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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

Key enzymes
Glycogen synthase
(UDP-glucose-glycogen glucosyltransferase)

(GT3) protein family 80 kDa two isozymes

glycogen synthase 1 glycogen synthase 2 muscle and other tissues liver

Regulation of glycogen synthase activity

highly regulated by allosteric effectors such as glucose-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 Site 1a Site 1b Site 2 Site 2a

Phosphorylation Site PKA PKA Serine 7 Serine 10 AMPK CK2


Site 3a
Site 3b Site 3c Site 3d Site 4

Serine 641
Serine 645 Serine 649 Serine 653 Serine 727


by dephosphorylation reactions dephosphorylation of glycogen synthase increase its activity By protein phosphatase 1 (PP1)

Phosphoprotein phosphatase 1 does not exist free in the cytosol, but is tightly bound to its target 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 phosphorylated by PKA and is allosterically activated by glucose 6phosphate

glycogen synthase can exist in phosphorylated and dephosphorylated forms Its active form, glycogen synthase a, is unphosphorylated. Phosphorylation of the hydroxyl side chains of several Ser residues of both subunits converts glycogen synthase a to glycogen synthase b, which is inactive unless its allosteric activator, glucose 6-phosphate, is present. Glycogen synthase is remarkable for its ability to be phosphorylated on various residues by at least 11 different protein kinases. The most important regulatory 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 by covalent modification .
AMP, activates muscle phosphorylase, speeding the release of glucose 1-phosphate from glycogen., ATP blocks the allosteric site to which AMP binds, inactivating phosphorylase 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 , , and subunit. The subunit is the site of the enzyme's catalytic activity while the other three
subunits serve regulatory functions.

and subunits inhibit the enzyme's catalysis and The 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 subunit, The binding of Ca activates the catalytic site of the 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

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 and PP1

Insulin Decrease cAMP Increase glucose uptake Increase activity of PP1 Enhance dephosphorylation Increase activity of glycogen synthase Decrease activity of GSKIII , glycogen phoshorylase kinase and glycogen phosphorylase

Glycogen storage disease

Inborn error of metabolism inherited disorders Genetic defects of enzyme activity involve in glycogen 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 and affect the ability to do anaerobic work (types V and VII) Diseases that can affect the liver and muscles and directly influence blood glucose and muscle metabolism (type III) Diseases that affect various tissues but have no direct effect on blood glucose or on the ability to do 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 content (2.54.1%). 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) confirm the diagnosis If the diagnosis cannot be established, metabolic challenge and exercise testing may be 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 uncooked cornstarch may be satisfactory

No specific treatment exists for the diseases of muscle that impair skeletal muscle ischemic exercise. Enzyme replacement is effective in Pompe disease (type II), which involves cardiac and skeletal muscle