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Transcript of CITRIC ACID CYCLE Student Edition 11/8/13 version Pharm. 304 Biochemistry Fall 2014 Dr. Brad...
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CITRIC ACID CYCLEStudent Edition 11/8/13 version
Pharm. 304 Biochemistry
Fall 2014
Dr. Brad Chazotte 213 Maddox Hall
[email protected] Site:
http://www.campbell.edu/faculty/chazotte
Original material only ©2002-14 B. Chazotte
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Goals• Learn the Citric Acid Cycle sequence, enzymes, intermediates, products,
and control mechanisms.
• Learn the different stages of cellular respiration.
• Know that the citric acid cycle involves the oxidation of 2-carbon units.
• Be familiar with the function of the pyruvate dehydrogenase complex, its reaction types, general structure, and control mechanisms.
• Understand how degradative reactions provide cycle intermediates.
• Be familiar with role of the cycle in providing biosynthetic precursors.
• Understand the role of anaplerotic reactions
Do NOT memorize specific enzyme mechanisms
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Complete Oxidation to Molecular OxygenGlucose Note: 1 cal =4.184J
C6H12O6 + 6 O2 6 CO2 + 6 H2O G° ’=-2823 kJ mole-1
Broken down into the half reactions:
C6H12O6 + 6 H2O 6CO2 + 24H+ + 24 e-
6 O2 + + 24H+ + 24 e- 12 H2O
Palmitic Acid
Palmitoyl-CoA + 23O2 + 131 Pi + 131 ADP CoA + 16CO2 + 146 H2O +131 ATP
Palmitic Acid + 23 O2 16 CO2 + 16 H2O G°’= -9790.5 kJ mole-1
129 ADP + 129Pi 129 ATP + 129 H2O G°’= +3941 kJ mole-1
129 ATP is the next yield since 2 ATP are needed to form palmitoyl-CoA from palmitic acid. To Form 1 ATP G°’= +30.54 kJ mole-1 = 7.3 kcal mole-1
Citric Acid Cycle
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Cellular Respiration Review
Citric Acid Cycle
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Lehninger 2000 Fig 16.1a
Stage 1 of Cellular Respiration
Citric Acid Cycle
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Lehninger 2000 Fig 16.1b
Stage 2 of Cellular Respiration
Citric Acid Cycle
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Lehninger 2000 Fig 16.1c
Stage 3 of Cellular Respiration
Citric Acid Cycle
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Overviewof the Citric Acid Cycle
Citric Acid Cycle
• The central metabolic hub of the cell
• The gateway to the aerobic metabolism for any molecule that can be converted into an acetyl group or a dicarboxylic acid.
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Berg, Tymoczko & Stryer, 2012 Chap. 17 p.497
Coenzyme A
Citric Acid Cycle
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Acetyl Coenzyme A
• Acetyl CoA is the “fuel” for the citric acid cycle
• Formed from the breakdown of glycogen, fats, and many amino acids.
• A high energy compound G° = -31 kJ mol-1
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Lehninger 2000 Fig 16.3
Coenzyme A components
Citric Acid Cycle
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Berg, Tymoczko & Stryer, 2012 Fig. 17.1
Mitochondrion Electron Micrograph
Citric Acid Cycle
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Berg, Tymoczko & Stryer, 2012 Fig. 17.2
Citric Acid Cycle: Schematic Overview
Citric Acid CycleHorton 2012 Fig. 13.5
succinate
-ketoglutarate
oxaloacetate
acetyl group
citrate
isocitrate
A B
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Berg, Tymoczko & Stryer, 2012 Fig. 17.3
Cellular Respiration Schematic
Citric Acid Cycle
“The function of the citric acid cycle is the harvesting of high energy electrons from carbon fuels”.
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Enzymes of the Citric Acid Cycle
1. Citrate synthase
2. Aconitase
3. Isocitrate dehydrogenase
4. -ketoglutarate dehydrogenase
5. Succinyl-CoA synthetase
6. Succinate dehydrogenase
7. Fumarase
8. Malate dehydrogenase
Citric Acid Cycle
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Intermediates of the Citric Acid Cycle
1. oxaloacetate (4C)
2. citrate (6C)
3. cis-aconitate (6C)
4. isocitrate (6C)
5. -ketoglutarate (5C)
6. succinyl-CoA (4C)
7. succinate (4C)
8. fumarate (4C)
9. malate (4C)
Citric Acid Cycle
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“Products” of the Citric Acid Cycle
Three (3) Hydride Ions (H-), that is six
(6) electrons are produced in the form of:
3 NADH (from isocitrate dehydrogenase,
-ketoglutarate dehydrogenase, & malate dehydrogenase)
1 FADH2 (from succinate dehydrogenase)
These electron carriers donate to electron transport which in turn drives oxidative phosphorylation to produce ATP
1 GTP (or ATP)(from succinyl CoA synthetase, a substrate-level phosphorylation)
2 CO2 (at isocitrate dehydrogenase & -ketoglutarate dehydrogenase)
Citric Acid Cycle
Horton 2002 Fig12.6
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Berg, Tymoczko & Stryer, 2012 Fig. 17.15
Citric Acid (Krebs) Cycle
Citric Acid Cycle
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Berg, Tymoczko & Stryer, 2012 Table 17.2
Citric Acid (Krebs) Cycle Rx List
Citric Acid Cycle
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Oxidation of Two Carbon Units[Citric Acid Cycle]
Citric Acid Cycle
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Berg, Tymoczko & Stryer, 2012 Fig. 17.4
Glycolysis to the Citric Acid Cycle
Citric Acid Cycle
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Pyruvate Dehydrogenase Complex
Preparation to enter the Citric Acid Cycle
Citric Acid Cycle
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Pyruvate Dehydrogenase Reaction
Pyruvate + CoA + NAD+ acetyl CoA + CO2 + NADH
This is an irreversible reaction that links glycolysis and the citric acid cycle.
Citric Acid Cycle
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Horton et al 2002, Table 12.1
Pyruvate Dehydrogenase Complex (E. Coli vs mammalian)
Citric Acid Cycle
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Berg, Tymoczko & Stryer, 2012 Fig. 17.7
Pyruvate Dehydrogenase Complex Schematic
Citric Acid Cycle
/ Pyruvate Dehydrogenase
Horton et al, 2002 Fig. 12.3
E1
E2
E3
PDH Azobacter vinelandii
core
completeBerg, Tymoczko & Stryer, 2001 Fig. 17.3
Voet, Voet, & Pratt 2012 Fig. 17.4
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Berg, Tymoczko & Stryer, 2012 Fig. 17.8
PDH Complex: Transacetylase (E2) Core
Citric Acid Cycle
/ Pyruvate Dehydrogenase
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Berg, Tymoczko & Stryer, 2012 Chap 17 p.500
Two of the cofactors in the Pyruvate Dehydrogenase Complex
Citric Acid Cycle
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Berg, Tymoczko & Stryer, 2012 Chap. 17 p. 500
PDH Complex’s Three Basic Reaction Types
Citric Acid Cycle
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Lehninger 2000 Fig 16.6
Citric Acid Cycle/ /
Pyruvate Dehydrogenase
Oxidative Decarboyxlation of Pyruvate by the PDH Complex
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Berg, Tymoczko & Stryer, 2012 Fig. 17.9
Pyruvate Dehydrogenase Complex Rx
Citric Acid Cycle
/ Pyruvate Dehydrogenase
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Berg, Tymoczko & Stryer, 2002 Chap 17 p. 500
Formation of TPP Carbanion
Citric Acid Cycle
TPP is the prosthetic group of pyruvate dehydrogenase.
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Pyruvate Dehydrogenase Complex: Mechanisms
Citric Acid Cycle
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Berg, Tymoczko & Stryer, 2012 Fig. 17.6
Pyruvate Dehydrogenase Complex: Decarboxylation Reaction of E1
Citric Acid Cycle
/ Pyruvate Dehydrogenase
The charged TPP ring functions as an electron sink that acts to stabilize the transferred negative charge
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Berg, Tymoczko & Stryer, 2002 Chap 17 p. 500
PDH Complex: Lipoamide Structure
Citric Acid Cycle
/ Pyruvate Dehydrogenase
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Structures and Interconversion of Lipoamide & Dihydrolipoamide
Voet, Voet & Pratt 2013 Figure 17.7
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Voet, Voet & Pratt 2013 Chap 17 p. 559
PDH Complex: Oxidation of the Hydroxyethyl Group and Transfer to Lipoamide
Citric Acid Cycle
/ Pyruvate Dehydrogenase
Catalyzed by pyruvate dehydrogenase component (E1).
Carbanion
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PDH Complex: Formation of Acetyl CoA by Transfer of Acetyl Group from Acetyllipoamide
Citric Acid Cycle
/ Pyruvate Dehydrogenase
Catalyzed by dihydrolipoyl transacetylase (E2).
Voet, Voet & Pratt 2013 Chap 17 p. 559
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PDH Complex: Regeneration of Oxidized Form of Lipoamide by Dihydrolipoyl Dehydrogenase
Citric Acid Cycle
/ Pyruvate Dehydrogenase
Voet, Voet & Pratt 2013 Chap 17 p. 559
Summary of Two-step Process above
Berg, Tymoczko & Stryer, 2012 Chap 17
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The Citric Acid Cycle
Citric Acid Cycle
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Leheninger 2000 Fig 16.7
Citric Acid Cycle Diagram: #11
Note that the acetyl group that enters the cycle does not give rise to the CO2 molecules given off in the decarboxylations in ONE TURN of the cycle.
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Citrate Synthase Structure
OPEN CLOSED
Berg, Tymoczko & Stryer Figure 17.10
Oxaloacetate binding induces the two domains to move toward each other in an 18 degree arc
This forms a binding site for acetyl CoA.
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Berg, Tymoczko & Stryer, 2012 Chap 17 p.504
Citric Acid Cycle: Condensation of Oxaloacetate & acetyl CoA
Citric Acid Cycle
Citrate synthaseCitrate synthase
G = -31.4 kJ mol-1Reaction 1
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Berg, Tymoczko & Stryer, 2012 Fig. 17.11
Citric Acid Cycle: Synthesis of Citryl CoA by Citrate Synthase
Citric Acid Cycle
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Leheninger 2000 Fig 16.7
Citric Acid Cycle Diagram: #2
2
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The purpose of this reaction is to convert the citrate molecule to a secondary alcohol.Voet, Voet & Pratt, 2013 Chap 17 p.563
Citric Acid Cycle: Isomerization of Citrate by Aconitase
Citric Acid Cycle
Aconitase Aconitase
G = +8.4 kJ mol-1 G = -2.1 kJ mol-1
Reaction 2
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Berg, Tymoczko & Stryer, 2012 Fig. 17.12
Citrate Binding to Aconitase’s Fe-S Complex
Citric Acid Cycle
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Aconitase: Mechanism & Stereochemistry
Voet & Voet Biochemistry 1995 Fig. 19.3
Citric Acid Cycle
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Leheninger 2000 Fig 16.7
Citric Acid Cycle Diagram: #3,4
3
4
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Voet, Voet, & Pratt Fig. 17.11
Citric Acid Cycle: Oxidative Decarboxylation of Isocitrate by Isocitrate Dehydrogenase
Citric Acid Cycle
Isocitrate dehydrogenase
Isocitrate dehydrogenase
G = -8.4 kJ mol-1Reaction 3
Do not dissociate from enzyme
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Berg, Tymoczko & Stryer, 2012 Chap 17 p.507
Citric Acid Cycle: Oxidative Decarboxylation of -ketoglutarate
Citric Acid Cycle
-ketoglutarate dehydrogenase complex
G = -30.1 kJ mol-1Reaction 4
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Leheninger 2000 Fig 16.7
Citric Acid Cycle Diagram: #5
5
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Berg, Tymoczko & Stryer, 2012 Chap 17 p.508
Citric Acid Cycle: Succinyl CoA Synthetase Reaction
Citric Acid Cycle
Succinyl CoA Synthetase
G = -3.3 kJ mol-1Reaction 5
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Berg, Tymoczko & Stryer, 2012 Fig. 17.13
Citric Acid Cycle: Succinyl CoA Synthetase Rx Mechanism
Citric Acid Cycle
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Rx’s of Succinyl-CoA Synthetase
Voet & Voet , & Pratt 2013 Fig. 17.12Citric Acid Cycle
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Leheninger 2000 Fig 16.7
Citric Acid Cycle Diagram: #6,7
6
7
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Voet, Voet & Pratt 2013 Chap 17 p. 567
Citric Acid Cycle: Succinate Dehydrogenase Rx
Citric Acid Cycle
Succinate dehydrogenase
G = 0 kJ mol-1Reaction 6
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FAD vs NAD+ Reduction
In general:
FAD functions biochemically to oxidize alkanes to alkenes. The oxidation of an alkane, e.g. succinate, to an alkene (fumarate) is sufficiently exergonic to reduce FAD to FADH2 but not to reduce NAD+.
NAD+ oxidizes alcohols to aldehydes or ketones. Alcohol oxidation can reduce NAD+ to NADH
Voet, Voet & Pratt 2013 p. 567; Voet & Voet 1996 p555Citric Acid Cycle
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Voet, Voet, & Pratt 2012 Chap. . 17 p. 567
Citric Acid Cycle: Hydration of Fumarate to Malate by Fumarase
Citric Acid Cycle
Fumarase
G = -3.8 kJ mol-1Reaction 7
Fumarase
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Berg, Tymoczko & Stryer, 2012 Chap. 17 p.510
Citric Acid Cycle
Fumarate/Malate Stereochemistry
Voet, Voet & Pratt 2006 Figure page 531
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Voet, Voet, & Pratt 2013 Chap 17 p. 567
Citric Acid Cycle: Oxidation of Malate to Oxaloacetate By Malate Dehydrogenase
Citric Acid Cycle
Malate dehydrogenase
G = +29.7 kJ mol-1Reaction 8
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Citric Acid Cycle Stoichiometry
Citric Acid Cycle
Acetyl CoA + 3 NAD+ + FAD + GDP + Pi + 2 H2O
2 CO2 + 3 NADH + FADH2 + GTP + 2H+ + CoA
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Berg, Tymoczko & Stryer, 2012 Fig. 17.15
Citric Acid (Krebs) Cycle
Citric Acid Cycle
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Berg, Tymoczko & Stryer, 2012 Table 17.2
Citric Acid (Krebs) Cycle Reactions
Citric Acid Cycle
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Citric Acid Cycle
Stoichiometry of ATP Formation Table
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Regulation of Entry Into and Metabolism Throughthe Citric Acid Cycle
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Pathway from Glucose to Acetyl CoA
Citric Acid Cycle Horton et la, , 2012 Fig. 13.11 Voet, Voet & Pratt 2013 Chap 17 page 569
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Berg, Tymoczko & Stryer, 2002 Fig. 17.17
Regulation of the Pyruvate Dehydrogenase Complex
Citric Acid Cycle
Berg, Tymoczko & Stryer, 2012 Fig. 17.18a
Berg, Tymoczko & Stryer, 2012 Fig. 17.18b
Berg, Tymoczko & Stryer, 2012 Fig. 17.17
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Control of Metabolic Flux in the CycleKey Factors:
• Substrate Availability
• Inhibition by accumulating products
• Allosteric feedback inhibition of enzymes that catalyze the cycle’s early reactions.
Lehninger 2000, p 587
Citric Acid Cycle
Enzyme Control Points:
Citrate synthase (Bacteria)
Isocitrate dehydrogenase
-ketoglutarate
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Berg, Tymoczko & Stryer, 2012 Fig. 17.19
Control of the Citric Acid Cycle
Citric Acid Cycle Voet, Voet, & Pratt 2013 Fig. 17.16
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The Citric Acid Cycle and Biosynthetic Precursors
Citric Acid Cycle
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Citric Acid Cycle
Anaplerotic Reactions Table(most common anaplerotic reactions)
Serve to replenish the citric acid cycle intermediates that are removed as biosynthetic precursors
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Degradative Pathways Generating Cycle Intermediates
• Oxidation of odd chain fatty acids lead to the production of succinyl-CoA
• Breakdown of the amino acids leucine, methionine and valine also lead to succinyl CoA production
• Transamination and Deamination of amino acids leads to the production of -ketoglutarate and oxaloacetate.
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Berg, Tymoczko & Stryer, 2012 Fig. 17.20
Citric Acid Cycle: Roles in Biosynthesis
Citric Acid Cycle
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Citric Acid Cycle
The Citric Acid Cycle in Anabolism: Diagram
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End of Lectures