The Krebs Tricarboxylic Acid Cycle

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The Krebs Tricarboxylic Acid Cycle

• The Final Common Pathway of Oxidative Metabolism
• 9/24/07

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? Liver
Gluconeogenesis 1? Liver, Kidney
e- Ox phos
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Citric Acid Cycle (CAC) Kreb Cycle Tricarboxylic
Acid Cycle
2/3 of O2 consumption needed for oxidation of
Acetyl CoA ? CO2

• Occurs exclusively in the
• mitochondrion (matrix)

• OAA acts as carrier or acceptor
• of acetyl CoA units is regenerated

• Burns acetyl CoA to CO2 during
• this oxidation es from acetyl CoA
• are trapped in the form of

NADH
Pyruvate Dehydrogenase Complex links glycolysis
to CAC
FADH
2e
2e
2e
2e
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The Three Stages of Metabolism
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The Krebs Cycle

• Citric Acid Cycle The TCA Cycle
• Pyruvate (actually the acetyl group) from
  glycolysis is degraded to CO2
• The acetyl group is formed in stage II of
  metabolism from carbohydrate and amino acid
  metabolism
• 1GTP (ATP in bacteria) and 1 FADH2 is produced
  during one turn of the cycle
• 3 NADH are produced during one turn of the cycle
• NADH and FADH2 energize electron transport and
  oxidative phosphorylation
• Eight reactions make up the Krebs cycle

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The Chemical Logic of the Krebs Cycle

• After condensing acetate with oxaloacetate to
  form citrate oxidation yields CO2, oxaloacetate
  is regenerated, and the energy is captured as
  NADH, FADH2, and GTP (ATP)
• Acetyl-CoA is called the stoichiometric
  substrate it is consumed in large amounts
• Oxaloacetate is called the regenerating
  substrate it is continuously regenerated (it is
  not consumed)
• The cycle is catalytic oxaloacetate is consumed
  and then regenerated.

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Overview of the Krebs Cycle A Mitochondrial
Process
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Anatomy of the Mitochondrion

• Which membrane is impermeable to protons and
  other ions?
• Which membrane will allow for the transport of
  molecules up to a molecular weight of about 1000?

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Pyruvate Dehydrogenase Complex
Cytoplasm Pyruvate
Multimolecular aggregate
3 Enzymes
5 Coenzymes
5 Reactions
Irreversible
CoA contains the vitamin Pantothenic acid
Links glycolysis to CAC
Product Inhibition
Mitochondrial matrix
NAD
FAD
CoA
Lipoic acid
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PDH Deficiency results in Congenital Lactic
Acidosis
Pyruvate cannot enter the CAC and results in ?
Lactic Acid
Primarily affects the brain neonatal death
3 Forms psychomotor retardation
v Possible treatment is ketogenic diet
Low in CHO
High in fats
Produces ketone bodies as an alternate form of
energy for the brain
Arsenic Poisoning Pyruvate Dehydrogenase
a-Ketoglutarate Dehydrogenase
Both require lipoic acid as a cofactor
Arsenite Trivalent form of arsenic
I Forms a stable complex with the thiol (-SH)
group of Lipoic Acid
II Glyceraldehyde 3-PO4 step forms complex
with inorganic Pi thus prevents ATP
formation in glycolysis
Affects the brain Death, neurologic problems
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v Allosteric Regulation
v Allosteric Regulation
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Aldo condensation
The entrance of acetyl CoA does not ? or ?
intermediates in the CAC
Isomerization
Oxidative decarboxylation
e
Irreversible (1)
One of the rate limiting Rxs of the CAC
ATP
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Oxidative decarboxylation
Very similar to the Pyruvate Dehydrogenase
complex
Irreversible (2)
e
Substrate Level Phosphorylation
Nucleoside Biphosphate Kinase
e
Oxidation reaction
Hydration reaction
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Reversible oxidation reaction
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Main Points of the Krebs Cycle

• Occurs in mitochondrion
• All enzymes are hydrophilic and occur in the
  matrix except for succinate dehydrogenase, which
  occurs in the inner mitochondrial membrane
• Citrate synthase, Isocitrate dehydrogenase and
  a-ketoglutarate dehydrogenase are the three
  irreversible reactions
• ICD is the main regulatory enzyme, and it is
  activated by ADP
• Succinate dehydrogenase is inhibited by malonate
  and oxaloacetate

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Summary
This ratio determines the rate of oxidative
phosphorylation
Named Respiratory Control of energy production
because oxidation and phosphorylation of ADP must
occur simultaneously
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Electrochemical gradient
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2 Shuttle systems to bring cytosolic NADH
into mitochondria for oxidative phosphorylation
1) Glycerophosphate shuttle 36 ATP
2) Malate-aspartate shuttle 38 ATP
Count ATPs Anerobic glycolysis 2
Glycolysis CAC oxidative
phosphorylation 38
NADH FADH2 ATP
1 Glycolysis 2
2 Glycolysis (G-3-P ? 1,3,BisP) 2 6
3 Pyruvate ? Acetyl CoA 2 6
4, 5, 6 CAC 6 18
7 CAC-FADH2 2 4
8 CAC substrate level ATP 2
Total 38
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