Download What happened to my cousin Patrick O’Neill?

Why is Patrick Paralyzed?
A case study by:
Maureen Knabb
Department of Biology
West Chester University
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Directions
• Read through the following case study (you
may work with ONE partner)
• Answer the Multiple choice questions AND
question prompts on a separate sheet of paper
• Highlight key terms and circle any
concepts/ideas that link metabolism to
previously learned material
• Answer questions 1-4 in “Thinking Beyond” at
the conclusion of the case study
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Why did Patrick lose his ability to move?
Patrick at 2:
Patrick at 21:
Movie in QuickTime
(mov)
~ To view this at home,
visit:
http://www.sciencecases.o
rg/patrick_paralyzed/patri
ck_paralyzed.mov
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Patrick’s History
• When Patrick was 16 years old, his hand started
twitching as he picked up a glass at dinner.
• Five months later (in February 2001), he fell down
the steps at his home and was unable to climb the
steps to the bus. He went to the ER for his
progressive weakness.
• At Children’s Hospital of Philadelphia he was
initially diagnosed with a demyelinating disease (loss
of the coating that surrounds neurons; myelin is
involved in conduction of electrical impulses).
• He was treated with anti-inflammatory drugs and
antibodies for 2 years with no improvement.
• What was wrong with Patrick?
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Q1: What could be responsible
for Patrick’s loss of mobility?
A: His nervous system is not functioning
properly.
B: His muscles are not functioning properly.
C: He cannot efficiently break down food for
energy.
D: All of the above are possible causes.
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Q2: Which of the following
processes requires energy?
A: Creating ion gradients across membranes.
B: Muscle shortening.
C: Protein synthesis.
D: All of the above.
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Why do nerve and muscle cells
need energy?
• Synthetic work = building macromolecules
– (e.g., Making protein)
• Mechanical work = moving molecules past each other
– (e.g., Muscle shortening)
• Concentration work = creating chemical gradients
– (e.g., Storing glucose)
• Electrical work = creating ion gradients
– (e.g., Unequal distribution of sodium and potassium ions)
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What is energy?
• Potential Energy = stored energy
– Chemical bonds
– Concentration gradients
– Electrical potential
• Kinetic Energy = movement energy
– Heat = molecular motion
– Mechanical = moving molecules past each other
– Electrical = moving charged particles
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Cycling between stored chemical
versus movement energy
• Stored chemical energy must be released
– Processes that RELEASE energy
• Make ATP
• Catabolic/ Exergonic
• Movement requires energy
– Processes that REQUIRE energy
• Use ATP
• Anabolic/ Endergonic
• Energy released > Energy required
• ATP plays a central role
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ATP plays a central role in energy cycling
+
Stored
chemical
energy is
released in
catabolic
reactions to
make ATP
ATP is used
in energy
requiring
reactions
like muscle
movement
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Q3: The high energy phosphate
bond in ATP is _____ and ____
energy to break the bond.
A: Easy to break, releases
B: Hard to break, requires
C: Easy to break, requires
D: Hard to break, releases
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This bond is easy to break
and requires energy!
Adenosine triphosphate (ATP)
H2O
Hydrolysis
of ATP
Formation of these new bonds
releases energy
H
Inorganic
phosphate (Pi)
H
Adenosine diphosphate (ADP)
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ATP plays a central role in
metabolism
• ATP is NOT the highest energy molecule
– intermediate energy
• ATP hydrolysis releases energy
– phosphate groups require low energy to break
– new bonds formed release more energy than
the energy required to break the bond
• Phosphorylation by ATP increases the
energy of other molecules
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Q4: What would happen if Patrick
lost his ability to make ATP?
A: His muscles would not be
able to contract.
B: His neurons would not be
able to conduct electrical
signals.
C: Both A and B.
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How is ATP generated?
• ATP is formed through metabolic
pathways.
• In metabolic pathways, the product of
one reaction is a reactant for the next.
• Each reaction is catalyzed by an
enzyme.
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What are enzymes?
• Enzymes (usually proteins) are biological catalysts,
highly specific for their substrates (reactants).
• Enzymes change reactants into products through
transition state intermediates.
• Enzymes are not consumed in the reaction.
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Enzymes as Catalysts
• Enzymes “speed up”
reactions by lowering
the “activation energy”
of a reaction.
• Enzymes DO NOT
change the overall
energy released in a
reaction.
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Q5: Which statement about
enzymes is correct?
A: Enzymes are always proteins.
B: Enzymes are consumed in a reaction.
C: Enzymes are always active.
D: All are correct.
E: None are correct.
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Enzyme Regulation
• Enzymes turn “on” and “off” based on the
need of the organism
– “ON” = Activators
• Positive allosteric regulation
– “OFF” = Inhibitors
• Irreversible = must make new enzyme!
• Reversible = inhibitor can “come off”
– Competitive = active site
– Noncompetitive = “other” site = allosteric site
• Feedback Inhibition
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Q6: In competitive inhibition…
A: the inhibitor competes with the normal
substrate for binding to the enzyme's active
site.
B: an inhibitor permanently inactivates the
enzyme by combining with one of its
functional groups.
C: the inhibitor binds with the enzyme at a site
other than the active site.
D: the competing molecule's shape does not
resemble the shape of the substrate molecule.
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How are metabolic pathways
regulated?
Explain what feedback
inhibition is. You may use your
text to help. Be sure to identify
and describe BOTH types.
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DNA mutations can disrupt
metabolic pathways
• Patrick suffered from a genetic disease
that altered the structure of one
protein.
• The protein was an enzyme.
• The enzyme could potentially:
• lose its ability to catalyze a reaction.
• lose its ability to be regulated.
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Q7: Consider the following metabolic pathway:
A
C
D
B
If the enzyme responsible for converting A to C
was mutated and nonfunctional, what would
happen?
A: A levels would increase; B, C, and D levels
would decrease.
B: A and B levels would increase; C and D levels
would decrease.
C: A, B and C levels would increase; D levels would
decrease.
D: A, B, C, and D levels would all decrease.
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Metabolic Pathways: Glycolysis
• Pathway present in almost every cell!
• Takes place in the cytoplasm of the cell.
• Occurs with or without oxygen.
• Oxidizes glucose (6 C) to 2 pyruvate (3 C).
• Overall yield = 2 ATP and 2 NADH + H+
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Important Electron Acceptors
Coenzymes
• NAD (Nicotinamide Adenine
Dinucleotide)
– NAD+ + 2H+ + 2 e- --> NADH+ + H+
• FAD (Flavin Adenine Dinucleotide)
– FAD + 2H+ + 2 e- --> FADH2
• Both molecules serve as coenzymes in
many reactions.
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Fermentation: Recycles NADH
• Occurs in the cytoplasm without O2
• NADH + H+ is reoxidized to NAD+
• Alcoholic Fermentation = yeast cells
– Converts pyruvate to ethanol and CO2
– Overall yield = 2 ATP
• Lactate Fermentation = animal cells
– Converts pyruvate to lactate
– Overall yield = 2 ATP
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Q8: Consider the following metabolic
pathway:
Pyruvate
Acetyl CoA
TCA cycle
Lactate
If Patrick’s enzyme responsible for converting
pyruvate to acetyl CoA was inhibited, what
would happen?
A: Pyruvate levels would increase; acetyl CoA and
lactate levels would decrease.
B: Pyruvate and lactate levels would increase;
acetyl CoA levels would decrease.
C: Pyruvate, acetyl CoA, and lactate levels would
increase.
D: Pyruvate, acetyl CoA, and lactate levels would
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all decrease.
Patrick suffered from lactate
acidosis
• Lactate (lactic acid) and pyruvate
accumulated in his blood.
• Acidosis led to:
– Hyperventilation
– Muscle pain and weakness
– Abdominal pain and nausea
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Anaerobic versus aerobic
metabolism
Na+
Glucose
Cell membrane
Glycolysis
No O2
2 ATP
Glucose
2 Lactate
(fermentation)
O2
2 Pyruvate
2 NADH + H+
Pyruvate
dehydrogenase
enzyme
CO2 diffuses out
of the cell
Mitochondria
H+
With O2
ee-
Pyruvate
CO2
Oxygen diffuses into the cell
cytoplasm
H+
e-
H+
e-
e-
O2
H2O
H+
Electron transport carriers
H+
NAD+
NADH +
H+
Acetyl CoA
3 NAD+
ATP
3 NADH +
H+
FAD
FADH2
GDP + Pi
citrate
Oxaloacetate
ADP + Pi
GTP
Krebs cycle
H+
Outer membrane
F0F1
ATPase
Intermembrane space
ATP
matrix
2 CO2
Inner membrane
What happened to Patrick?
• He inherited a mutation
leading to a disease called
pyruvate dehydrogenase
complex disease (PDCD) – an
enzyme deficiency in the
mitochondria.
• Pyruvate dehydrogenase is an
enzyme that converts pyruvate
to acetyl CoA inside the
mitochondria.
• The brain depends on glucose
as a fuel. PDCD degenerates
gray matter in the brain.
• Pyruvate accumulates, leading
to alanine and lactate
accumulation in the blood
(lactate acidosis).
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Q9: Why did Patrick become
paralyzed?
A: He inherited a genetic disease that resulted in the
partial loss of an enzyme necessary for aerobic
breakdown of glucose.
B: The enzyme that is necessary for metabolizing fats
was defective.
C: He was unable to synthesize muscle proteins due to
defective ribosomes.
D: He suffered from a severe ion imbalance due to a
high salt diet.
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Q10: Which food(s) can be
metabolized to generate acetyl CoA?
A: Carbohydrates
B: Fats
C: Proteins
D: Both carbohydrates
and fats
E: Carbohydrates, fats
and proteins
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Are there any treatment options
for PDH deficiency?
• High fat, low carbohydrate diet (ketogenic diet)
Fatty acids 
• Fatty acids can form acetyl CoA which can enter
the Krebs cycle
33
Are there any treatment options
for PDH deficiency?
• Dichloroacetate (DCA) blocks the enzyme that
converts PDH from active to inactive forms
DCA blocks here
• PDH remains in the active form
34
Q11: Dichloroacetate (DCA)
administration would lead
to…
A: Increased production of acetyl CoA.
B: Decreased lactate accumulation.
C: Increased ATP production.
D: All of the above.
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Q12: The loss of which of the
following molecules was the
most critical for Patrick’s
paralysis?
A: Pyruvate dehydrogenase
B: Acetyl CoA
C: Lactate
D: ATP
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What happened to Patrick?
• Although his family tried to care for him at home,
Patrick remained in hospitals and nursing homes
until he died in 2006.
• Patrick died due to pneumonia, sepsis, and renal
failure when he was only 21 years old.
• His family mourns his loss but feels grateful that
he was able to survive for 5 years on a respirator,
4 years beyond his doctor’s predictions.
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Thinking Beyond
1. How can Patrick’s case help explain the
importance of cellular respiration in
organisms?
2. Explain how a single mutation in the
production of one enzyme led to Patrick’s
death.
3. What if there was a defect in the gene coding
for ATP synthase or phosphofructokinase in
plants. Predict the implications of such
mutations.
4. Brainstorm and describe possible treatment
options.
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