fatty acid synthesis

• De novo synthesis of fatty acids

  Occurs in liver, kidney, adipose tissue & lactating mammary gland

  
• Enzymes for fatty acid synthesis

  Located in cytosomal fraction of the cell
• Fatty acid synthase system

  Extramitochondrial or cytoplasmic
• Major fatty acid synthesized de novo

  Palmitic acid (16C saturated fatty acid)

  
• Locations of de novo fatty acid synthesis

  • Liver
  • Adipose tissue
  • Kidney
  • Brain
  • Lactating mammary glands

  
• Source of carbon atoms for fatty acid synthesis

  Acetyl CoA
• Source of reducing equivalents (NADPH)

  HMP shunt & malic enzyme reaction
• For every molecule of acetyl CoA delivered to cytoplasm, one molecule of NADPH is formed
• De novo fatty acid synthesis

  1. Production of acetyl CoA & NADPH

  2. Conversion of acetyl CoA to malonyl CoA

  3. Reactions of fatty acid synthase complex

  
• Acetyl CoA


  Starting material for de novo synthesis of fatty acids

  
• Acetyl CoA production


  Oxidation of pyruvate, fatty acids, degradation of carbon skeleton of certain amino acids & from ketone bodies
• Mitochondria are not permeable to acetyl CoA
• Transfer of acetyl CoA from mitochondria to cytosol

  1. Acetyl CoA condenses with oxaloacetate in mitochondria to form citrate

  2. Citrate is freely transported to cytosol by tricarboxylic acid transporter

  3. In cytosol it is cleaved by ATP citrate lyase to liberate acetyl CoA & oxaloacetate

  4. Oxaloacetate in the cytosol is converted to malate

  5. Malic enzyme converts malate to pyruvate, generating NADPH & CO2
• Coupled transport of acetyl CoA & NADPH

  • The transport of acetyl CoA from mitochondria to cytosol is coupled with the cytosomal production of NADPH & CO2 which is highly advantageous to the cell for optimum synthesis of fatty acids
• Conversion of acetyl CoA to malonyl CoA

  1. Acetyl CoA is carboxylated to malonyl CoA by the enzyme acetyl CoA carboxylase

  2. This is an ATP-dependent reaction & requires biotin for CO2 fixation

  3. The mechanism of action is similar to that of pyruvate carboxylase
• Acetyl CoA carboxylase

  A regulatory enzyme
• Fatty acid synthase (FAS)


  • A multifunctional enzyme that exists as a dimer with two identical units in eukaryotic cells
  • Each monomer possesses the activities of seven different enzymes & an acyl carrier protein (ACP) bound to 4'-phosphopantetheine
  • Fatty acid synthase functions as a single unit catalyzing all the seven reactions
• Fatty acid synthesis by FAS

  1. The two carbon fragment of acetyl CoA is transferred to ACP of fatty acid synthase

  2. The acetyl unit is then transferred from ACP to cysteine residue of the enzyme

  3. The enzyme malonyl CoA-ACP transacylase transfers malonate from malonyl CoA to bind to ACP

  4. The acetyl unit attached to cysteine is transferred to malonyl group (bound to ACP)

  5. The malonyl moiety loses CO2 which was added by acetyl CoA carboxylase

  6. β-Ketoacyl ACP reductase reduces ketoacyl group to hydroxyacyl group using NADPH

  7. β-Hydroxyacyl ACP undergoes dehydration to introduce a double bond

  8. Enoyl-ACP reductase catalyses a second NADPH-dependent reduction to produce acyl-ACP

  9. The four-carbon unit attached to ACP is butyryl group

  10. The carbon chain attached to ACP is transferred to cysteine residue & the reactions are repeated 6 more times to lengthen the fatty acid chain by 2 carbons each time

  11. At the end of 7 cycles, the 16-carbon fully saturated fatty acid palmitate bound to ACP is produced

  12. The enzyme palmitoyl thioesterase separates palmitate from fatty acid synthase
• Fatty acid synthase (FAS) structure


  • It is a dimer composed of two identical subunits (monomers)
  • Each subunit contains the activities of 7 enzymes of FAS & an ACP with 4'-phosphopantetheine SH group
  • The 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 enzyme ketoacyl synthase) of the other subunit
  • Each monomer of FAS contains all the enzyme activities of fatty acid synthesis, but only the dimer is functionally active
  • The functional unit consists of half of each subunit interacting with the complementary half of the other
• Advantages of FAS complex

  • The two functional subunits of FAS independently operate & synthesize two fatty acids simultaneously
  • The FAS complex offers great efficiency that is free from interference of other cellular reactions for the synthesis of fatty acids
  • There is a good coordination in the synthesis of all enzymes of the FAS complex
• Acetyl CoA carboxylase


  • Enzyme that controls a committed step in fatty acid synthesis
  • Exists as an inactive protomer (monomer) or an active polymer
  • Citrate promotes polymer formation & increases fatty acid synthesis
  • Palmitoyl CoA & malonyl CoA cause depolymerization of the enzyme, inhibiting fatty acid synthesis
• Regulation of acetyl CoA carboxylase

  • Hormones regulate the enzyme by phosphorylation (inactive form) & dephosphorylation (active form)
  • Glucagon, epinephrine & norepinephrine inactivate the enzyme by cAMP dependent phosphorylation
  • Insulin dephosphorylates & activates the enzyme, promoting fatty acid synthesis
• Insulin


  Stimulates tissue uptake of glucose & conversion of pyruvate to acetyl CoA, facilitating fatty acid formation
• High carbohydrate or fat-free diet

  Increases the synthesis of acetyl CoA carboxylase & fatty acid synthase, promoting fatty acid formation

  
• Fasting or high fat diet

  Decreases fatty acid production by reducing the synthesis of acetyl CoA carboxylase & fatty acid synthase
• Source of NADPH for fatty acid synthesis

  Citrate (acetyl CoA) transport or hexose monophosphate shunt, with HMP shunt providing 50-60% of the required NADPH

  
• Fatty acid chain elongation

  1. Can occur in mitochondria or endoplasmic reticulum (microsomes)

  2. Microsomal chain elongation is more predominant and involves successive additions of malonyl CoA with the participation of NADPH, catalysed by elongases

  3. Mitochondrial chain elongation is a reversal of β-oxidation, with acetyl CoA molecules successively added to the fatty acid chain using NADPH
• Fatty acid synthesis


  The process of building fatty acid chains
• Fatty acid synthesis steps

  1. Glucose converted to pyruvate via glycolysis

  2. Pyruvate taken up into mitochondria and converted to acetyl-CoA

  3. Acetyl-CoA carboxylated to form malonyl-CoA

  4. Fatty acid synthase enzyme catalyzes the addition of malonyl-CoA units to build the fatty acid chain

  5. NADPH provides reducing power for the reactions
• Acetyl-CoA carboxylase enzyme


  • Rate-limiting step in fatty acid synthesis
  • Highly regulated by allosteric effectors, phosphorylation, hormones, and fatty acids
• Malonyl-CoA


  • The building block for fatty acid synthesis
  • Also inhibits enzymes that transport fatty acids into mitochondria for oxidation
• Fatty acid synthase (FAS1)

  • Enzyme that catalyzes the addition of malonyl-CoA units to build the fatty acid chain
  • Contains a cysteine residue with a thiol group and an acyl carrier protein (ACP) component
• NADPH


  Provides the reducing power for fatty acid synthesis reactions
• Acetyl-CoA is an additional precursor that can be used in fatty acid synthesis
• Building fatty acids


  1. Add acetyl-CoA group to ACP end

  2. Transfer acetyl group from ACP to cysteine

  3. Add malonyl-CoA group to ACP end

  4. Decarboxylate and condense acetyl and malonyl groups on ACP end to form 4-carbon acyl chain

  5. Reduce beta-keto group on acyl chain to hydroxyl group

  6. Dehydrate hydroxyl group to form trans-double bond
• Acetyl-CoA


  1. carbon molecule
• Malonyl-CoA


  1. carbon molecule
• NADPH


  Provides hydride ions to reduce beta-keto group
• Fatty acid synthase type 1

  • Enzyme that catalyses the entire fatty acid synthesis process
• Acetyl transaclase


  Enzyme that transfers acetyl group from acetyl-CoA to ACP