De novo

• De novo synthesis of fatty acid


  The fresh synthesis of fatty acids
• Fatty acid synthesis


  • Majority of fatty acids are supplied through diet
  • Fatty acids are synthesised whenever there is a caloric excess in the diet
  • Excess carbohydrate and protein can be converted to fatty acids and stored as triacylglycerol
  • Involves similar steps as β-oxidation of fatty acids but in reverse
• Mammals


  • Can synthesise major portion of the saturated fatty acid as well as monounsaturated fatty acids
• De novo synthesis of fatty acid

  The system for the fresh synthesis of fatty acids
• Location of de novo fatty acid synthesis

  • Takes place in liver and lactating mammary glands and to a lesser extent in adipose tissue, kidney
  • The enzyme machinery is located in cytoplasm
  • Referred to as extra mitochondrial or cytoplasmic fatty acid synthase system
• Palmitic acid


  The major fatty acid synthesised
• Fatty acid synthesis


  1. Acetyl CoA is the primer and forms carbons 15 and 16 of palmitate

  2. Addition of all the subsequent 2-C units is through malonyl CoA formation

  3. Acetyl CoA and NADPH are the prerequisites
• Acetyl CoA produced in the mitochondria


  • Cannot enter into cytoplasm through inner mitochondrial membrane
  • Combines with Oxaloacetate in mitochondria to form citrate
  • Citrate is transported to cytosol and cleaved by citrate lyase to liberate acetyl CoA and Oxaloacetate
• For fatty acid synthesis, 8 acetyl CoA are transported from the mitochondria to cytosol, which is linked with the synthesis of 8 NADPH
• 14 NADPH are required to synthesise one molecule of Palmitate
• The remaining 6 NADPH are supplied from HMP shunt
• Acetyl CoA carboxylase


  Regulatory enzyme in fatty acid synthesis
• Fatty acid synthase complex (FAS)


  • A multifunctional enzyme
  • A dimer with two identical subunits
  • Each monomer possesses the activities of seven different enzymes and an acyl carrier protein (ACP) bound to 4'phosphopantetheine-SH group
  • Two subunits lie in antiparallel (head to tail) orientation
  • The -SH group of phosphopantetheine of one subunit is in close proximity to the -SH of cysteine residue of the other subunit
  • Each monomer of FAS contains all the enzyme activities of fatty acid synthesis
  • Dimer form of enzyme is functionally active
• Components of fatty acid synthase complex


  • Acetyl transferase [AT]
  • Malonyl transferase [MT]
  • β-Keto acyl synthase [KS]
  • β-Keto acyl reductase [KR]
  • β-Hydroxy acyl dehydratase [HD]
  • Enoyl reductase [ER]
  • Thioestarase [TE]
  • Acyl carrier protein [ACP]
• Fatty acid synthesis


  1. Acetyl CoA is transferred to cysteinyl SH group of ACP

  2. Malonyl CoA-ACP transferase transfers malonate from malonyl CoA to bind to ACP

  3. Acetyl unit is transferred to malonyl group attached to ACP, malonyl moiety loses CO2 and forms β-ketoacyl enzyme

  4. β-Ketoacyl-enzyme is reduced to β-hydroxy butyryl enzyme complex using NADPH+H+

  5. H2O is removed from β-OH butyryl enzyme to form α,β unsaturated acyl enzyme

  6. Unsaturated bond in α,β unsaturated acyl enzyme is reduced using NADPH+H+ to form butyryl or acyl enzyme

  7. Carbon chain attached to ACP is transferred to cysteine residue and the reactions are repeated 6 more times to synthesise palmitic acid

  8. Completely synthesized fatty acid is released from the enzyme system by the action of thioesterase enzyme
• Of the 16 carbons present in palmitate, only two come from acetyl CoA directly
• The remaining 14 are from malonyl CoA (produced from acetyl CoA)
• Fatty acid chain elongation and desaturation


  1. Occurs in the microsomes of endoplasmic reticulum and mitochondria

  2. Palmitate is activated to palmitoyl CoA

  3. Malonyl CoA serves as the donor of two carbons at a time in series of reactions

  4. Major elongation reaction involves the formation of stearyl CoA [C18] from palmitoyl CoA [C16]

  5. Elongation of stearyl CoA in brain increases during myelination to provide C22 and C24 fatty acids of sphingolipids

  6. Mitochondrial elongation is less active and uses acetyl CoA as the source of two carbon units
• 8 acetyl CoA + 7 ATP + 14 NADPH + 14 H+ → Palmitate + 8 CoA + 7 ADP + 7 Pi + 6 H2O + 14 NADP+
• Acetyl CoA carboxylase


  • Controls a committed step in fatty acid synthesis
  • Exists as an inactive monomer or an active polymer
  • Citrate promotes polymer formation, hence increases fatty acid synthesis
  • Palmitoyl CoA causes depolymerisation of the enzyme and inhibits fatty acid synthesis
• Glucagon, epinephrine & norepinephrine


  Inactivate acetyl CoA carboxylase by cAMP dependent phosphorylation and inhibit fatty acid synthesis
• Insulin


  Dephosphorylates and activates acetyl CoA carboxylase, promoting fatty acid synthesis
• High carbohydrate and fat free diet


  Increases the synthesis of acetyl CoA carboxylase and fatty acid synthase, promoting fatty acid synthesis
• Fasting and high fat diet


  Decreases fatty acid production
• NADPH influences fatty acid synthesis