An incomplete citric acid cycle in

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Possible evolution of the Citric Acid Cycle
A metabolic hub

• An incomplete citric acid cycle in
• some anaerobic bacteria
• aKG dehydrogenase (inner mito.
• membrane) is missing no
• electron transport chain
• Recall steps 1, 3, 4 are irreversible
• so reversing to succinyl CoA is
• readily possible
• aKG and succinyl-CoA are the
• starting materials for biosynthesis
• Oxaloacetate to succinyl-CoA
• pathway recycles NADH back
• to NAD a fermentation pathway

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TCA cycle is amphibolic
Citric acid cycle provides precursors for
biosynthetic pathways a second important role
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Four anaplerotic reactions generate oxaloacetate
or malate. All these enzymes are tightly regulated
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Recall gluconeogenesis bypass through
mitochondrion Pyruvate carboxylase is the most
important TCA cycle replenishing (anaplerotic)
rxn. PEP carboxykinase (reversible) can also
replenish oxaloacetate
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REGULATION of TCA cycle -energy charge most
impt. -regulate strongly exergonic
(irreversible) steps -inhibition by product
accumulation -slowed by depletion of NAD ATP,
NADH, and citrate levels commonly regulate
glycolysis and the TCA cycle and provide a way
to match the rates of the two processes. TCA
cycle enzymes are also associated into a
complex in vivo (a metabolon)
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-This cycle effects net conversion of acetate
to succinate/ other 4-carbon intermediates.
Thus fats/amino acids that break down to
acetate can be converted eventually to
oxaloacetate, then to PEP and then to glucose/
glycogen via gluconeogenesis -Note that there
is no loss of carbon as CO2, as in the TCA
cycle. -New enzymes are isocitrate lyase and
malate synthase. -Each turn consumes 2
acetyl-CoA and generates 1 succinate for
synthesis
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• In germinating plants, the glyoxylate cycle
  occurs
• in a specialized organelle the glyoxysome
• Enzymes of the TCA cycle that are also needed for
• the glyoxylate cycle are present as duplicate
• isozymes (citrate synthase, aconitase,
• malate dehydrogenase)
• Metabolites interchange among three compartments
• in the cell.

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Coordinated regulation of the glyoxylate and
the citric acid cycle pathways occurs in the
processing of isocitrate Isocitrate
dehydrogenase is regulated by covalent
modification phosphorylation inactivates the
enzyme. The kinase is in turn inactivated by
buildup of TCA cycle intermediates, signaling
a depleted energy state in the cell TCA cycle
intermediates inhibit isocitrate lyase,
blocking the glyoxylate cycle an
energy-depleted cell should not convert fat to
sugar via gluconeogenesis