STRUCTURE OF GLYCOGEN

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STRUCTURE OF GLYCOGEN
Found in the form of granules within the cell.
Highly branched polysaccharide of glucose
consisting of (a-1,4)linked glucose molecules
with an (a-1,6)branch every 4-6 glucose residues.
Important to provide large number of ends at
which phosphorylase and glycogen synthase can
act. Formed joined to a tyrosine residue on the
protein glycogenin.
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GLYCOGEN BREAKDOWN
PHOSPHORYLASE
(GLUCOSE)n Pi (GLUCOSE)n-1
G-1-P
PHOSPHOROLYSIS OF a(1-4)LINKAGES UP TO 4 GLUCOSE
RESIDUES FROM AN a(1-6)BRANCH POINT
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GLYCOGEN SYNTHESIS
HEXOKINASE
GLUCOSE ATP GLUCOSE-6-PHOSPHATE
ADP
PHOSPHOGLUCOMUTASE
GLUCOSE-6-PHOSPHATE
GLUCOSE-1-PHOSPHATE
GLUCOSE-1-PHOSPHATE URIDYLTRANSFERASE
GLUCOSE-1-PHOSPHATE UTP
UDP-GLUCOSE PPi
GLYCOGEN SYNTHASE
UDP-GLUCOSE GLYCOGEN (n)
GLYCOGEN(n1) UDP
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PHOSPHORYLASE REGULATION
PHOSPHORYLASE b KINASE
2ADP
2ATP
T FORM
T FORM
(INACTIVE)
(INACTIVE)
2Pi
2H20
SERINE 14 N-TERMINUS (AMP-INDEPENDENT)
PROTEIN PHOSPHATASE
ATP and/or G-6-P
Glucose (Liver)
AMP
R FORM
R FORM
(ACTIVE)
(ACTIVE)
PHOSPHORYLASE a
PHOSPHORYLASE b
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STRUCTURE OF PHOSPHORYLASE KINASE
REGULATORY SUBUNITS

• ENTIRELY IN b FORM IN RESTING
• MUSCLE
• ACTIVATED BY
• (i) INCREASED Ca 2
• - CONTRACTION
• - a1-ADRENERGIC AGENTS
• - ANGIOTENSIN
• - VASOPRESSIN
• PHOSPHORYLATION
• - cAMP-DEPENDENT PROTEIN
• KINASE

b
b
a
a


d
d
g
g
ACTIVE SITE
g
g


d
d
a
a
b
b
CALCIUM-BINDING PROTEIN (CALMODULIN)
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cAMPPK
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DEPHOSPHORYLATION OF PHOSPHORYLASE AND
PHOSPHORYLASE KINASE
PROTEIN PHOSPHATASE 1 95 ACTIVITY TOWARDS
PHOSPHORYLASE 95 ACTIVITY TOWARDS b-SUBUNIT OF
PHOSPHORYLASE KINASE 85 ACTIVITY TOWARDS
GLYCOGEN SYNTHASE (Sites 1a, 2, 3(a,b,c)) TIGHT
COMBINATION WITH GLYCOGEN VIA GLYCOGEN BINDING
SUBUNIT. RELEASED ON PHOSPHORYLATION BY cAMPPK
(SITES 1 2) INHIBITED BY PROTEIN PHOSPHATASE 1
INHIHIBITOR (PI-1) WHEN PI-1 ACTIVATED BY
PHOSPHORYLATION BY cAMPPK.
GLYCOGEN
GLYCOGEN
INACTIVE

ACTIVE
ACTIVE
INACTIVE
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CONTROL OF GLYCOGEN SYNTHASE
NINE PHOSPHORYLATION SITES (SERINE RESIDUES) -
SITE 2 AT THE N TERMINUS, REMAINDER AT C
TERMINUS. REQUIRE PHOSPHORYLATION AT BOTH N AND
C TERMINUS FOR INACTIVATION.
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CONTROL OF GLYCOGEN SYNTHASE BY ADRENALINE AND
INSULIN
ADRENALINE INHIBITS GLYCOGEN SYNTHASE BY cAMP
DEPENDENT MECHANISM
ADRENALINE PROPRANOLOL ACTIVITY 20
100 PHOSPHATE 5MOLES/SUBUNIT
3MOLES/SUBUNIT 50 OF Pi IN SITES 3a,b,c.
50 IN SITES 1a, 1b, AND 2. 75 DECREASE IN
ACTIVITY RESULTS FROM SITES 3a,b,c. CATALYSED BY
GSK-3 WHICH IS cAMP-INDEPENDENT, THEREFORE MAJOR
INACTIVATING EFFECT IS DUE TO INHIBITION OF
PHOSPHATASE RATHER THAN ACTIVATION OF KINASE
INSULIN TREATMENT REDUCES Pi BY 0.5 MOLES
Pi/SUBUNIT FROM SITES 3a,b,c (NOT cAMP
MEDIATED) THEREFORE EITHER IT INHIBITS GSK3 OR
ACTIVATES PHOSPHATASE ALSO ? GLUCOSE TRANSPORT
(GLUT4) AND ? G-6-P
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CONTROL OF GLYCOGEN METABOLISM BY cAMP
ADRENALINE
GLUCAGON
(Muscle)
(Liver)
b-RECEPTOR
RECEPTOR
ATP cAMP
2C R2 (cAMP)4
PI-1
(Active)
PP2A
PI-1
PPI- PI-1
PP1 G
PhK
PP2A
Sites 1 2
(More Active)
Sites 1a, 2,1b
(Inactive)
Site 2
GS
(Less Active)
Phosa Phos b
X
(Inactive)
(Active)
Most impt. sites 3a,b,c
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CONTROL OF GLYCOGEN SYNTHASE BY INSULIN
GLUCOSE
INSULIN
GLUT4
RECEPTOR
Glucose
IRS-1, SHC
Grb2/mSOS
RAS
PI-3K
G-6-P
RAF
PKB
MEK
?GSK3
MAP KINASE
(Inactive)
C
p90rsk
?PP1G
Site 1

(More active)
Other pathways ?
N
GLYCOGEN SYNTHASE
(ISPK, MAPKAK-1)
p90rsk
The relative importance of these pathways may
vary from tissue to tissue
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CONTROL OF GLYCOGEN METABOLISM BY INSULIN
GLUCOSE
INSULIN
Receptor
Glut4
TYROSINE KINASE
GSK-3
GLUCOSE
PKB
MAPK
(Active)
(Active)
G-6-P
ISPK (p90rsk)
ISPK
GSK-3
(Active)
(Inactive)
? PHOSPHORYLASE ? GLYCOGEN SYNTHASE
PP1G
(More Active)
GS
Site1
(Less Active)
X
PHOSKa
(More Active)
GS
(More Active)
PHOSKb
ADRENALINE PPIG SITES 1 2
PHOSa PHOSb
(Less Active)
(Inactive)
(Active)
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GLYCOGEN METABOLISM IN LIVER
  MANY EFFECTS THROUGH Ca2 RATHER THAN cAMP VIA
ADRENALINE (?1), ANGIOTENSIN II AND
VASOPRESSIN.   PHOSPHORYLASE DIFFERENT
ISOENZYME FROM MUSCLE. NOT CONTROLLED BY AMP OR
G-6-P. GLUCOSE BINDS TO ACTIVE SITE AND
COMPETITIVELY INHIBITS THE ENZYME AND MAKES MORE
SUSCEPTIBLE TO DEPHOSPHORYLATION BY STABILISING
T STATE   GLYCOGEN SYNTHASE - PHOSPHORYLATION
DECREASES Vmax RATHER THAN INCREASING Km FOR
UDPG. NO SITES 1a AND 1b. GLUCAGON AND GLUCOSE
MAIN EFFECTORS. G-6-P PROMOTES DEPHOSPHORYLATION
BY PP1 AS WELL AS ALLOSTERICALLY
ACTIVATING. PP1-G GLYCOGEN BINDING SUBUNIT
SMALLER AND NO EVIDENCE FOR CONTROL BY
PHOSPHORYLATION. G SUBUNITS ANCHOR PHOSPHATASE
TO GLYCOGEN PARTICLES AND DECREASES SENSITIVITY
TO PI-1. BINDS STRONGLY TO PHOSa BUT NOT PHOSb
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GLYCOGEN METABOLISM IN LIVER 11
GLUCAGON INCREASES cAMP LEADING TO INCREASED
PHOS KINASE AND PHOSa ACTIVITY. PHOSa ACTS AS
ALLOSTERIC INHIBITOR TO INHIBIT PPI-G AND PREVENT
DEPHOSPHORYLATION. SIMILAR EFFECTS OCCUR WITH
ADRENALINE VIA INCREASED Ca2 AND PHOS KINASE.
BOTH PHOSPHORYLATE GLYCOGEN SYNTHASE VIA cAMPPK
AND Ca2/CALMODULIN DEPENDENT PROTEIN KINASES.
INSULIN ACTIVATES cAMP-PDE VIA PI-3-KINASE
PATHWAY LEADING TO DECREASE IN cAMP AND REDUCTION
IN PHOS KINASE AND PHOSa AND DECREASE IN
GLYCOGENOLYSIS. ALSO ATTENUATES THE ALLOSTERIC
INHIBITION OF PPI-G CAUSING RELEASE OF PP1-G AND
DEPHOSPHORYLATION OF GLYCOGEN SYNTHASE AND
PHOSPHORYLASE KINASE. EFFECT OF GLUCOSE
ENHANCES GLYCOGEN DEPOSITION. PHOSa FUNCTIONS AS
GLUCOSE RECEPTOR. BINDS TO ACTIVE SITE AND
COMPETITIVELY INHIBITS THE ENZYME. ALSO INDUCES
CONFORMATIONAL CHANGE (STABILISES THE T STATE)
CAUSING SER 14 TO BECOME ACCESSIBLE TO PP1-G
LEADING TO DEPHOSPHORYLATION. CAUSES RELEASE OF
PP1-G ALLOWING IT TO INTERACT WITH GLYCOGEN
SYNTHASE SWITCHING IT ON.
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REGULATION OF PHOSPHORYLASE AND GLYCOGEN
SYNTHASE BY GLUCOSE
CH2OH
CH2OH
O
O

Phosa
Phosa
Phosa
Phosa
GLUCOSE
P
P
P
P
Phosphorylasea-Glucose-Phosphatase
Complex T conformation
Phosphorylasea-Phosphatase
Complex R conformation (Active)
Phosb
Phosb
2
Glycogen Synthase D
Phosphorylaseb T conformation (Inactive)
Glycogen Synthase I

Less Active
(Cf Effect of 5AMP)
Active
Inhibited by Phosphorylasea