The Krebs cycle, also known as the citric acid cycle or tricarboxylic acid (TCA) cycle, is a series of chemical reactions that generates energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. The cycle produces carbon dioxide, ATP, NADH, and FADH2 which are used to generate more ATP through oxidative phosphorylation. The cycle occurs in the mitochondrial matrix and consists of eight steps that regenerate the starting molecule oxaloacetate from citrate. Overall, the Krebs cycle generates between 2-3 ATP, 6 NADH, 2 FADH2, and 2 GTP per acetyl-CoA molecule which can then generate between

1. Kreb’s Cycle
(aka, tricarboxylic acid
(TCA)cycle, citric acid cycle)
“The wheel is turnin’ and the sugar’s a
burnin’”
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2. Overall goal
• Makes ATP
• Makes NADH
• Makes FADH2
• Requires some carbohydrate to run
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3. Geography
• Glycolysis in the cytosol
• Krebs in mitochondrial matrix
• Mitochondrion
– Outer membrane very permeable
• Space between membranes called intermembrane space
(clever huh!)
– Inner membrane (cristae)
• Permeable to pyruvate,
• Impermeable to fatty acids, NAD, etc
– Matrix is inside inner membrane
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4. Conversion of pyruvate to Acetyl
CoA
CH3
O
O
O
pyruvate
CO2HSCoA
CH3
SCoA
O
acetyl CoA
NADHNAD+
pyruvate dehydrogenase complex
• 2 per glucose (all of Kreb’s)
• Oxidative decarboxylation
• Makes NADH
• -33.4kJ
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5. Fates of Acetyl CoA
CH3
SCoA
O
acetyl CoA
Kreb's
CO2, ATP, NADH...energy
ketone bodies
no CHO present
TAG's
• In the presence of CHO an using energy
– Metabolized to CO2, NADH, FADH2,GTP and, ultimately, ATP
• If energy not being used (Lots of ATP present)
– Made into fat
• If energy being used, but no CHO present
– Starvation
– Forms ketone bodies (see fat metabolism slides)
– Danger!
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6. Kreb’s Cycle
CH3
C
O
SCoA
acetyl CoA
C O
CH2
C
O
C
OO
O
oxaloacetate
CoASH
citrate synthase
C
OO
CH2
C
CH2
C
OH C O
O
O O
citrate
aconitase
C
OO
CH
CH
CH2
C
C O
O
OO
OH
isocitrate
NAD
NADH
CO2
C
OO
C
CH2
CH2
C
OO
O
isocitrate dehydrogenase
alpha ketoglutarate
NAD
NADH
CoASH
CO2
C
CH2
CH2
C
OO
OSCoA
succinyl CoA
alpha ketoglutarate
dehydrogenase
GDP
GTP
CoASH
C
C
C
C
OO
O O
H
H
succinate
succinyl CoA
synthetase
FAD
FADH2succinate
dehydrogenase
C
CH2
CH2
C
OO
O
O
fumarate
OH2
C
CH
CH2
C
OO
O O
OH
malate
fumarase
NAD
NADH
malate
dehydrogenase
Kreb's Cycle
OH2
+
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7. Net From Kreb’s
• Oxidative process
– 3 NADH
– FADH2
– GTP
• X 2 per glucose
– 6 NADH
– 2 FADH2
– 2 GTP
• All ultimately turned into ATP (oxidative
phosphorylation…later)
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8. Citrate Synthase Reaction (First)
acetyl CoA oxaloacetate
CoASH
citrate synthase
citrate
OH2
CH3
C
O
SCoA
C O
CH2
C
O
C
OO
O
C
OO
CH2
C
CH2
C
OH C O
O
O O
+
• Claisen condensation
• -32.2kJ
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9. Aconitase Reaction
citrate
aconitase
isocitrate
C
OO
CH2
C
CH2
C
OH C O
O
O O
C
OO
CH
CH
CH2
C
C O
O
OO
OH
• Forms isocitrate
• Goes through alkene intermediate (cis-aconitate)
– elimination then addition
• 13.3kJ
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10. Isocitrate Dehydrogenase
isocitrate
NAD NADH CO2
isocitrate dehydrogenase
alpha ketoglutarate
C
OO
CH
CH
CH2
C
C O
O
OO
OH
C
OO
C
CH2
CH2
C
OO
O
• All dehydrogenase reactions make NADH or FADH2
• Oxidative decarboxylation
• -20.9kJ
• Energy from increased entropy in gas formation
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11. α-ketoglutarate dehydrogenase
alpha ketoglutarate
NAD NADH
CoASH
CO2
succinyl CoA
alpha ketoglutarate
dehydrogenase
C
OO
C
CH2
CH2
C
OO
O
C
CH2
CH2
C
OO
OSCoA
• Same as pyruvate dehydrogenase reaction
• Formation of thioester
– endergonic
– driven by loss of CO2
• increases entropy
• exergonic
• -33.5kJ
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12. Succinyl CoA synthetase
succinyl CoA
GDP GTP CoASH
succinate
succinyl CoA
synthetase
C
CH2
CH2
C
OO
OSCoA
C
CH2
CH2
C
OO
O
O
• Hydrolysis of thioester
– Releases CoASH
– Exergonic
• Coupled to synthesis of GTP
– Endergonic
– GTP very similar to ATP and interconverted later
• -2.9kJ
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13. Succinate dehydrogenase
succinate
FAD FADH2
succinyl CoA
dehydrogenase
fumarate
C
CH2
CH2
C
OO
O
O
C
C
C
C
OO
O O
H
H
• Dehydrogenation
• Uses FAD
– NAD used to oxidize oxygen-containing groups
• Aldehydes
• alcohols
– FAD used to oxidize C-C bonds
– 0kJ
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14. Fumarase
fumarate
OH2
malate
fumarase
C
C
C
C
OO
O O
H
H
C
CH
CH2
C
OO
O
OH
O
• Addition of water to a double bond
• -3.8kJ
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15. Malate Dehydrogenase
oxaloacetate
malate
NAD NADH
malate
dehydrogenase
C
CH
CH2
C
OO
O
OH
O
C O
CH2
C
O
C
OO
O
• Oxidation of secondary alcohol to ketone
• Makes NADH
• Regenerates oxaloacetate for another round
• 29.7 kJ
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16. Net From Kreb’s
• Oxidative process
– 3 NADH
– FADH2
– GTP
• X 2 per glucose
– 6 NADH
– 2 FADH2
– 2 GTP
• All ultimately turned into ATP (oxidative
phosphorylation…later)
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17. Total Energy per glucose
• Cytosol
– Glycolysis
• 2 NADH
• 2 ATP
• Mitochondrion
– Pyruvate dehydrogenase
• 2 NADH
• Krebs
– 6 NADH
– 2 FADH2
– 2 GTP
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18. Total Energy/glucose
• In mitochondrion:
– Each NADH makes 2.5 ATP
– Each FADH2 makes 1.5 ATP
– GTP makes ATP
• So…
– From in mitochondrion
• 8 NADH X 2.5 ATP/NADH = 20 ATP
• 2 FADH2 X 1.5 ATP/FADH2= 3 ATP
• 2 GTP X 1 ATP / GTP = 2 ATP
• TOTAL in mitochondrion 25 ATP
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19. Total Energy/ glucose
• Cytosol
– 2 ATP
– 2 NADH
• NADH can’t get into mitochondrion
• In eukaryotes two pathways,
– transferred to FADH2
» get 1.5 ATP/ FADH2
– Or transferred to NADH
» Get 2.5 ATP/ NADH
– (Not a problem in prokaryotes (why?))
– 2 NADH X 1.5 ATP = 3 ATP
– Or 2 NADH X 2.5 ATP = 5 ATP
» + =2 ATP
» Total 3+ 2 or 5 + 2 so either 5 or 7
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20. ATP/glucose
• Eukaryotes
– Mitochondrial: 25 ATP
– Cytosolic: 5 or 7 ATP
– Total 30 or 32 ATP/glucose
– 30 ATP X 7.3kcal X 4.18 kJ = 915 kJ
ATP kcal
If 32 ATP = 976 kJ
• Prokaryotes
– 32 ATP X 7.3kcal X 4.18 kJ = 976 kJ
ATP kcal
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