is Why Patrick Paralyzed?
Learning Objectives:
1.
2.
3.
4.
Explain how energy is transferred through chemical reactions including the role of enzymes in this process. (Terms to know: endergonic and exergonic, difference in energy between ATP and ADP, catalyst, activation energy, substrate, product.) Compare the three major steps in the breakdown of food for energy in terms of substrates and products. Predict what would happen to the amount of product or substrate if an enzyme was not working. Use knowledge of converging metabolic pathways to predict treatment options for a metabolic disease caused by a mutation in an enzyme in this pathway.
2
Why did Patrick lose his ability to move?
Patrick at 2: Patrick at 21: Movie in QuickTime (mov)
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?
4
Clicker Question 1
What could be responsible for Patrick's loss of mobility?
A.
His nervous system is not functioning properly. His muscles are not functioning properly. He cannot efficiently break down food for energy. All of the above are possible causes.
5
B.
C.
D.
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)
6
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
7
Exergonic Reactions "Energy out"
Starting substances (reactants) have more potential energy in chemical bonds than final substances (products). Example: ___________________________. Spontaneous Matter: Energy: High potential energy glucose
Exergonic
Low potential energy Energy released (mostly 8 as heat)
Endergonic Reactions "Energy in"
Starting substances (reactants) have less energy than final substances (products), Example:_________________________. Spontaneous Matter: Energy:
glucose High potential energy
Endergonic
Low potential energy Energy required (from solar energy in plants)
9
Cycling between stored chemical versus movement energy
Stored chemical energy must be released
Processes that RELEASE energy
Allow ATP production Catabolic/ Exergonic
Movement requires energy
Processes that REQUIRE energy
Use ATP Anabolic/ Endergonic
Energy released Energy required ATP plays a central role
10
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
Adenosine triphosphate (ATP)
The net effect of ATP hydrolysis is the release of energy.
H2O
Hydrolysis of ATP
H
H
Inorganic phosphate (Pi)
Adenosine diphosphate (ADP)
12
ATP plays a central role in metabolism
ATP is a source of energy for living things 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
Clicker Question 2
The high energy phosphate bond in ATP is _____ and ____ energy.
A. B. C. D.
Easy to break, releases Hard to break, requires Easy to break, requires Hard to break, releases
14
Clicker Question 3
What would happen if Patrick lost his ability to make ATP?
A.
B.
C.
His muscles would not be able to contract. His neurons would not be able to conduct electrical signals. Both A and B.
15
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.
16
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. Liver and intestinal cells make enzyme Alcohol dehydrogenase (ADH) converts Substrate: into product: alcohol (ethanol) acetaldehyde
17
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.
18
Clicker Question 4
Which statement about enzymes is correct?
A. B.
C. D. E.
Enzymes are always proteins. Enzymes are consumed in a reaction. Enzymes are always active. All are correct. None are correct.
19
Enzyme Regulation
Enzymes turn "on" and "off" based on demands of the organism
"ON" = Activators Hormone glucagon turns on enzymes used to break down glucose for energy.
"OFF" = Inhibitors Alcoholics take Antabuse because it blocks acetaldyhyde dehydrogenase enzyme. http://www.chem.purdue.edu/courses/chm333/enzyme_
20
Clicker Question 5
In competitive inhibition...
A.
B.
C.
D.
the inhibitor competes with the normal substrate for binding to the enzyme's active site. an inhibitor permanently inactivates the enzyme by combining with one of its functional groups. the inhibitor binds with the enzyme at a site other than the active site. the competing molecule's shape does not resemble the shape of the substrate molecule.
21
How are metabolic pathways regulated?
Feedback inhibition animation
22
Metabolic Pathways:
energy
C6H12O6 + 6O2 6CO2 + 6H2O Two main types of energy releasing pathways: aerobic and anaerobic Eukaryotic cells use mainly aerobic respiration (O2) Metabolic pathways (energy in bite-sized pieces) C6H12O6 + O2
energy energy energy energy
CO2 + H2O
23
Clicker Question 6
Considering the previous slide, where do the atoms from glucose go?
A. They are converted into heat and then lost. B. They are all converted into ATP. C. They are released as CO2 and H2O in metabolism. D. They are converted into other types of sugars and stored.
24
DNA mutations can disrupt metabolic pathways
Patrick suffered from a genetic disease that altered the structure of one protein. The was protein an enzyme. The enzyme could potentially: lose its ability to catalyze a reaction. lose its ability to be regulated. What would be the result of this type of mutation?
25
DNA Mutations in Patrick's Disease
The genetic disease that Patrick had affected an enzyme in the metabolic pathway that uses glucose to produce ATP. Let's look at that pathway.
26
Process of Converting Potential Energy from Food into ATP:
27
27
Overall Reaction: Four Steps
Shows each major event, with location, 2 reactants, products, and purpose.
1
3 4
28
Clicker Question 7 Which of the following steps in the metabolism of glucose yields the most ATP?
A. B. C. D.
Glycolysis Acetyl Co-A formation Kreb's cycle Electron transport chain
29
Comparison Table
Substrates Ccontaining Glycolysis Acetyl CoA formation Krebs Cycle ETC
30
Products ATP NADH FADH2
Step 1: 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+ Add to Comparison Table.
31
http://instruct1.cit.cornell.edu/Courses/biomi290/MOVIES/GLYCOLYSIS.HTML
Important Electron Acceptors Coenzymes
NAD (Nicotinamide Adenine Dinucleotide)
NAD+ + 2H+ + 2 e- --> NADH+ + H+ FAD + 2H+ + 2 e- --> FADH2
FAD (Flavin Adenine Dinucleotide)
Both molecules serve as coenzymes in many reactions.
32
Step 2: Mitochondrial Reactions: Convert Pyruvate to Acetyl CoA
Pyruvate transported into inner compartment
Add to Comparison Table.
33
Step 3: Krebs Cycle
Add to Comparison Table.
34
Step 4: Electron Transport
Electrons are passed between several molecules Electrons give up energy as passed along
35
Why we die if we can't breathe:
At the end of the chain electrons are given to oxygen.
With H+ forms water. Why O2 is needed by most living things.
36
Step 4: ETC & ATP Synthesis
Large concentration gradient of Hydrogen builds up across the mitochondrial membrane
Works like hydroelectric dam
37
Each Step of Metabolism = Funnel
Glucose
Glycolysis
Pyruvate NADH
Pyruvate - Acetyl CoA
Acetyl CoA NADH
Krebs Cycle Electron Transport Chain
Krebs Cycle CO2
NADH FADH2
38 NAD+
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 Converts pyruvate to lactate Overall yield = 2 ATP
39
Lactate Fermentation = animal cells
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
40
Anaerobic metabolism
Glucose Glycolysis Glucose
2 NAD+
Cell membrane
2 ATP 2 Pyruvate 2 Lactate (fermentation) NAD+ Mitochondria cytoplasm
No O2
2 NADH
41
Anaerobic versus aerobic metabolism
Glucose Glycolysis Glucose
2 NAD+
Cell membrane
2 ATP 2 Lactate (fermentation) 2 Pyruvate NAD+ 2 NADH Mitochondria H+ H+ cytoplasm With O2 ee-
No O2
O2
Pyruvate dehydrogenase enzyme
H+
e-
e-
e-
O2 H2O
ATP
PyruvateNAD+ Electron transport carriers
CO2
NADH
3 NAD+ Acetyl CoA citrat e 3 NADH FAD FADH2
H+
Outer membrane
ADP + Pi
ATPase
ATP 2 CO2
Krebs cycle
matrix
Inner membrane
42
Clicker Question 8 Which of the following is true of the enzyme pyruvate dehydrogenase?
A. B. C. D.
It works in the cytoplasm of the cell. Its substrate is Acetyl CoA. Its products are pyruvate and NAD+. A defect in it could lead to the build up of pyruvate and lactate.
43
What happened to Patrick?
He inherited a mutation leading to a disease called pyruvate dehydrogenase complex disease (PDCD). Alanine Pyruvate dehydrogenase (PDH) 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. When PDH activity is reduced, pyruvate accumulates, leading to alanine and lactate accumulation in the blood (lactate acidosis).
Glucose Pyruvate Lactate
Mitochondrial Membrane Pyruvate Pyruvate Dehydrogenase PDH Acetyl-CoA
Lipids
Krebs cycle
Ketone bodies 44
Clicker Question 9
Why did Patrick become paralyzed?
A.
B.
C.
D.
He inherited a genetic disease that resulted in the partial loss of an enzyme necessary for aerobic breakdown of glucose. The enzyme that is necessary for metabolizing fats was defective. He was unable to synthesize muscle proteins due to defective ribosomes. He suffered from a severe ion imbalance due to a high salt diet.
45
Clicker Question 10
Which food(s) can be metabolized to generate acetyl CoA?
A.
ATP Production Pathways Glucose Glycerol
Glycolysis
Amino Acids
Carbohydrates Fats Proteins Both carbohydrates and fats Carbohydrates, fats and proteins
Amino Acids Fatty Acids Amino Acids
B.
C.
Krebs Cycle
D.
E.
Electron Transport System
46
Are there any treatment options for PDH deficiency? Glucose
High fat, low carbohydrate diet (ketogenic diet)
Glycerol Amino Acids
Glycolysis
Fatty acids can form acetyl CoA which can enter the Krebs cycle
Amino Acids Fatty Acids Amino Acids Krebs Cycle
ATP Production PathwaysElectron Transport System 47
Clicker Question 11
Why is PDH deficiency treated with a high-fat, low carbohydrate diet?
A.
B.
C.
D.
Because fats generate more ATP per molecule than glucose. Because the metabolism of fats does not produce NADH or FADH2. Because fats can be metabolized to Acetyl CoA without the utilization of pyruvate dehydrogenase. All of these are reasons to treat PDH deficiency 48 with a high-fat, low-carbohydrate diet.
Are there any treatment options for PDH deficiency?
Dichloroacetate (DCA) blocks the enzyme that inactivates PDH.
DCA blocks here
Kinase
PDH Active
Phosphatase
PDH-P Inactive
PDH remains in the active form
49
Clicker Question 12
Dichloroacetate (DCA) administration would lead to...
A.
B. C.
No change in the amount of active PDH. Less active PDH. More active PDH.
50
Even though Patrick lost PDH activity, ultimately Patrick's disease was due to his inability to make ATP.
51
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.
52
Rank this case using the following Clicker Question 13 scale:
This case was . . . Engaging Boring 1 2 3 4
5
Rank this case using the following Clicker Question 14 scale:
This case made me feel . . . Emotional Unemotional 1 2 3 4 5