Coordinated regulation of glycolysis/gluconeogenesis

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Coordinated regulation of glycolysis/gluconeogenes
is
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(No Transcript)
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High blood glucose
Insulin secretion
Synthesis of hexokinase II, PFK-1, pyruvate kinase
Movement of GLUT4 to plasma membrane of myocyte
Activation of insulin-sensitive protein kinase
Activation of protein kinase B
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p.903
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p.887
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Glucose
p.903
Glucose
GLUT2
Pancreatic b cell
Glucose
Glycolysis
pyruvate
Citric acid cycle
NADH,FADH2
Oxidative phosphorylation
ATP
closed
K
Ca2
ATP-gated K channel
- - - - - - -
Open

- - - - - - -
Insulin secretion

Voltage-dep. Ca2 channel
Membrane depolarization
Ca2
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Movement of GLUT4 to plasma membrane of myocyte
p.396
Glc
Glc
Glc
Glc
Glc
Glc
Glc
Glc
Glc
Glc
Insulin receptor
Cytosol of myocyte
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Activation of insulin-sensitive kinase
p. 588
Insulin
Insulin receptor
Insulin- sensitive kinase
Insulin- sensitive kinase
GM
Glycogen synthase a
Glycogen phosphorylase
PP1
PP1
Phosphorylase kinase
Glycogen synthesis ? Glycogen degradation ?
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Activation of protein kinase B (PKB)
p.587
Insulin
Insulin receptor
PIP2
PI3-K
PI3-K
PIP3
PDK-1
PDK-1
PKB
PKB
IRS-1
GSK-3
GSK-3
Glycogen synthase a
Glycogen synthase a
Glycogen synthesis
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GSK3 inactivate glycogen synthase by
phosphorylation
p.587
Phosphorylation by Casein kinase II
P
P
P
P
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GSK3 can be inactivated by phosphorylation
p.587
PKB
P
P
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High blood glucose affect hexokinase IV activity
p.578
Glc
nucleus
Glc
Hexokinase IV
GLUT2
Glc
Hexokinase IV
Regulator protein
Glc
Glc
Glc
Glc
Glc
Glc
Glc
Hepatocyte
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Insulin regulate PFK-1 activity
Insulin
Insulin receptor
Phosphoprotein phosphatase
Phosphoprotein phosphatase
PFK-2 FBPase-2
FBPase-1
FBPase-1
PFK-1
PFK-1
PFK-2 FBPase-2
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Low blood glucose
Glucagon secretion
Inactivation of pyruvate kinase L (liver form)
Activation of FBPase-2 and inactivation of PFK-2
Inactivation of glycogen synthase
Activation of glycogen phosphorylase
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p.436
Regulation pathway initiated by glucagon secretion
Glucagon receptor
Glucagon receptor
Adenylyl cyclase
Adenylyl cyclase
b
cAMP
g
ATP
Protein kinase A
Protein kinase A
Pyruvate kinase L
PFK-2 FBPase-2
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Regulation of PFK-1 by glucagon
Protein kinase A
Protein kinase A
PFK-2 FBPase-2
PFK-1
PFK-1
FBPase-1
FBPase-1
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p. 588
Regulation of glycogen synthesis and breakdown by
glucagon
Protein kinase A
Protein kinase A
Glycogen synthase a
Glycogen phosphorylase
PP1
PP1
Phosphorylase kinase
Glycogen synthesis ? Glycogen degradation ?
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Hexokinase

• There are four isozymes (I, II, III and IV) of
  hexokinase encoded by four different genes.
• Hexokinase I and II are allosterically inhibited
  by their product, glucose 6-phosphate. Hexokinase
  IV is not inhibited by G-6-P.

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Hexokinase

• Hexokinase I and II are the predominant forms
  existing in muscle. Hexokinase IV is the
  predominant form in liver.
• Hexokinase I and II will be half-saturated at
  about 0.1mM, but hexokinase IV will not be
  half-saturated until 10mM.

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Hexokinase

• Hexokinase has different functions in liver and
  muscle.
• Muscle consumes glucose, using it for energy
  production.
• Liver maintains blood glucose homeostasis by
  removing or producing glucose.

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Muscle hexokinase

• Because blood glucose concentration is about 4 to
  5 mM, hexokinase in the muscle (which will be
  half saturated at 0.1mM) is always working at or
  near its maximal rate.

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Liver hexokinase

• However, liver hexokinase (half-saturated at
  10mM) will not ever reach its maximal rate even
  after meal.

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Phosphofructokinase-1

• PFK-1 catalyze the committing step of glycolysis.
• This enzyme is regulated by ATP, AMP, ADP,
  citrate and fructose 2,6-bisphosphate.

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ATP regulate the affinity of PFK-1 towards its
substrate F-6-P

• Not only as a substrate, ATP is also one of the
  end product of the glycolytic pathway.
• ATP inhibit PFK-1 by binding to an allosteric
  site and lowering the affinity of the enzyme for
  F-6-P.

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Molecules regulate PFK-1 and FBPase-1 activity
ATP
citrate
PFK-1
PFK-1
FBPase-1
PFK-1
ADP
AMP
F2.6BP

• ADP and AMP relieve the inhibition by ATP.
• Citrate increases the inhibitory effect of ATP.
• F-2,6-BP is the strongest activator of PFK-1.

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Regulation of gluconeogenesis

• Pyruvate carboxylase
• FBPase-1

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Pyruvate carboxylase

• Pyruvate carboxylase is being positively
  regulated by acetyl-CoA.
• The accumulation of acetyl-CoA signals that
  cells energy demands are met.
• Acetyl-CoA also indirectly inhibit pyruvate
  dehydrogenase complex.