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9 Glycogen
9 Glycogen
Glycogen Metabolism
CH2OH
H
CH2OH
O
H
OH
OH
H
O
OH
CH2OH
H
OH
H
O
H
OH
OH
CH2OH
O
H
OH
OH
H
O
O
H
OH
H
H
OH
H
O
glycogen
H
1
O
6 CH2
5
H
OH
3
H
CH2OH
O
H
2
OH
H
1
O
CH2OH
O
H
4 OH
H
H
O
OH
O
H
OH
H
OH
OH
CH2OH
H
Glycogen catabolism
(breakdown):
O
H
OH
OH
OH
H
OPO32
glucose-1-phosphate
Pyridoxal phosphate
(PLP), a derivative of
vitamin B6, serves as
prosthetic group for
Glycogen Phosphorylase.
H
O
P
O
H2
C
O
OH
N
H
CH3
Enz
(CH2)4
O
P
O
HC
H2
C
N+
H
O
N
H
CH3
Enz
(CH2)4
P
O
HC
H2
C
N+
H
O
N
H
CH3
Glycogen
Phosphorylase:
a homodimeric
PLP
enzyme, subject to
allosteric control.
It transitions between
relaxed (active) &
tense (inhibited)
conformations.
GlcNAc
Diagram comparing
relaxed and tense
Human Liver
conformations.
Glycogen Phosphorylase
GlcNAc
inhibitor
PLP
PDB 1EM6
A class of drugs
developed for treating
PLP
the hyperglycemia of
diabetes (chloroindolecarboxamides), inhibit
liver Phosphorylase
allosterically.
These inhibitors bind GlcNAc
at the dimer interface,
stabilizing the inactive Human Liver
(tense) conformation. Glycogen Phosphorylase
Question: Why would an inhibitor of Glycogen
Phosphorylase be a suitable treatment for diabetes?
GlcNAc
inhibitor
PLP
PDB 1EM6
Enzyme-Ser-OPO32
CH2OH
H
O
H
OH
OH
OH
H
OPO32
Enzyme-Ser-OH
CH2OPO32
O
H
H
H
H
OH
2
OPO
3
OH
H
OH
glucose-1-phosphate
Enzyme-Ser-OPO32
CH2OPO32
O
H
H
H
H
OH
OH
OH
H
OH
glucose-6-phosphate
Glycogen
Glucose-1-P
Glucose
Hexokinase or Glucokinase
Glucose-6-Pase
Glucose-6-P
Glucose + Pi
Glycolysis
Pathway
Pyruvate
Glucose metabolism in liver.
O
CH2OH
Glycogen
synthesis
HN
O
H
H
OH
H
O
H
O
OH
H
OH
UDP-glucose
P
O
O
O
CH2
O
H
OH
H
OH
UDP-Glucose Pyrophosphorylase
CH2OH
HN
O
H
H
OH
H
O
OH
OH
CH2OH
H
OH
HN
H
O
H
O
OH
H
OH
UTP
PPi
O
O
UDP-glucose
CH2
O
H
CH2
glucose-1-phosphate
OH
H
OH
OH
H
OH
Tyr
active site
active site
Tyr
Glycogenin dimer
6 CH
2OH
H
4
OH
O
H
OH
H
1
tyrosine residue
of Glycogenin
UDP-glucose
O
O
O
OH
O-linked
glucose H
residue 4
OH
Uridine
HO
C CH
H2
NH
6 CH
2OH
O
H
OH
H
C
1
OH
+ UDP
C CH
H2
NH
CH2OH
CH2OH
A glycosidic
bondH is formed
the anomeric C1 of
O between
O
H
H
H
H
C O
the OH
glucose
from
UDP-glucose
and
the
H
H moiety derived
OH
O
C CH
O of a tyrosine side-chain
hydroxyl oxygen
of Glycogenin.
OH
H
H
OH
OH
NH
6 CH
2OH
O-linked
glucose H
residue 4
O
H
OH
OH
UDP-glucose
C CH
H2
NH
OH
O
H
OH
+ UDP
OH
(14)
linkage
H
C
H
O
OH
H
CH2OH
O
H
OH
CH2OH
H
OH
C CH
H2
NH
+ UDP
Glycogen Synthesis
UTP UDP + 2 P i
glycogen(n) + glucose-1-P
Glycogen Phosphorylase
glycogen(n + 1)
Pi
Glycogen
Glucose-1-P
Glucose
Hexokinase or Glucokinase
Glucose-6-Pase
Glucose-6-P
Glucose + Pi
Glycolysis
Pathway
Pyruvate
Glucose metabolism in liver.
Adenylate cyclase
(active)
catalysis
ATP
Signal
cascade by
which
Glycogen
Phosphorylase
is activated.
Phosphodiesterase
AMP
Protein kinase A
(inactive)
Protein kinase A
(active)
ATP
ADP
Phosphorylase kinase
(b-inactive)
Phosphatase
Pi
ADP
Phosphorylase
(b-allosteric)
Phosphorylase (P)
(a-active)
Phosphatase
Pi
Glycogen
Glucose-1-P
Glucose
Hexokinase or Glucokinase
Glucose-6-Pase
Glucose-6-P
Glucose + Pi
Glycolysis
Pathway
Pyruvate
Glucose metabolism in liver.
Phosphorylase Kinase
inactive
Phosphorylase Kinase-Ca++
partly active
P-Phosphorylase Kinase-Ca++
fully active
Phosphorylase Kinase
inactive
Phosphorylase Kinase-Ca++
partly active
P-Phosphorylase Kinase-Ca++
fully active
Glycogen Storage
Diseases are genetic
glycogen
enzyme deficiencies
associated with excessive glucose-1-P
glycogen accumulation
Glucose-6-Phosphatase
within cells.
glucose-6-P
glucose + Pi
Some enzymes whose
fructose-6-P
deficiency leads to
Phosphofructokinase
glycogen accumulation
fructose-1,6-bisP
are part of the interconnected pathways
Glycolysis continued
shown here.
Symptoms, in addition to
glycogen accumulation
hypoglycemia (low blood
glucose) when fasting, liver
enlargement.
liver dysfunction and early
death.
inability to exercise.