BIOC 460 DR. TISCHLER LECTURE 27

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BIOC 460 - DR. TISCHLER LECTURE 27
GLYCOGEN ALLOSTERIC CONTROL
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OBJECTIVES
Glycogenolysis pathway 1. Identify the
substrates, products and cofactors of glycogen
phosphorylase 2. Compare and explain the
different fates of glucose-6-phosphate from
glycogenolysis in liver and in muscle. 3. Disting
uish between the tense and relaxed forms of
glycogen phosphorylase in terms of activity of
this enzyme. 4. Describe the function of
phosphorylase kinase in promoting mobilization of
glycogen relative to phosphorylation state of
glycogen phosphorylase. 5. Explain the
physiological basis (i.e., rationale of the
effect) for a) AMP activating and ATP
inhibiting glycogen phosphorylase b) calcium
activating phosphorylase kinase
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OBJECTIVES
Glycogenesis pathway 1. Identify the substrates
and products of glycogen synthase. 2. Explain
the physiological basis (i.e., rationale of the
effect) for glucose-6-phosphate allosterically
activating glycogen synthase 3. Compare the two
forms of glycogen synthase (i.e., d-form and
i-form).
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PHYSIOLOGICAL PREMISE Muscle is remarkably well
adapted metabolically to handle activities from a
short duration lift of a heavy load to running a
marathon. During the first few seconds of
initiating muscle activity, creatine phosphate
provides energy to immediately maintain the
amount of ATP in the cell. This instantaneous
source of energy buys you the time to begin
breaking down glycogen as a source of energy.
Fortuitously, muscle does not contain
glucose-6-phosphatase so that instead of making
glucose, muscle breaks down glycogen to provide
fuel just for that cell. The large glycogen
stores in bulky muscles enable the athlete to
sprint using anaerobic glycolysis while the
long-distance runner relies on aerobic
metabolism. In adapting to long-term exercise,
the body diverts blood towards the aerobic
skeletal muscles, which largely use fats as an
energy source for hours. Failure to make the
switch from glycogen to fats is termed "hitting
the wall" since glycogen cannot sustain muscle
energy levels for extended periods of time.
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Figure 1. The glycogen structure showing the
glycosidic bonds

• liver stores glycogen that provides 75 of
  glucose needed (mostly by RBC and brain) during
  first 24 hours of food deprivation
• muscle stores glycogen solely for its own
  needs lack of G-6-Pase prevents formation and
  secretion of glucose for use by other tissues
• highly branched structure to increase
  solubility provides many more sites for removal
  of glucose units that are phosphorylated by
  glycogen phosphorylase

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Glycogen
LIVER PATHWAY
Pi
glycogen phosphorylase
Glucose-1-phosphate
phosphoglucomutase
glucose-6-phosphatase
Glucose-6-phosphate
Glucose
Pi
glycolysis
X
(inhibited by lack of fructose-2,6-bisP)
Figure 2a. Glycogenolysis and the fate of
glycogen in liver and kidney
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Glycogen
MUSCLE PATHWAY
Pi
glycogen phosphorylase
Glucose-1-phosphate
phosphoglucomutase
Glucose-6-phosphate
glycolysis
Pyruvate
Figure 2b. Glycogenolysis and the fate of
glycogen in muscle.
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Glucose
Figure 3. Pathway of glycogen synthesis
(glycogenesis)
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activation by calcium in muscle inhibition by
glucose-6-P
G-6-P (muscle/liver) ATP (in muscle)
Figure 4. Regulation of glycogen phosphorylase
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Figure 5. Regulation of glycogen synthase
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GLYCOGEN STORAGE DISEASES
Type I Von Gierke Disease Hypoglycemia due to
defect of the final step of gluconeogenesis Decre
ased mobilization of glycogen produces
hepatomegaly.
Type V McArdle Disease Skeletal muscle
affected, but liver enzyme is normal No
hypoglycemia - muscle glycogen does not produce
glucose Temporary weakness and cramping of muscle
after exercise No rise in blood lactate during
strenuous exercise Muscle contains a high level
of glycogen
Type VI Hers Disease Liver affected, but
skeletal muscle enzyme is normal Severe
hypoglycemia with food deprivation
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Medical Scenario S.S, a 9-month-old female
suffers from hypoglycemia and hepatomegaly. She
was breast fed for 6 months after which frequent
feedings were given. Examination shows a stubby
baby in the 3rd percentile for height and weight.
The liver is enlarged and can be felt 5 inches
below the ribs 9nomrally should not be felt).
Additional blood analyses are provided in the
table below. Her brothers aged 9 (brother 1) and
10 (brother 2) had shown similar symptoms and are
being treated with corn starch enriched feedings
to which oral bicarbonate is added. Their current
blood analyses are also included in the table.
A liver biopsy of the patient showed reduced
activity of glucose-6-phosphatase. PCR analysis
revealed a G-to-T transition leading to a
gly270?val alteration.