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Why is Patrick Paralyzed

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Patrick's History ... CQ1: What could be responsible for Patrick's loss of mobility? ... If Patrick's enzyme responsible for converting pyruvate to acetyl CoA was ... – PowerPoint PPT presentation

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Title: Why is Patrick Paralyzed


1
Why is Patrick Paralyzed?
  • Maureen Knabb
  • Department of Biology
  • West Chester University

2
Why did Patrick lose his ability to move?
  • Patrick at 2
  • Patrick at 21
  • Movie in QuickTime (mov)

3
Patricks 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 Childrens Hospital of Philadelphia he was
    initially diagnosed with a demyelinating disease.
  • He was treated with anti-inflammatory drugs and
    antibodies for 2 years with no improvement.
  • What was wrong with Patrick?

4
CQ1 What could be responsible for Patricks 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.

5
CQ2 Which of the following processes requires
energy?
  • A Creating ion gradients across membranes.
  • B Muscle shortening.
  • C Protein synthesis.
  • D All of the above.

6
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)

7
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

8
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 gt Energy required
  • ATP plays a central role

9
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
9
10
CQ3 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

11
This bond is easy to break and requires energy!
Adenosine triphosphate (ATP)
H2O
Hydrolysis of ATP
Formation of these new bonds releases energy
H
H
Inorganic phosphate (Pi)
Adenosine diphosphate (ADP)
11
12
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

13
CQ4 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.

14
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.

15
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.

15
16
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.

16
17
CQ5 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.

18
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

19
CQ6 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.

20
How are metabolic pathways regulated?
Feedback inhibition animation
21
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.

22
CQ7 Consider the following metabolic pathwayA
C DBIf 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.

23
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

24
Important Electron AcceptorsCoenzymes
  • NAD (Nicotinamide Adenine Dinucleotide)
  • NAD 2H 2 e- --gt NADH H
  • FAD (Flavin Adenine Dinucleotide)
  • FAD 2H 2 e- --gt FADH2
  • Both molecules serve as coenzymes in many
    reactions.

25
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

26
CQ8 Consider the following metabolic pathway
Pyruvate Acetyl CoA TCA
cycle LactateIf
Patricks 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
    all decrease.

27
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

28
Anaerobic versus aerobic metabolism
0
Na
Cell membrane
Glucose
No O2
Glycolysis
2 Lactate
(fermentation)
2 ATP
O2
Glucose
2 Pyruvate
Oxygen diffuses into the cell
2 NADH H
Mitochondria
Pyruvate dehydrogenase enzyme
cytoplasm
With O2
H
H
H
e-
e-
e-
O2
e-
e-
H
H2O
Electron transport carriers
NAD
H
Pyruvate
ATP
Outer membrane
NADH H
H
3 NADH H
FAD
FADH2
CO2
ADP Pi
F0F1 ATPase
Acetyl CoA
3 NAD
CO2 diffuses out of the cell
GDP Pi
citrate
Intermembrane space
GTP
Krebs cycle
Oxaloacetate
ATP
2 CO2
matrix
Inner membrane
29
What happened to Patrick?
  • He inherited a mutation leading to a disease
    called pyruvate dehydrogenase complex disease
    (PDCD).
  • 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).

30
CQ9 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.

31
CQ10 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

32
Are there any treatment options for PDH
deficiency?
  • High fat, low carbohydrate diet (ketogenic diet)
  • Fatty acids can form acetyl CoA which can enter
    the Krebs cycle

Fatty acids ?
33
Are there any treatment options for PDH
deficiency?
  • Dichloroacetate (DCA) blocks the enzyme that
    converts PDH from active to inactive forms
  • PDH remains in the active form

DCA blocks here
34
CQ11 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.

35
CQ12 The loss of which of the following
molecules was the most critical for Patricks
paralysis?
  • A Pyruvate dehydrogenase
  • B Acetyl CoA
  • C Lactate
  • D ATP

36
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 doctors
    predictions.
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