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Glycogen Metabolism

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Main storage locations Muscle and Liver. aprox 2600 calories stored ... excercise-induced cramps and pain, myoglobinuria. skeletal muscle. muscle phosphorylase ... – PowerPoint PPT presentation

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Title: Glycogen Metabolism


1
Glycogen Metabolism
  • Ready source of energy
  • available for anaerobic metabolism as well as
    aerobic.
  • Main storage locations Muscle and Liver
  • aprox 2600 calories stored (1 kg or so)
  • Extended use in muscle by Cori cycle
  • Anaerobic glycolysis to lactic acid in muscle
  • Lactate goes to liver via blood
  • liver uses oxidative fatty acid metabolism to
    power gluconeogenisis to form more glucose.
  • Storage diseases are major problems.

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http//www.indstate.edu/thcme/mwking/glycogen.html
5
Glycogen structure
6
Glycogen structure
  • Polymeric glucose
  • 1-4 Alpha linkage
  • Branch points about every 8-14 units
  • 1-6 alpha linkage.
  • Approximately 100,000 units per molecule.
  • Single reducing end

7
Degradation
  • Three enzymes
  • Glycogen phosphorylase
  • forms glucose-1-P
  • does not function within 5 residues of a branch
    point
  • Glycogen Pi ?? G-6-P Glycogen-1

8
Figure 18-3 The reaction mechanism of glycogen
phosphorylase.
Page 630
9
Degradation
  • Three enzymes
  • Glycogen de-branching enzyme
  • Removes branches from glycogen by hydrolyzing 1-6
    linkages
  • removed branches then depolymerized by glycogen
    phophorylase.
  • 92 of glycogen ends up as glucose-1-P
  • 8 (branch points) glucose

10
Figure 18-5 Reactions catalyzed by debranching
enzyme.
Page 631
11
Degradation
  • Three enzymes
  • Phosphoglucomutase
  • converts G-1-P to G-6-P
  • in muscle this goes down glycolytic pathway
  • in liver hydrolyzed to glucose and shipped to
    blood stream.

12
Figure 18-4 The mechanism of action of
phosphoglucomutase.
Page 631
13
Synthesis
  • Again as we always find there is a different
    pathway up than down
  • Required thermodynamically
  • Glycogen Pi ? G-1-P Glycogen-1 DG -5-8
    kJ/Mole under physiological conditions
  • We need an energy boost to over come the
    thermodynamic barrier.
  • Here comes ATP to the rescue
  • Actually UTP but ATP makes UTP

14
Synthesis
  • G-1-P UTP ? UDP-G PPi
  • PPi H2O ? 2Pi
  • UDP-G Glycogen ? Glycogen-G UDP
  • G-1-P UTP Glycogen ? Glycogen-G 2Pi
    UDP
  • UDP ATP ? UTP ADP
  • Net hydrolysis of 1 High energy phosphate Bond.

15
Synthesis
  • Glycogenin initiates glycogen synthesis
  • Dimeric enzyme
  • Formation initiated by glucose attachment to
    Active site tyrosine. (Attachment catalyzed by
    opposing dimer)
  • Several additional residues attached to the
    initial glucose . at 4-8 units then glycogen
    synthase takes over
  • The Glycogen remains associated with glycogenin
    until some minimum size reached.

16
Synthesis of Glycogen
  • Three enzymes
  • Two elongation
  • UDP-Glucose pyrophosphorylase
  • Glycogen synthase
  • One Branching
  • Amylo-(1,4?1,6)Transglycosolase

17
Figure 18-6 Reaction catalyzed by UDPglucose
pyrophosphorylase.
Page 633
18
Synthesis
  • Glycogen synthase
  • Sythesizes 1-4 glycogen linkages.
  • substrate is still UDP-G
  • glycogen will have up to 100,000 units

19
Figure 18-7 Reaction catalyzed by glycogen
synthase.
Page 633
20
Figure 18-8 The branching of glycogen.
Page 634
21
Branching
  • Donor strand must be at least 11 sugars long
  • Receiving strand must be 11 sugars long
  • branch point must be 4 sugars from closest branch

22
Synthesis
  • Amylo (1,4?16) Transglycosylase (Branching
    Enzyme)
  • Transfers 7 residues from a chain of at least 11
    residues
  • Branch points must be at least 4 units apart.
  • 1?4 linkage hydrolysis DG -15.5 kJ
  • 1?6 linkage hydrolysis DG -7.1 kJ
  • Branches increase polymer solubility
  • Increase of non-reducing ends from which
    glucose can be obtained

23
Fate of glucose
24
Figure 18-9 The control of glycogen phosphorylase
activity.
Page 635
25
Figure 18-13 Schematic diagram of the major
enzymatic modification/demodification systems
involved in the control of glycogen metabolism in
muscle.
Page 639
26
Figure 18-21 The antagonistic effects of insulin
and epinephrine on glycogen metabolism in muscle.
Page 645
27
Degradation
  • Three enzymes
  • Phosphoglucomutase
  • converts G-1-P to G-6-P
  • in muscle this goes down glycolytic pathway
  • in liver hydrolyzed to glucose and shipped to
    blood stream.
  • Enzyme has a Phosphate bound to serine that is
    transferred glucose-1-P to make Glucose-1,6P
  • Enzyme then transfers 1P group from glucose to
    serine.
  • Reaction near DG0. Reaction direction controlled
    by removal or addition of substrates

28
Fate of glucose
29
Control of Glycogen Synthesis and Breakdown
  • Need to have glucose available at constant
    concentrations ( 5 mM) for the brain, as well as
    for muscle contraction.
  • Homeostasis achieved by control of glycogen
    phosphorylase and glycogen synthase
  • Phosphorylase is controlled allosterically and by
    covalent modification phosphorylation
  • Synthase is also controlled by phosphorylation
  • The critical role of hormones insulin and glucagon

30
Phosphorylase is also controlled by
phosphorylation
  • Early work showed that Gly. Phos. existed in an
    a and b forms
  • Subsequently learned that a and b differed by
    phosphorylation at Ser 14
  • Phosphorylated form is allosterically
    unresponsive and turned on! The apo enzyme is
    still allosterically regulated
  • Controlled by a hormone driven cascade

31
Hormonal Control of Glycogen Synthesis and
Degradation
  • Many hormones control blood glucose
    concentration insulin, glucagon, epinephrine,
    and glucocorticoids
  • Insulin stimulates glycogen synthesis, inhibits
    glycogen breakdown (liver, muscle)
  • Glycogen breakdown triggered by epinephrine
    (liver, muscle), glucagon (liver, adipose).
    Different signals for each.

32
Regulatory cascades control glycogen synthesis
and mobilization
  • Both phosphorylase and glycogen synthase can
    exist in PO4/non-PO4 forms
  • The activity of these enzymes is controlled
    inversely
  • G-6-P is a key allosteric regulatory molecule

Phosphorlyl.
Synthase.
Phosphorlyl.
Synthase.
33
Glucagon vs Epinephrine
  • Both are responsible for glycogenolysis
  • Glucagon maintains steady state levels of glucose
    in the blood stimulates liver --gt glucose (also
    gluconeogenesis)
  • Epinephrine part of a stress response
    fight/flight rapid generation in muscles
    (secondarily liver) 2000-fold increase in rate
    of glycolysis

34
Review
  • Synthesis/degradation of glycogen is tightly
    regulated.
  • Synthesis of glycogen requires priming by
    glycogenin. Each new sugar is delivered by
    UDP-glucose. Synthase is regulated by
    phosphorylation, stimulated by insulin.
  • Glycogenolysis is controlled by phosphorylation,
    under dual control. Non-covalent regulation
    ATP/AMP. Covalent control is mediated by
    phosphorylation this is stimulated by glucagon
    and epinephrine. These have different functions
    in glucose homeostasis basal versus stress
    mediated control

35
Where we are
  • Done looking at glycogen
  • Look at problems 1-11
  • We will head toward the TCA cycle and Chap 21
    next
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