BMSC230 Mod. 9

• Fatty acids


  Serve as signaling molecules
• Fatty acid synthesis


  Similar processes to degradation

  
• Acetyl CoA


  Building block
• NADPH


  Reduces the keto groups
• Fatty acid synthesis


  1. Move Acetyl CoA from mitochondria into the cytosol

  2. Acetyl CoA is converted to active form malonyl CoA

  3. Palmitate is synthesized in a 5 step elongation cycle

  
• Citrate


  Moves acetyl groups
• Acetyl CoA is produced in mitochondria (from oxidation of pyruvate or degradation of fatty acids)
• Mitochondrial membrane is impermeable to acetyl CoA
• Acetyl CoA transport


  1. Acetyl CoA reacts with oxaloacetate to form citrate

  2. Citrate that doesn't enter CAC is shuttled out by transport protein in mitochondrial membrane

  3. Once in the cytosol, ATP citrate lyase cleaves citrate into Acetyl CoA and oxaloacetate
• Oxaloacetate


  Reduced to malate by NADH
• Malate


  Converted to pyruvate by malic enzyme and produces 1 NADPH
• Activation of Acetyl CoA

  1. Must be combined with CO2 to form malonyl CoA in a carboxylation reaction catalyzed by acetyl CoA carboxylase

  2. Process driven by hydrolysis of ATP

  3. This is the committed step of the pathway
• Acetyl CoA carboxylation


  1. Diotin-enzyme + ATP + HCO3 -> CO2-biotin + ADP + Pi + H+

  2. CO2-biotin + acetyl CoA -> Malonyl CoA + biotin-enzyme
• Fatty Acid Synthase Complex

  Catalyzes fatty acid synthesis

  
• Fatty acid synthesis


  1. Condensation

  2. 1st Reduction

  3. Dehydration

  4. 2nd Reduction (Repeat)

  
• Fatty acid degradation


  1. Cleavage

  2. 2nd Oxidation

  3. Hydration

  4. 1st Oxidation (Repeat)

  
• Fatty Acid Synthase


  Complex (dimer) with specific catalytic sites
• Phosphopantethene prosthetic group


  Forms thioester linkages, moves substrate around

  
• Catalytic sites on Fatty Acid Synthase

  • Acetyl transacylase
  • β-Ketoacyl reductase
  • Dehydratase
  • Enoyl reductase
  • Malonyl transacylase
  • β-Hydroxyacyl reductase
  • Condensing enzyme
• Fatty acid synthase has 7 catalytic sites (all except ACP site)
• ACP (Acyl Carrier Protein)


  Major component of Coenzyme A, has a free sulfhydryl group where fatty acid intermediates are linked

  
• Before fatty acid synthesis

  Acetyl CoA and malonyl CoA are linked to ACP by the sulfhydryl group to form acetyl ACP and malonyl ACP
• Acetyl group in acetyl ACP will be 15-16 carbons long or the last 2 carbons will be in palmitate
• Odd chain fatty acids are created by starting with propionyl CoA
• 32 molecules of NADPH are required for the synthesis of palmitate
• Sources of NADPH


  • Pentose phosphate pathway
  • Reduction of oxaloacetate to malate
• Overall stoichiometry for palmitate synthesis: 8 Acetyl CoA + 7 ATP + 14 NADPH -> palmitate + 14 NADP+ + 8 CoA + 6 H2O + 7 ADP + 7 Pi
• Fatty acid synthesis


  1. Butyry ACP formed

  2. Palmitate is a 16 carbon molecule

  3. 6 more rounds must occur

  4. Butyry ACP taken to step 1 to combine with malonyl ACP

  5. Occurs until all carbons are fully reduced except 7 carbon carboxyl group linked to ACP

  6. Final molecule is palmitoyl ACP

  
• Palmitate needs to be released from ACP
• Thioesterase


  Hydrolytically cleaves link between carboxyl of fatty acid and sulfhydryl group of ACP

  
• Overall stoichiometry: 8 Acetyl CoA + 7 ATP + 14 NADPH -> palmitate + 14 NADP+ + 8 CoA + 6 H2O + 7 ADP + 7 Pi
• Sources of NADPH


  • PPP (Pentose Phosphate Pathway)
  • Oxidative decarboxylation of malate to pyruvate
• 8 molecules of Acetyl CoA are required to make palmitate, and 8 NADPH are needed
• 6 other NADPH come from the Pentose Phosphate Pathway
• Metabolism in tumour cells

  • FA metabolism is altered - tumour cells have higher FA synthesis rates
  • Therapeutic intervention: inhibitors of acetyl-CoA carboxylase can inhibit tumour cell growth and cause cell death
• Elongation of fatty acids

  1. 2 carbon units added to carboxyl end in both saturated and unsaturated chains

  2. Malonyl CoA is substrate, similar reactions as in ACP complex

  3. Enzymes located on cytoplasmic side of ER lumen

  
• Desaturation of fatty acids

  1. Enzymes on cytoplasmic side of ER lumen

  2. Stearoyl CoA desaturase catalyzes conversion of stearoyl CoA to oleoyl CoA

  
• Mammals cannot synthesize double bonds past carbon 9, so we have dietary requirements for unsaturated fatty acids with double bonds past C9
• Omega fatty acids


  • Precursors for other unsaturated fatty acids and some hormones
  • Arachidonate (4 double bonds) can be synthesized from linoleate
  • Arachidonate is a precursor for eicosanoids (signaling molecules)

  
• Foods containing omega fatty acids

  • Canola, corn oil, nuts, certain fish