ANABOLIC FUNCTION OF KREBS CYCLE

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ANABOLIC FUNCTION OF KREBS CYCLE
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• Role of the citric acid cycle in anabolism.
• Besides its role in the oxidative catabolism of
  carbohydrates, fatty acids, and amino acids, the
  citric acid cycle can act in synthesis, as well
  as in breakdown.
• It can provide precursors for many biosynthetic
  pathways.
• Intermediates of the citric acid cycle are drawn
  off as precursors in many biosynthetic pathways.
• Some of the organic acids, which are
  intermediates in the citric acid cycle, are the
  precursors for the synthesis of other molecules
• For example, in the liver intermediates from the
  TCA cycle are continuously withdrawn into
  pathways of fatty acid synthesis, amino acid
  synthesis, gluconeogenesis and heme synthesis.

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Citric acid cycle intermediates are always in flux

• Intermediates are removed for
• biosynthesis in..
• amphibolic reactions
• removal of intermediates.
•  

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Diagram of the citric acid cycle, indicating
positions at which intermediates are drawn off
for use in anabolic pathways (red arrows)
Several intermediates of the cycle may serve
other functions
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• Citrate may leave the mitochondria (via the
  citrate shuttle) to deliver acetyl-CoA into the
  cytoplasm for fatty acid synthesis.

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• Biosynthesis of fatty acids and cholesterol.
• Citrate ATP CoA ?Acetyl CoA OAA ADP Pi

Fatty acid biosynthesis
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Cataplerosis of Citrate via citrate shuttle
Malonyl CoA
Acetyl-CoA
Oxaloacetate
Fatty Acids
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• Acetyl-CoA is a major building block for
  long-chain fatty acid synthesis.
• Since pyruvate dehydrogenase is a mitochondrial
  enzyme and the enzymes needed for fatty acid
  biosynthesis are extramitrochondrial, the
  acetyl-CoA is recovered as citrate, cleaved back
  to acetyl-CoA in the cytosol by ATP-citrate
  lyase. (this incvolves the citrate shuttle, and
  is the precursor to fatty acid synthesis ).

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Overview of Cholesterol biosynthesis
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• alpha-ketoglutarate can serve as precursor for
  glutamate by simple transamination. Glutamate can
  then act as precursor for other amino acids and
  purine nucleotides.
• In the brain, alpha-ketoglutarate is converted to
  glutamate and GABA, both important
  neurotransmitters.

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• Succinyl-CoA is a high-energy intermediate that
  can be used for heme synthesis and to activate
  ketone bodies in extrahepatic tissues.
• Succinyl-CoA is a central intermediate of heme
  groups.

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• Succinyl CoA is used in the biosynthesis of heme
  The citric acid cycle intermediate succinyl CoA
  condenses with glycine in the mitochondrion to
  form ?-ALA (?-aminolevulinic acid in the first
  (also the rate-limiting and the most highly
  regulated) reaction in the heme biosynthetic
  pathway.

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• Succinate dehydrogenase catalyzes formation of
  fumarate from succinate in the Krebs cycle in a
  catabolic reaction.
• This reaction connects the Krebs cycle to the
  urea cycle or Krebs-Hanseleit cycle, which is an
  anabolic process, as the fumarate formed in the
  catabolic mode of the Krebs cycle may be used in
  the anabolic synthesis of urea in the urea cycle.
• These two cycles are referred to as the Krebs
  bicycle.

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Urea Cycle
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• Malate can leave the mitochondria (via the malate
  shuttle) for gluconeogenesis.

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Cataplerosis of Malate via malate shuttle
Phosphoenolpyruvate (PEP)
Oxaloacetate
Malate
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• Pyruvate, oxaloacetate, and alpha-ketoglutarate
  can be transaminated (have an amino group added)
  to form the amino acids alanine, aspartate, and
  glutamate
• Transamination of pyruvate yields alanine.
• Transamination of oxaloacetate yields aspartate.
• Oxaloacetate can be converted to glucose in
  gluconeogenesis.
• Oxaloacetate can serves as precursors for
  aspartate, by simple transamination, and the
  aspartate can act as precursors for other amino
  acids and nucleotides
• oxaloacetate to aspartate
• oxaloacetate to PEP---aromatic A.A., formation of
  3-PG., gluconeogenesis
• Transamination of alpha ketoglutarate yields
  glutamate.

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glucose
gluconeogenesis
Oxaloacetate is the starting material for
glucogneonesis
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Several biosynthetic pathways utilize the citric
acid cycle intermediates as starting materials
(anabolism). Pathways that utilize citric acid
cycle intermediates include. (1) Glucose
biosynthesis (gluconeogenesis) (2) Lipid
biosynthesis (Lipid anabolism ) (3) Amino acid
biosynthesis (4) Porphyrin biosynthesis
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Summary of amphibolic pathways

• Fatty acid biosynthesis
• citrate ? acetyl CoA and oxaloacetate
• acetyl CoA can build fatty acids
• Heme biosynthesis
• succinyl CoA glycine ? porphyrins
• Transaminases
• oxaloacetate ? Aspartate
• ?-ketoglutarate? Glutamate
• pyruvate ? Alanine

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TCA Cycle It aint just ATP.
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TCA Cycle provides intermediates for many
biosynthetic processes
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• As intermediates are removed to serve as
  biosynthetic precursors, they are replenished by
  anaplerotic reactions.
• Under normal circumstances, removal and
  replenishment are in dynamic balance so
  intermediates stay almost constant.
• Thus it is that . citric acid cycle
  intermediates are always in flux