ppp glycogen metabolism part 2 - medicinebau.comppp_glycogen_metabolism ... glycogen phosphorylase...
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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