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Biochemistry I
Lecture 31
April 8, 2013
Lecture 31: Hormonal Regulation of Glucose/Glycogen [Liver]
Glycogen Metabolism:
The Rules:
1. Regulation makes physiological sense.
2. Opposing pathways are coordinately regulated (if
one is on, other is off)
3. Low blood glucose (or request for additional
glucose) causes:
 Enzymes become phosphorylated via hormone
signal. Directly affecting glycogen metab.
 F2-6P levels become low due to enz.
Phosphorylation (F2-6P follows glucose
levels), affecting glycolysis/gluconeogenesis.
CH2OH
O
O
CH2OH
CH2OH
CH2OH
CH2OH
O
O
O
O
O
CH2OH
CH2OH
O
O
O
O
O
O
CH2OH
O
O
O
CH2OH
CH2 OH
O
[glycogen
synthase]
O
CH2OH
O
O
O
O
O
O
O
O
O
CH2OH
CH2OH
CH2OH
OH
CH2OH
CH2OH
P
O
O
O
O
O
[glycogen
phosphorylase]
O
O
CH2 OH
O
OH
Hormonal Control of Pathways:



Secretion of epinephrine (also known as
adrenaline) occurs during dangerous
situations, indicative of high energy
needs. Secretion of epinephrine is under
control of the central nervous system.
This leads to the phosphorylation of
many enzymes.
Secretion of glucagon from the - cells
in the pancreas occurs when blood
glucose levels are low. This also leads to
the phosphorylation of many enzymes.
Secretion of insulin from the -cells
pancreas occurs when blood glucose
levels are high. This leads to the
dephosphorylation of the enzymes that
were phosphorylated due to epinephrine
or glucagon.
Pancreas
Adrenal Gland
 cells
epinephrine (adrenaline)
glucagon
1
epinephrine
receptor
Glycogen
breakdown
Gluconeogenesis
Glucose
Blood
Muscle
Dephosphorylation
Cyclase
GDP
G-protein
(GTP)
4
ATP
G-protein
(GDP)
O
ATP
5
Activated kinase
1
N
NH2
O
O P
O
O
P
Protein kinase A
OH
N
O N
OH OH
cAMP
OH
N
Activates
Glycogen
synthase
N
O N
OH
N
protein
phosphatase
N
Glycogen
synthase
Glycogen
phosphorylase
Glycogen
phosphorylase
Insulin
NH2
O
P
O
cAMP
Protein kinase A
Glycogen
phosphorylase
Insulin
receptor
O
O
P
O
O
O
O P
Adenyl
O
GTP
2 3
Glycogen
synthase
Glycogen Glucose
synthesis oxidation
Outside
glucagon
receptor
6
insulin
glucagon
Molecular events that lead to protein:
Phosphorylation
Cell
Membrane
 cells
P
P
P
Glycogen
synthase
Glycogen
phosphorylase
OH
OH
O
Biochemistry I
Lecture 31
April 8, 2013
A. Low Blood Sugar or Epinephrine: Proteins phosphorylated.
1. Glucagon and/or epinephrine bind to G-protein coupled receptors on the surface of the cell.
2. The Binding of ligand to receptor generates a binding site for G-protein/GDP complex inside the cell via
allosteric changes, thus transmitting the signal across the membrane.
3. Receptor-G-protein interaction exchanges GDP for GTP, G-protein-GTP complex binds to Adenylate
cyclase, activating it, also by an allosteric change.
4. Adenylate cyclase converts ATP to cAMP. cAMP
is called a '2nd messenger' .
N
N
O
O
O
N
N
N
P O
O
N
O P
Each receptor binding event produces 1000-2000
N
O P
O
O
N
O
molecules of cAMP. G-protein/GTP complex decays
O
N
O
O
to GDP complex, ending cAMP synthesis unless
O P
O
OH
O
hormones are still present.
OH OH
cAMP
ATP
(3'-5' cyclic AMP)
5. cAMP activates protein kinase A.
6. Protein kinase A activation results in the phosphorylation of the following targets related to glycogen
metabolism, resulting in the breakdown of glycogen to glucose-1-phosphate.
N
a. glycogen synthase (inactivating it)
b. glycogen phosphorylase, activating it, leading to glycogen breakdown.
B. High Blood Sugar: Proteins dephosphorylated -Glycogen synthesized, Glucose used for energy production (if
needed).
O
H3C
To reverse the above effects we need to de-phosphorylate the proteins that were
CH3
N
N
phosphorylated in the above reactions. Thus occurs in two steps:
N
1. cAMP levels drop since they are no longer elevated due to absence of glycogen
N
O
and/or epinephrine. Caffeine inhibits the decay of cAMP.
CH3
2. A protein phosphatase is activated leading to loss of phosphate groups.
glycogen synthase becomes active, leading to the synthesis of glycogen.
Caffeine
Control of Glycogen Metabolism: Glycogen synthesis and degradation is directly
controlled by protein phosphorylation.
Low Glucose
High Glucose Levels
CH2OH
CH2OH
O
O
O
CH2OH
CH2 OH
CH2 OH
O
CH2 OH
O
CH2OH
CH2OH
CH2 OH
OH
O
O
CH2OH
O
O
O
O
O
O
O
CH2OH
CH2 OH
CH2OH
O
O
CH2OH
O
O
O
CH2OH
CH2OH
CH2 OH
O
OH
O
O
CH2OH
O
O
O
O
CH2 OH
CH2OH
O
O
CH2OH
CH2 OH
O
CH2OH
O
OH
O
CH2OH
O
O
O
O
O
O
O
O
O
O
O
O
CH2OH
[glycogen
synthase]
O
OH
2
O
CH2 OH
O
O
O
O
P
O
O
O
O
O
CH2OH
CH2OH
CH2 OH
CH2 OH
O
O
O
[glycogen
synthase]
CH2 OH
CH2OH
O
O
[glycogen
phosphorylase]
O
O
CH2OH
O
O
O
P
O
O
O
O
O
[glycogen
phosphorylase]
CH2OH
O
O
O
Biochemistry I
Lecture 31
A. Regulation of PFK-1/bisPhosphatase by
energy sensing and F26P
April 8, 2013
B. Regulation of glycogen synthesis & degradation by
enzyme phosphorylation.
O
H2
C
P O
O
O
OH
H2C
CH2OH
O
HO
O
O
OH
[glycogen
phosphorylase]
OH
Glycolysis
OFF
AMP
ON
[PFK-1]
ADP
OFF
[Fructose-bis
phosphatase-1]
ATP
ON
F 2,6 P
H2
C
P O
O
O
O
O
O
CH2OH
CH2OH
CH2OH
CH2OH
O
O
O
H2C
O
HO
O
CH2OH
CH2 OH
CH2OH
O
O
O
O
O
O
O
CH2 OH
[glycogen
synthase]
P
O
O
O
O
O
O
O
CH2OH
O
O
O
O
CH2OH
CH2OH
OH
O
O
O
CH2OH
O
O
Gluconeogenesis
OFF
P
O
O
O
O
O
CH2OH
CH2OH
CH2OH
CH2OH
O
O
OH
O O
OH
OH
C. Regulation of Glycolysis/Gluconeogenesis in the liver by F-2,6P Levels.
Glucose
OPO3
CH2
H2
C OH
O
High blood
Glucose
Protein Phosphorylation
HIGH
LOW
F2,6P levels
LOW
HIGH
ADP
OH
Fructose-6phosphate
PFK-2
OH
OH
ATP
bisPhos-2
ADP
PFK-1
OPO3
Low blood
Glucose
ATP
CH2
bisPhos-1
OPO3
H2C
O
OPO3
CH2
CH2OH
O
OH
1-6 fructose
phosphate
OPO3
OH
2-6 fructose phosphate
(Regulatory)
OH
OH
PYR
Gluconeogenesis
Low Blood Glucose  low F2,6P
High Blood Glucose Levels  high F2,6P
(Enzymes phosphorylated)
(Enzymes dephosphorylated)
Fructose-6-P
ATP
[PFK-2]
Enz
Glycolysis
OH
Pi
ATP
[FBPase-2]
[PFK-2]
P
Enz
ADP
Enz
P
Fructose-6-P
Pi
[FBPase-2]
OH
Enz
ADP
OH
Fructose 2,6bisP
Fructose 2,6bisP
F2,6 Allosteric regulation of Glycolysis and Gluconeogenesis
ATP
Fructose-6-P
[PFK]
Activated
by F2-6P
Pi
[Fructose-1-6
bisphosphatase]
Inhibited F2-6P
ADP
ATP
Fructose-6-P
[PFK]
Activated
by F2-6P
Pi
[Fructose-1-6
bisphosphatase]
Inhibited F2-6P
ADP
Fructose 1,6bisP
Glycolysis
Gluconeogenesis
Fructose 1,6bisP
Glycolysis
Gluconeogenesis
F2-6P is required for glycolysis to be active in the liver. If f26P levels are low (glucose demand) the liver will not
undergo glycolysis.
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