regulation of glycogen metabolism.pptx

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Regulation of glycogen metabolism

Coordinated Regulation of Glycogen Synthesis

and Breakdown

REGULATION OF GLYCOGEN METABOLISM IS EFFECTED BY A

BALANCE IN ACTIVITIES BETWEEN GLYCOGEN SYNTHASE &PHOSPHORYLASE

The synthetic and degradative pathways of Glycogen are

reciprocally regulated to prevent futile cycles



Regulation of glycogen synthase activity

• highly regulated by allosteric effectors such asglucose-6-phosphate

• Also regulated by covalent modification

• by phosphorylation reactions• Phosphorylation of glycogen synthase decreases

its activity

•

by glycogen synthase kinase 3 (GSK-3)• AMPK

• and protein kinase A (PKA)



Name Phosphorylation Site Kinase

Site 1a PKA

Site 1b PKA

Site 2 Serine 7 AMPK Site 2a Serine 10 CK2

Site 3a Serine 641 GSK3

Site 3b Serine 645 GSK3

Site 3c Serine 649 GSK3

Site 3d Serine 653 GSK3

Site 4 Serine 727

http://en.wikipedia.org/wiki/Protein_kinase_A


http://en.wikipedia.org/wiki/AMP-activated_protein_kinase

http://en.wikipedia.org/wiki/Casein_kinase_2

http://en.wikipedia.org/wiki/GSK3








http://en.wikipedia.org/wiki/Casein_kinase_2

http://en.wikipedia.org/wiki/AMP-activated_protein_kinase





• by dephosphorylation reactions

• dephosphorylation of glycogen synthase

increase its activity

• By protein phosphatase 1 (PP1)



PP1

• Phosphoprotein phosphatase 1 does not existfree in the cytosol, but is tightly bound to itstarget proteins by one of a family of glycogen

targeting proteins that bind glycogen and each of the three enzymes, glycogen phosphorylase,phosphorylase kinase, and glycogen synthase

• PP1 is itself subject to covalent and allosteric

regulation: it is inactivated when phosphorylatedby PKA and is allosterically activated by glucose 6-phosphate



Summary

• glycogen synthase can exist in phosphorylated anddephosphorylated forms Its active form, glycogensynthase a, is unphosphorylated. Phosphorylation of the hydroxyl side chains of several Ser residues of both

subunits converts glycogen synthase a to glycogensynthase b, which is inactive unless its allostericactivator, glucose 6-phosphate, is present .

• Glycogen synthase is remarkable for its ability to be

phosphorylated on various residues by at least 11different protein kinases. The most importantregulatory kinase is glycogen synthase kinase 3 (GSK3)



Key enzymes

• Glycogen phosphorylase

• biologically active as a dimer of two identical

subunits

• 97.434 kDa

• major isozymes of glycogen phosphorylase

are found in muscle, liver, and brain.



Regulation of glycogen phosphrylase activity

•

regulated by both allosteric control and bycovalent modification .

AMP, activates muscle phosphorylase, speeding the release

of glucose 1-phosphate from glycogen.,

• ATP blocks the allosteric site to which AMP binds, inactivatingphosphorylase

• Glucose allostericaly inhibit hepatic glycogen phosphorylase

glycogen phosphorylase exists in two interconvertible forms:

• glycogen phosphorylase a, which is catalytically active, and

glycogen phosphorylase b, which is less active



• Phosphorylation by

• Glycogen phosphorylase kinase

• homotetramer of tetramers (16 subunits) arranged in an

approximate “butterfly” shape. Each of the four tetramers is

composed of an α, β, γ and δ subunit. The γ subunit is the site

of the enzyme's catalytic activity while the other three

subunits serve regulatory functions.

• α and β subunits inhibit the enzyme's catalysis and The δ

subunit is a calmodulin and has 4 calcium ion binding sites



• Phosphorylase kinase also exist in active phosphorylated form

(a) and inactive dephosphorylated form (b)

• It is phosphorylated by many ways

• cAMP dependent protein kinase ( PKA )

• Ca in musle

•

• cAMP, increases in concentration in response to stimulation

by adrenaline (in muscle) or glucagon (in liver). Elevated

[cAMP] initiates an enzyme cascade, in which a catalyst

activates a catalyst, which activates a catalyst

• . Ca in muscle binds to phosphorylase kinase through its δ

subunit, The binding of Ca activates the catalytic site of the γ

subunit while the molecule remains in the dephosphorylated

b form



Again dephosphorylation of both glycogen phosphorylase and

phosphorylase kinase by phosphoprptein phosphatase PP1



Cascade mechanism of phosporylation



Summary

• in liver

• Phosphorylase allosterically regulated by

glucose

• Phosphorylase kinase activated by cAMP

dependent protein kinase – PKA



• In muscle

• Phosphorylase allosterically regulated by AMP

and ATP

• Phosphorylase kinase activated by both PKA

and by Ca



Hormonal regulation of glycogen

metabolism

• Glucagon and adrenaline

• Increase cAMP

•

Enhance phosphorylation process• Increase Activity of glycogen phosphorylase

kinase and glycogen phoshorylase

•

Decrease activity of glycogen synthase andPP1



• Insulin

• Decrease cAMP

• Increase glucose uptake

• Increase activity of PP1

• Enhance dephosphorylation

• Increase activity of glycogen synthase

• Decrease activity of GSKIII , glycogenphoshorylase kinase and glycogen

phosphorylase

•



Glycogen storage disease

• Inborn error of metabolism

• inherited disorders

•

Genetic defects of enzyme activity involve inglycogen metabolism



• 4major types

• Diseases that predominantly affect the liver and

have a direct influence on blood glucose (types I,VI, and VIII)

• Diseases that predominantly involve muscles andaffect the ability to do anaerobic work (types Vand VII)

• Diseases that can affect the liver and muscles anddirectly influence blood glucose and musclemetabolism (type III)

•

Diseases that affect various tissues but have nodirect effect on blood glucose or on the ability todo anaerobic work (types II and IV)

•



Type 1 a b and c



• Hepatomegally

• Fasting hypoglycamia

•

Lactic acidosis• Hyper lipidaemia

• Ketosis

•Hyperuricaemia



Type 2

• Lysosomal storage disease

• muscle weakness,

•

cardiomegaly,• heart failure

• Bad prognosis

•death in the first year of life is usual



Type 5

• Diminished exercise tolerance;

• muscles have abnormally high glycogen con-

tent (2.5 –4.1%).

• Little or no lactate in blood after exercise.



• The diagnosis of glycogen storage disease can

often be confirmed by DNA mutation testing

in blood cells.

• When mutation testing is not available,

enzyme measurements in the tissue suspected

to be affected (either liver or muscle) confirmthe diagnosis

• If the diagnosis cannot be established,

metabolic challenge and exercise testing maybe needed



• Treatment of hepatic glycogen storage disease

is aimed at maintaining satisfactory blood

glucose levels or supplying alternative energy

sources to muscle.

• In glucose-6-phosphatase deficiency (type I),

the treatment usually requires nocturnal

intragastric feedings of glucose during the first

1 or 2 years of life. Thereafter, snacks or

nocturnal intragastric feedings of uncookedcornstarch may be satisfactory



• No specific treatment exists for the diseases of

muscle that impair skeletal muscle ischemic

exercise. Enzyme replacement is effective inPompe disease (type II), which involves

cardiac and skeletal muscle

regulation of glycogen metabolism.pptx

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