glycogen metabolism ppt

GLYCOGEN METABOLISM

Dr. Phari DajangjuJNMC, AMU

IntroductionStorage form of GlucosePolymer held by glycosidic linkagesStored in Liver and MusclesSource of fuel for brain

StructureIn cytoplasm as granulesinner linear chainOuter branched Central Glycogenin protein

Function

Storage formEnergy for brainReserve fuel for muscle contraction

GLYCOGENOLYSIS

Enzymes of Glycogenolysis

PhosphorylaseBifunctional-Debranching

enzyme

Phospho- glucomutase

Glucose-6-Phosphatase

Step 1:Depolymerization (Release of Glu-1-P)

Enzyme:PhosphorylaseCo Enzyme:Pyridoxal phosphate Orthophosphate splits between C1 and C4 of

adjacent glucoseStops 4 units before branching point

Step 2: Remodelling & Debranching

Bifunctional enzymeTransferaseAlpha-1,6-glucosidaseRelease of free glucose residueLinear Glycogen

Step 3:Conversion of Glu-1-P to Glu-6-

PEnzyme: PhosphoglucomutaseThe active site of Mutase has

phosphorylated serineGlu-1,6-bisP intermediate formed

Step 4: Fate of Glu-6-P

Reaction catalysed by Phosphotase

Regulation of Glycogenolysis

Regulation of enzyme Glycogen Phosphorylase

Hormonal action of Glucagon/Epinephrine

Mechanism is similar in Liver and MuscleEpinephrine in Muscle

Glycogen Phosphorylase

2 Isozyme Glycogen Phosphorylase a and bEach exists in R and T stateDimer with Serine residue Phosphorylase kinase promotes

Phosphorylase b—>a

Phosphorylase kinase

Structure-4 subunits, 4 of eachActivation-1.Phosphorylation of beta -partial activation2.Calcium attaches to delta-full activation

Regulation of glucose breakdown

in musclesLow energy state-1.Epinephrine through Phosphorylase

kinase Phosphorylase b—->a2.AMP from degradation of ATP as allosteric

activator of Phosphorylase b from T—>R stateResting state-1.ATP shift Phophorylase b R—>T state2.High Glu-6-P favour T state

Regulation of glycogen breakdown

in Liver

Liver Phosphorylase sensitive to free GluFree Glu binds to active site, causes

covalent modification R—>T stateLow Glu..activate Phosphorylase aInsulin promotes uptake of Glu and

phosphorylation to Glu-6-P

Glucagon signal pathway

Alpha cells of pancreas secrete GlucagonEpinephrine by adrenal medulla Epinephrine bind to alpha adrenergic

receptorSimilar cascade of reactions

NAMRATA CHHABRA, M.D.

Role of Insulin in Glycogen degradation

Both Phosphorylase and Phosphorylase kinase are dephosphorylated and inactivated by protein phosphatase.

Protein phosphatase is stimulated by Insulin, Therefore Insulin by inhibiting the

activation of these enzymes inhibits the overall process of glycogenolysis.

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GLYCOGENESIS

GLYCOGENESIS

Mainly in Liver and MusclesLiver Glycogen functions as storage and export

of glucose for maintaining levelMuscle glycogen as readily available source of

glucose

Phases of Glycogenesis

Activation Initiation

ElongationGlycogen Branching

ACTIVATION OF GLUCOSE

Step 1:Phosphorylation of Glucose

Step 2:Conversion of Gluc-6-P to Gluc-1-P

Enzyme UDP Glu Pyrophosphorylase

Step-3- Conversion of Glucose-1-P to UDP-Glucose

INITIATION

InitiationGlycosidic bond between the C1 of the glucose moiety of UDP-glucose and the hydroxyl oxygen of a tyrosine side-chain of Glycogenin.

Glucosyl Transferase

UDP is released as a product.

Each subunit of glycogenin catalyzes the addition of eight glucose units to its partner in the glycogenin dimer.

At this point, glycogen synthase takes over to extend the glycogen molecule.

ElongationCatalyzed by Glycogen SynthaseNew glucosyl units added to nonreducing

terminal residues of glycogen. Formation of α-1,4-glycosidic linkage. .

Incorporation of UDP-Glucose into-glycogen

Glycogen Branching

Amylo-(1,4)—>(1,6)-transglucosidaseIncreases the solubilityIncreases terminal residue which are

sites for action of Synthase and Phosphorylase

Regulation of glycogen synthesis

Glycogen SynthaseGS 1 in muscles, GS2 in LiverPhosphorylation inactivates a-->bGlu-6-P is allosteric effector

NAMRATA CHHABRA, M.D.

Role of Insulin in Glycogenesis

Promotes Glycogenesis

Causes activation of Phosphoprotein Phosphatase resulting dephosphorylation of Glycogen Synthase

In liver insulin increases the activity of phosphodiesterase, promoting hydrolysis of cAMP

Insulin thus antagonizes effects of the cAMP cascade induced by glucagon & epinephrine.

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REGULATION

NAMRATA CHHABRA, M.D.

General mechanisms involved in the regulation of enzyme activities

Regulation of enzyme activity

Induction/Repression

Covalent modification

Allosteric modification

Substrate/product

concentration14-Jan-17

NAMRATA CHHABRA, M.D.

Key enzymes involved in the regulation of glycogen

metabolism

Glycogen synthase- For Glycogenesis

Glycogen Phosphorylase

Both these enzymes are reciprocally regulated.

NAMRATA CHHABRA, M.D.

Reciprocal regulation of Enzymes

Glycogen Synthase & Phosphorylase activity are reciprocally regulated

At the same time as phosphorylase is activated by a rise in concentration of cAMP (via phosphorylase kinase), glycogen synthase is converted to the inactive form.

Thus, inhibition of glycogenolysis enhances net glycogenesis, and inhibition of glycogenesis enhances net glycogenolysis

Both processes do not occur at the same time.

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NAMRATA CHHABRA, M.D.

Substrate concentration and allosteric modification

Substrate Glucose-6-PGlycogen Synthase is allosterically

activated by glucose-6-P. High blood glucose concentration leads to

elevated intracellular glucose-6-P. When glycolytic pathway is saturated,

excess glucose-6-P activates Glycogen synthase14-Jan-17

NAMRATA CHHABRA, M.D.

Covalent modification- General concepts Reversible phosphorylation and dephosphorylation

Hormone mediated cAMP mediated cascade

Phosphorylation is mediated by Protein kinase A

Dephosphorylation is carried out by Phosphatase

Insulin causes dephosphorylation by stimulating Phosphatase and Phosphodiesterase (enzyme that breaks down cAMP)

Glucagon causes phosphorylation by stimulating Protein kinase A

14-Jan-17

NAMRATA CHHABRA, M.D.

Regulation of glycogen synthase by covalent

modificationGlycogen synthase exists in both

phosphorylated or dephosphorylated statesActive glycogen synthase a is

dephosphorylated and inactive glycogen synthase b is phosphorylated

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NAMRATA CHHABRA, M.D.

Covalent modification of glycogen synthase

Glycogen synthase

a

Glycogen synthaseb

Phosphatase Protein kinase A

ATPPi

H2O ADP

Active

Inactive14-Jan-17

p

NAMRATA CHHABRA, M.D.

Regulation of Glycogenolysis by Covalent Modification The cAMP cascade results in phosphorylation of a serine hydroxyl of Glycogen Phosphorylase, which promotes transition to the active state. The phosphorylated enzyme is less sensitive to allosteric inhibitors. Thus, even if cellular ATP and glucose-6-phosphate are high, Phosphorylase will be active.

14-Jan-17

NAMRATA CHHABRA, M.D.

Role of cAMP In Glycogen degradationcAMP activates cAMP dependent Protein Kinase

Phosphorylation of inactive phosphorylase kinase b to a

Phosphorylation of inactive Glycogen Phosphorylase b to a

In the liver, cAMP is formed in response to glucagon, muscle is insensitive to glucagon.

In muscle, increased cAMP formation is the action of norepinephrine

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NAMRATA CHHABRA, M.D.

Role of calcium in muscle degradation

Phosphorylase Kinase is partly activated by binding of Ca++

Further activation is brought by phosphorylation.

Phosphorylase KinaseDephosphorylated

(inactive)

Phosphorylase kinase- Ca++

Partly active

Phosphorylase kinase- Ca++

Phosphorylated- active

Ca++

ATP

14-Jan-17

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