Chapter 16 (Part 3)

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Chapter 16 (Part 3)

• Fatty acid Synthesis

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Fatty Acid Synthesis

• In mammals fatty acid synthesis occurs primarily
  in the liver and adipose tissues
• Also occurs in mammary glands during lactation.
• Fatty acid synthesis and degradation go by
  different routes
• There are four major differences between fatty
  acid breakdown and biosynthesis

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The differences between fatty acid biosynthesis
and breakdown

• Intermediates in synthesis are linked to -SH
  groups of acyl carrier proteins (as compared to
  -SH groups of CoA)
• Synthesis in cytosol breakdown in mitochondria
• Enzymes of synthesis are one polypeptide
• Biosynthesis uses NADPH/NADP breakdown uses
  NADH/NAD

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ACP vs. Coenzyme A

• Intermediates in synthesis are linked to -SH
  groups of acyl carrier proteins (as compared to
  -SH groups of CoA)

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Fatty Acid Synthesis Occurs in the Cytosol

• Must have source of acetyl-CoA
• Most acetyl-CoA in mitochondria
• Citrate-malate-pyruvate shuttle provides
  cytosolic acetate units and reducing equivalents
  for fatty acid synthesis

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Fatty Acid Synthesis

• Fatty acids are built from 2-C units derived from
  acetyl-CoA
• Acetate units are activated for transfer to
  growing FA chain by conversion to malonyl-CoA
• Decarboxylation of malonyl-CoA and reducing power
  of NADPH drive chain growth
• Chain grows to 16-carbons (eight acetyl-CoAs)
• Other enzymes add double bonds and more Cs

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Acetyl-CoA Carboxylase
Acetyl-CoA HCO3- ATP ? malonyl-CoA ADP

• The "ACC enzyme" commits acetate to fatty acid
  synthesis
• Carboxylation of acetyl-CoA to form malonyl-CoA
  is the irreversible, committed step in fatty acid
  biosynthesis

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Acetyl-CoACarboxylase
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Regulation of Acetyl-CoA Carboxylase (ACCase)

• ACCase forms long, active filamentous polymers
  from inactive protomers
• Accumulation of palmitoyl-CoA (product) leads to
  the formation of inactive polymers
• Accumulation of citrate leads to the formation of
  the active polymeric form
• Phosphorylation modulates citrate activation and
  palmitoyl-CoA inhibition

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Regulation of Acetyl-CoA Carboxylase (ACCase)

• Unphosphorylated ACCase has low Km for citrate
  and is active at low citrate
• Unphosphorylated ACCase has high Ki for
  palmitoyl-CoA and needs high palmitoyl-CoA to
  inhibit
• Phosphorylated E has high Km for citrate and
  needs high citrate to activate
• Phosphorylated E has low Ki for palmitoyl-CoA and
  is inhibited at low palmitoyl-CoA

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Fatty Acid Synthesis

• Step 1 Loading transferring acetyl- and
  malonyl- groups from CoA to ACP
• Step 2 Condensation transferring 2 carbon unit
  from malonyl-ACP to acetyl-ACP to form 2 carbon
  keto-acyl-ACP
• Step 3 Reduction conversion of keto-acyl-ACP
  to hydroxyacyl-ACP (uses NADPH)
• Step 4 Dehydration Elimination of H2O to form
  Enoyl-ACP
• Step 5 Reduction Reduce double bond to form 4
  carbon fully saturated acyl-ACP

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Step 1 Loading Reactions
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Step 2 Condensation Rxn
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Step 3 Reduction
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Step 4 Dehydration
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Step 5 Reduction
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Step 6 next condensation
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Termination of Fatty Acid Synthesis
Acyl-CoA synthetase
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Organization of Fatty Acid Synthesis Enzymes

• In bacteria and plants, the fatty acid synthesis
  reactions are catalyzed individual soluble
  enzymes.
• In animals, the fatty acid synthesis reactions
  are all present on multifunctional polypeptide.
• The animal fatty acid synthase is a homodimer of
  two identical 250 kD polypeptides.

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Animal Fatty Acid Synthase
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Further Processing of Fatty acids Desaturation
and Elongation
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Regulation of FA Synthesis

• Allosteric modifiers, phosphorylation and
  hormones
• Malonyl-CoA blocks the carnitine acyltransferase
  and thus inhibits beta-oxidation
• Citrate activates acetyl-CoA carboxylase
• Fatty acyl-CoAs inhibit acetyl-CoA carboxylase
• Hormones regulate ACC
• Glucagon activates lipases/inhibits ACC
• Insulin inhibits lipases/activates ACC

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Allosteric regulation of fatty acid synthesis
occurs at ACCase and the carnitine acyltransferase
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Glucagon inhibits fatty acid synthesis while
increasing lipid breakdown and fatty acid
b-oxidation Insulin prevents action of glucagon