Why is Patrick Paralyzed?

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1 Why is Patrick Paralyzed? 1

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

3 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? 3

4 CQ1: 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. 4

5 CQ1: 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. 5

6 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

7 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. 7

8 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) 8

9 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 9

10 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 10

11 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 11

12 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 12

13 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 13

14 This bond is easy to break and requires energy! Adenosine triphosphate (ATP) H 2 O Hydrolysis of ATP Formation of these new bonds releases energy H H Inorganic phosphate (P i ) Adenosine diphosphate (ADP) 14

15 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 15

16 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. D: Neither muscles or neurons would be affected 16

17 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. D: Neither muscles or neurons would be affected 17

18 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. 18

19 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. 19

20 Enzymes speed up reactions by lowering the activation energy of a reaction. Enzymes DO NOT change the overall energy released in a reaction. Enzymes as Catalysts 20

21 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. 21

22 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. 22

23 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 23

24 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. 24

25 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. 25

26 How are metabolic pathways regulated? Feedback inhibition animation 26

27 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. 27

28 CQ7: 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. 28

29 CQ7: 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. 29

30 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 + 30

31 Important Electron Acceptors Coenzymes NAD (Nicotinamide Adenine Dinucleotide) NAD + + 2H e - --> NADH + + H + FAD (Flavin Adenine Dinucleotide) FAD + 2H e - --> FADH 2 Both molecules serve as coenzymes in many reactions. 31

32 Fermentation: Recycles NADH Occurs in the cytoplasm without O 2 NADH + H + is reoxidized to NAD + Alcoholic Fermentation = yeast cells Converts pyruvate to ethanol and CO 2 Overall yield = 2 ATP Lactate Fermentation = animal cells Converts pyruvate to lactate Overall yield = 2 ATP 32

33 CQ8: 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 all decrease. 33

34 CQ8: 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 all decrease. 34

35 Predict some of Patrick s symptoms 35

36 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 36

37 Anaerobic versus aerobic metabolism Glucose Na+ Cell membrane Glucose Pyruvate dehydrogenase enzyme Glycolysis CO 2 diffuses out of the cell 2 ATP 2 NADH + H + 2 Pyruvate With O 2 Pyruvate CO 2 NAD+ NADH + H+ Acetyl CoA 3 NAD+ No O 2 2 Lactate (fermentation) Mitochondria e Oxaloacetate H+ H+ e H+ e e e H+ Electron transport carriers H+ citrate 3 NADH + H+ FAD Krebs cycle FADH 2 GDP + Pi GTP Oxygen diffuses into the cell O 2 ATP H 2 O ATP ADP + Pi H+ F 0 F 1 ATPase cytoplasm Outer membrane Intermembrane space O 2 matrix 2 CO 2 Inner membrane

38 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). 38

39 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. 39

40 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. 40

41 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 41

42 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 42

43 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 43

44 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 44

45 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. E: None of the above 45

46 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. E: None of the above 46

47 CQ12: 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 47

48 CQ12: 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 48

49 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 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. 49

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