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Lecture 24½
Krebs Cycle
Overview
Condensation
• Formation of citrate
– One of the methyl-Hs can easily come off acetyl CoA
– Gives a very reactive species that reacts with oxaloacetate
• Citrate
– Contains 6 carbons
– 3 carboxylic groups  Tricarboxylic acid (TCA)
– Very symmetrical, but the enzyme can still distinguish
which carboxylic group comes from acetyl CoA &
oxaloacetate  prochiral
• Citrate can leave the mitochondria or be oxidised
– Depending on whether the cell is doing lipogenesis or needs
energy
Regulation
• Krebs cycle activity is controlled early on
– At isocitrate dehydrogenase (ICDH)
– alpha-ketoglutarate dehydrogenase (aKGDH)
• ICDH and OGDH are stimulated by rise in
Ca2+
– Such as is found during exercise
• ICDH & OGDH are also sensitive to NAD
levels
– Activity is dependent on availability of NAD
Important Features of Krebs Cycle
• During the cycle, 2 carbon atoms come in, 2 carbon
atoms has gone
– but on each cycle only 1 carbon atom from acetyl CoA gets
released as carbon dioxide
• The other carbon dioxide comes from oxaloacetate
• Generates 3 NADH, 1 reduced FAD, i.e. FADH2 plus a
GTP
– Each NAD gives 2.5 ATP in oxidative phosphorylation
• Oxaloacetate is not ‘net’ consumed in the cycle
– acts as carrier
• Fluoroacetate is a strong inhibitor of the cycle
– Creates fluorocitrate which inhibits citrate utilisation
– Very toxic and used as poison(1080)
Carriers
•
Krebs cycle can only go faster if we
provide enough carrier
– need more oxaloacetate during
exercise
•
In muscle pyruvate carboxylase
supplies extra oxaloacetate
– Anaplerotic reaction - “filling”
reaction
– So not only the liver has pyruvate
carboxylase
•
Krebs cycle regenerates the carrier
CoA
– Enables fatty acids to be oxidised
faster
•
Sequence of reactions from
succinate to oxaloacetate have
similar ‘strategy’ to oxidation of fatty
acids
– –CH2- going to –C=O
– Oxidation with FAD  hydration 
oxidation with NAD
Summary
Acetyl-CoA
Regenerates CoA
oxaloacetate
citrate
Citrate could leave
to cytoplasm in
liver and WAT
isocitrate
Identical sequence of
reactions to FA
oxidation:
FAD, water, NAD
Controlled by calcium &
NAD, loss of CO2
ketoglutarate
Controlled by calcium &
NAD, loss of CO2
Succinyl-CoA
succinate
Generates GTP