Glycogen Metabolism and Gluconeogenesis

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Chapter 15

• Glycogen Metabolism and Gluconeogenesis

2
Glycogen
CH2OH
H
O
D-Glucose to ?-Amylose to Glycogen
H
H
OH
O
OH
H
CH2OH
CH2OH
CH2
O
H
H
H
O
H
O
O
H
H
H
H
H
H
OH
H
H
OH
OH
O
HO
OH
OH
H
OH
H
OH
H
?-Amylose to Amylopectin or Glycogen (? (1?4)
glycosidic bond)
?-D-Glucose
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Metabolism Summary
Glycogen
Glycogen synthesis Glucogen breakdown
Ribose 5 - phosphate
Glucose-6-phosphate
GLUCOSE
(Pentose phosphate pathway nucleotide synthesis)
Gluconeogenesis Glycolysis
Pyruvate
Homolactic fermentation
Acetyl CoA
Amino Acids
Lactate
Citric Acid Cycle ? Electron Transport
Oxidative Phosphorelation
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Glucogen Breakdown

• Glycogen
• Polymer of ?(1?4)-linked glucose with
  ?(1?6)-linkages every 8-14 residues
• Stored in the cells (muscle liver) as granules
  of up to 120,000 units
• Granules contain enzymes for breakdown
• Breakdown occurs from NON-reducing end (Figure
  15.2)

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4
4
1
5
Glucogen Breakdown

• Glycogenolysis
• Glycogen phosphorylase
• Glycogenn Pi ? Glycogenn-1 Glucose-1-phosphate
  
• Glycogen debranching enzyme
• Glycogen-?(1?6) branch ? Glycogen-?(1?4) branch
• Phosphoglucomutase
• Glucose-1-phosphate ? Glucose-6-phosphate
• Glucose-6-phosphatase (liver only)
• Glucose-6-phosphate H2O ? Glucose Pi

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Glucogen Breakdown

• Glycogenolysis
• Glycogen phosphorylase
• Glycogenn Pi ? Glycogenn-1 Glucose-1-phosphate
  
• Dimer regulated by allosteric and covalent
  modification
• Phosphorelase a active form has phosphoryl
  group at Ser
• ATP, G6P, and Glucose allosteric inhibitors
• AMP allosteric activator causes T ? R shift
• Active site too narrow to accommodate glycogen
  less than 4-5 residues from a branching point
• (Figure 15-4)

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Glucogen Breakdown
CHO

• Glycogenolysis
• Glycogen phosphorylase
• Glycogenn Pi ? Glycogenn-1 G1P
• Pyridoxal-5-phosphate (PLP, vit. B6) cofactor
• Bound via Schiff base (imine) from aldehyde to
  Lys
• Proton donor in acid-base catalysis mechanism

OH
OPO3-C2H
N H
CH3
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Glucogen Breakdown

• Glycogenolysis
• Glycogen debranching enzyme
• Glycogen-?(1?6) branch ? Glycogen-?(1?4) branch
• Two enzymatic functions
• Transferase
• ? (1?6) glucosidase

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Glycogen
CH2OH
H
O
D-Glucose to ?-Amylose to Glycogen
H
H
OH
O
OH
H
CH2OH
CH2OH
CH2
O
H
H
H
O
H
O
O
H
H
H
H
H
H
OH
H
H
OH
OH
O
HO
OH
OH
H
OH
H
OH
H
?-D-Glucose
? (1?4) ? (1?6) glycosidic bonds
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Glucogen Breakdown

• Glycogenolysis
• Phosphoglucomutase
• Glucose-1-phosphate ? Glucose-6-phosphate
• Works like phosphoglyceromutase with n1 lag on
  PO4 release from enzyme

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Metabolism Summary
Glycogen
Glycogen synthesis Glucogen breakdown
Ribose 5 - phosphate
Glucose-6-phosphate
GLUCOSE
(Pentose phosphate pathway nucleotide synthesis)
Glycolysis Gluconeogenesis
Pyruvate
Homolactic fermentation
Acetyl CoA
Amino Acids
Lactate
Citric Acid Cycle ? Electron Transport
Oxidative Phosphorelation
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Glycogen Synthesis

• McArdles Disease (lack glycogen phosphorylase)
  showed that breakdown and synthesis were separate
• Three enzymes of synthesis counter the enzymes of
  glycogen catabolism (fig 15-8)
• UDP-glucose pyrophosphorylase
• Glycogen synthase
• Glycogen branching enzyme

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Glucogen Synthesis

• UDP-Glucose pyrophosphorylase
• Glucose-1-phosphate UTP ? UDP-Glucose PPi
• PPi H2O ? 2 Pi
• NET 0 -33.5 kJ/mol -33.5 kJ/mol
• Glycogen synthase
• UDPG glycogenn ? UDP glycogenn1
• Inhibited by ATP, ADP, and Pi
• Phosphorelated b form is less active
• Extends chains - GLYCOGENIN forms 7-UDPG glycogen
  primer
• Glycogen branching enzyme
• Amylose (1,4 ?1,6)-transglycosylase
• Attachments must be 4 units or more apart

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Metabolism Summary
Glycogen
Glycogen synthesis Glucogen breakdown
Ribose 5 - phosphate
Glucose-6-phosphate
GLUCOSE
(Pentose phosphate pathway nucleotide synthesis)
Glycolysis Gluconeogenesis
Pyruvate
Homolactic fermentation
Acetyl CoA
Amino Acids
Lactate
Citric Acid Cycle ? Electron Transport
Oxidative Phosphorelation
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Glycogen Metabolism

• Synthesis and breakdown would be
  counterproductive if not regulated cycle to
  cleave UTP
• Flux control of a pathway is best when an enzyme
  operating far from equilibrium is opposed by a
  separately controlled enzyme so that vf and vr
  vary independently in both rate and direction

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Glycogen Metabolism
Key Control at glycogen synthase and glycogen
phosphorylase
GLYCOGENn
Glycogen synthase
Glycogen phosphorylase
Glucose-1-phosphate Glycogenn-1
UDP-Glucose GLYCOGENn-1
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Glycogen Metabolism

• Synthesis and breakdown would be
  counterproductive if not regulated cycle to
  cleave UTP (figure 15-8)
• 3 levels of control
• Allosteric ATP, G6P, AMP (direct allosteric)
• Covalent (De)phosphorelation of glycogen
  synthase and glycogen phosphorylase
• Hormonal insulin and glucagon

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Glycogen Breakdown

• Glycogen phosphorylase is activated by
  phosphorylation and MANY sub-layers of control
  (Amplification cascade - figure 15-12)
• Phosphorylase Kinase
• Responsive to phosphorylation and Ca2 via
  Calmodulin binding
• cAMP-dependent protein kinase (cAPK)
• Controlled by cAMP (low ATPp. 442) via
• Adenylate cyclase ? hormone binding at membrane
• Phosphoprotein phosphatase-1
• Dephosphorylates both PK CAPK
• Regulated by Glucagon, Insulin and Epinephrine

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Glycogen Synthesis

• Glycogen synthase is INactivated by
  phosphorylation and also has MANY sub-layers of
  control (Amplification cascade - figure 15-12)
• Phosphorylase Kinase and 6 other kinases
• Responsive to phosphorylation and Ca2 via
  Calmodulin binding
• cAMP-dependent protein kinase (cAPK)
• Controlled by cAMP (low ATPp. 442) via
• Adenylate cyclase ? hormone binding at membrane
• Phosphoprotein phosphatase-1
• Dephosphorelates both PK CAPK
• Regulated by Glucagon, Insulin and Epinephrine

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Glycogen Hormonal Control

• Pancreatic Hormonal Peptides
• Glucagon
• Controls glycogen metabolism in the liver
• Released after a meal or with exercise
• Controlled by epinephrine
• Insulin
• controls glycogen metabolism in the muscles and
  other tissues
• Released in response to high glucose
• Stimulates phosphorylation of of PPK1, enhancing
  net synthesis
• Adrenal Hormones
• Epinephrine and norepinephrine (noradrenaline)
  affect both cell types
• Made from the amino acid Tyrosine

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Glycogen Hormonal Control

• Pancreatic peptides
• Adrenal Hormones
• Most of these communicate with the cells through
  SECOND MESSENGERS triggered by ? ? adrenergic
  receptors (figure 15-21)
• ? receptors cAMPsmall ? in cAMP cause large ?
  in enzyme phosphorylation, activating glycogen
  synthase and deactivating glycogen phosphorylase
• ? receptors trigger Ca2 to increase

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Glycogen Hormonal Control
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• Figure 15-21

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Metabolism Summary
Glycogen
Glucose-6-phosphate
GLUCOSE
Pyruvate
Aerobic Glycolysis
Acetyl CoA
Amino Acids
Lactate
Citric Acid Cycle ? Electron Transport
Oxidative Phosphorelation
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Citric Acid Cycle

• Citric Acid Cycle
• Tricarboxylic Acid Cycle
• Krebs Cycle
• Oxidative Fuel Metabolism from Acetyl CoA
• Glucose
• Amino Acids
• Fatty Acids
• The HUB of metabolism
• Takes place in the mitochondria in eukaryotes

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Citric Acid Cycle

• Figure 16-1, 16-2
• Two molecules of CO2 released in every round of
  the cycle, but they are not the two Cs that just
  entered the cycle from Acetyl CoA
• The starting point compound, oxaloacetate, is
  regenerated making it a continuous cycle to
  metabolize Acetyl CoA
• Net Reaction
• 3 NAD FAD GDP Pi acetyl-CoA 2 H2O ?
• 3 NADH FADH2 GTP CoA 2
  CO2 3 H
• Four electron pairs are transferred from Acetyl
  CoA to make CO2 3 to NAD 2 to FAD

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NET ENERGY FROM GLUCOSE