosphorylate glycogen phosphorylase and become

phosphorylated

**at the de phosphorylation of glycogen phosphorylase "is taking place in this

direction" by an enzyme called (phospho protein phosphatase)

**when glycogen phosphorylase is phosphorylated it is activated and when de

phosphorylated it will be inactivated

**glycogen phosphorylase is found in 2 forms 1-glycogen phosphorylase b (the

less active)

2-glycogen phosphorylase a (the most active)

**when (glycogen phosphorylase b) is phosphorylated it is converted to (glycogen

phosphorylase a) and when glycogen phosphorylase a is dephosphorated is is

converted to glycogen phosphorylase b which is less active or ,in active

**allosteric regulation means that glycogen phosphorylase is found in two states

the R-state and the T-state

**glycogen phosphorylase in allosteric regulation has positive allosteric effectors

and negative allosteric effectors

**each form of glycogen phosphorylases is found in two states the R-state and

the T-state

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**what happens to glycogen phosphorylase a in the liver?

When you have a carbohydrate rich food you will have a high level of glucose in

the blood (high energy) and this will allosterically convert the glycogen

phosphorylase a from the R-state to T-state of GPa

**glucose is a negative allosteric effector for the GPa

**in most of the cases in the body there is no glucose "playing around" because it

is poison to cells ,so the cell will deal with it and not leaving the glucose in cells so

the T-state will be converted to the R-state in most of the times

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**GPb in the muscle is allosterically converted from R-state to T-state by ATP and

glucose-6-phosphate

**ATP and glucose-6-phosphate represents high energy

** when the muscle contracts and losses all its ATP from creatinephosphate

there will be an accumulation of AMP(AMP represents low energy)so it will convert

the T-state to the R-state of the GPb until the hormone comes (glucagon or

epinephrine)to give a signal to phosphorylate GPb to be converted to GPa in order

to start glycogen degredation

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Once these enzymes bind to their receptors, they will activate g proteins including

adenylate cyclase system, which would convert ATP to cAMP and cAMP when

activate protein kinase A from inactive to active form.

Protein kinase A is the enzyme that is not phosphorylated but it phosphorylates

other proteins such as phosphorylase kinase that is going to phosphorylate

glycogen phosphorylase as well as phosphorylating glycogen synthase.

now remember, when glycogen phosphorylase is phosphorylated it is activated

and at the same time when glycogen synthase is phosphorylated by protein

kinase it is inactivated.

So it is nonsense to activate glycogen phosphorylase and at the same time

activate glycogen synthase, this is their reciprocal regulation, activation of

glycogen phosphorylase and inactivation of glycogen synthase by the

phosphorylation by glucagon or epinephrine indirectly by signal transduction.

Does the body require the adenylate Cyclase to be active all the time? And what is

the function of Cyclase?

It converts ATP to cAMP, which is considered one of the second messengers, this

cAMP will activate protein kinase A by allosteric regulation, it will dissociate the

catalytic subunit from the regulatory subunit of protein kinase A and thus activate

the catalytic subunit to start phosphorylating other proteins, so protein kinase A is

a common kinase enzyme that will phosphorylate many proteins including

glycogen phosphorylase and glycogen synthase.

In order to control this system, the cell could degrade the cAMP and get rid of it

converting it to AMP by an enzyme called phosphodiesterase. Phosphodiesterase

will control the system by decreasing the concentration of cAMP and thus

inhibiting protein kinase A thus stopping the phosphorylation or the Covalent

modification of glycogen phosphorylase and glycogen synthase.

It was found that phosphodiesterase which degrades cAMP, is inhibited by

caffeine. At high levels of glucagon and epinephrine the body degrades glycogen.

At high levels of insulin the opposite happens, glycogen is synthesized, and the

degradation of glycogen is inhibited.

Insulin is For the synthesis of glycogen and glycolysis while epinephrine or

glucagon is for degradation of glucose and inhibiting glycolysis and activating

gluconeogenesis.

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Phosphorylase Kinase Regulation

How phosphorylase kinase is

regulated?

Protein kinase A will

phosphorylate phosphorylase

kinase. Phosphorylase kinase

could be activated in 2

pathways.

It Could be activated first, by

phosphorylation by protein

kinase A, then by calcium to

give fully active phosphorylase

kinase.

Or it could be activated

allosterically first by calcium so

it's partially active, then it is

phosphorylated to fully active

phosphorylase kinase.

This is very important because when the muscle is Contracting there's no enough

energy under phosphorylase kinase did not yet receive the signal from the

glucagon or epinephrine but because of the continuous muscle contraction high

levels of calcium is produced, which is going to partially activate the

phosphorylase kinase and help the muscle to degrade its glycogen, even before

the phosphorylation starts by the signals of hormones.

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Glucagon is a hormone protein when epinephrine is not a hormone protein, it is a

hormone but not a protein.

As a summary, when glucose levels are low, epinephrine or glucagon increases

glucose concentration by favoring glycogen breakdown by activating glycogen

phosphorylase and inhibiting glycogen synthesis by inhibiting glycogen synthase.

Insulin stimulates phosphoprotein phosphatase, which removes phosphate group

from glycogen enzymes, which are glycogen phosphorylase and glycogen

synthase.

So phosphoprotein phosphatase will dephosphorylate glycogen phosphorylase a,

and glycogen synthase a, which means there would be inhibition of glycogen

degradation and activation of glycogen synthesis.

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Insulin Signaling

Countering the Epinephrine/Glucagon System is the

Insulin System

Insulin Stimulates Phosphoprotein Phosphatase to

Remove

Phosphates From Glycogen Enzymes

1. Favoring Glycogen Synthesis (Activates Glycogen

Synthase)

and

2. Inhibiting Glycogen Breakdown (Inhibits Glycogen Phosphorylase)

Insulin Also Stimulates Uptake of Glucose by Cells,

Reducing Blood Glucose Levels

So insulin counteracts the reactions of epinephrine and glucagon.

How insulin activates glycogen synthase?

It dephosphorylates phosphate from glycogen synthase and convert it to non

phosphorylated glycogen synthase which is the active form ->Inhibiting glycogen

breakdown by inhibiting glycogen phosphorylase.

How it inhibits glycogen phosphorylase?

By activating phosphoprotein phosphatase which will dephosphorylate the

glycogen phosphorylase.

Insulin also stimulates uptake of glucose by cells, how?

By Simulating low glucose transporters like gluts, that binds with glucose taking

them inside the cells.

What does insulin do this glucose in the cells?

Start the glycolysis pathway.

Thank you