Why is Patrick Paralyzed? by LoRnJMp


									Why is Patrick Paralyzed?

        Maureen Knabb
     Department of Biology
     West Chester University

Why did Patrick lose his ability to move?

Patrick at 2:    Patrick at 21:
                 Movie in QuickTime (mov)

             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.
• He was treated with anti-inflammatory drugs and
  antibodies for 2 years with no improvement.
• What was wrong with Patrick?

CQ1: What could be responsible
for Patrick’s loss of mobility?

 A: His nervous system is not functioning
 B: His muscles are not functioning properly.
 C: He cannot efficiently break down food for
 D: All of the above are possible causes.
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.

 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)

             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

  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
   ATP plays a central role in energy cycling

   Stored                                   ATP is used
  chemical                                   in energy
  energy is                                  requiring
 released in                               reactions like
reactions to                                movement
  make ATP

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

      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

               phosphate (Pi)           Adenosine diphosphate (ADP)
      ATP plays a central role in
• 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
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
 C: Both A and B.

     How is ATP generated?

• ATP is formed through metabolic
• In metabolic pathways, the product of
  one reaction is a reactant for the next.
• Each reaction is catalyzed by an

            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.

            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

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.

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
CQ6: In competitive inhibition…
A: the inhibitor competes with the normal
    substrate for binding to the enzyme's active
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
How are metabolic pathways

 Feedback inhibition animation

    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.
   CQ7: Consider the following metabolic pathway:
                  A       C     D
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.
   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+

    Important Electron Acceptors
• 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.

    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
CQ8: Consider the following metabolic pathway:
     Pyruvate        Acetyl CoA      TCA cycle
If Patrick’s enzyme responsible for converting
pyruvate to acetyl CoA was inhibited, what would
 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
 D: Pyruvate, acetyl CoA, and lactate levels would
   all decrease.                                   26
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

   Anaerobic versus aerobic metabolism
                                                                                                                                                        Cell membrane
                                                                                   No O2
                              Glycolysis            2 ATP                                                2 Lactate          (fermentation)                         O2
             Glucose                                        2 Pyruvate
                                          2 NADH + H+                                                               Oxygen diffuses into the cell
   Pyruvate                                   With O2                              H+                     H+                                        cytoplasm
dehydrogenase                                                              e-
                                                                                                          e-           O2
   enzyme                                                                          H+                                   H2O
                                                                                Electron transport carriers
                                                            NAD+                           H+
                                                             NADH +                                                                    H+       Outer membrane
                                                                                  3 NADH +         FAD
                                              CO2              H+                                        FADH2
                                                                                     H+                                ADP + Pi
                       CO2 diffuses out             Acetyl CoA      3 NAD+                                                            F0F1
                          of the cell                                                                                                ATPase
                                                                                                                 GDP + Pi
                                                                                                                                     Intermembrane space
                                                                                      Krebs cycle
                                                                                                         2 CO2
                                                                                                                                  Inner membrane
         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).                29
CQ9: Why did Patrick become
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.

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
 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
 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

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.

CQ12: The loss of which of the
following molecules was the
most critical for Patrick’s
A: Pyruvate dehydrogenase
B: Acetyl CoA
C: Lactate

   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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