fatty acid biosynthesis

• Fatty acid biosynthesis is not the exact reverse of fatty acid catabolism
• The process of fatty acid biosynthesis would be thermodynamically unfavorable if it were simply the reverse of catabolism
• Fatty acid biosynthesis involves distinct pathways and enzymes compared to catabolism
• Cell Membrane Components


  • Form the outer membrane of all cells, creating a gradient between the extracellular and intracellular environment
  • Essential for compartmentalization and the existence of different tissue types
• Signaling Molecules


  • Fatty acids act as signaling molecules, impacting cellular behavior and homeostasis
  • Can be endogenously created or ingested as nutrients
• Physiological Needs


  Synthesis is highly responsive to physiological needs
• Maximal when


  Carbohydrates and energy are abundant and fatty acid levels are low
• Activation


  • Allosterically activated by citrate from the mitochondria
  • Active in the 'fed state' and regulated by insulin
  • Energetically favorable conditions are required (abundant ATP)
• Mnemonic: OIL RIG - Oxidation Is Loss (of electrons), Reduction Is Gain (of electrons)
• Formation of Malonyl-CoA


  1. Committed Step: Formation of malonyl-CoA is the committed step in fatty acid biosynthesis

  2. Enzyme: Acetyl-CoA carboxylase (ACC)

  3. Reaction:Acetyl-CoA+ATP+HCO3−→Malonyl-CoA+ADP+Pi+H+

  4. Requirements: Requires ATP and bicarbonate

  5. Importance: Inhibits the rate-limiting step of β-oxidation by preventing carnitine acetyltransferase from functioning
• Acetyl-CoA Carboxylase (ACC)


  • Biotin Carrier Protein: Carries biotin
  • Biotin Carboxylase: Activates CO₂ by attaching it to biotin in an ATP-dependent reaction
  • Transcarboxylase: Transfers activated CO₂ from biotin to acetyl-CoA, producing malonyl-CoA
• Mechanism of Acetyl-CoA Carboxylase

  1. Stage 1: ATP-dependent carboxylation of biotin

  2. Stage 2: Transfer of carboxyl group from biotin to acetyl-CoA, forming malonyl-CoA
• Fatty Acid Synthase (FAS)


  • Multifunctional Enzyme: A single polypeptide with multiple activities
• Stages of Fatty Acid Biosynthesis

  1. Condensation: β-ketoacyl synthase catalyzes the condensation of acetyl-CoA and malonyl-CoA, releasing CO₂

  2. Reduction: β-ketoacyl reductase reduces the β-keto group to a hydroxyl group

  3. Dehydration: Dehydratase removes water, creating a double bond

  4. Reduction: Enoyl reductase reduces the double bond, forming a saturated fatty acyl group
• Detailed Steps in Fatty Acid Biosynthesis

  Formation of Malonyl-CoA

  Enzyme: Acetyl-CoA carboxylase (ACC)

  Reaction:Acetyl-CoA+ATP+HCO3−→Malonyl-CoA+ADP+Pi+H+

  Mechanism:

  Biotin Carboxylation: Biotin is carboxylated using bicarbonate and ATP.

  CO₂ Transfer: The carboxyl group is transferred to acetyl-CoA, forming malonyl-CoA.

  2. Role of Acyl Carrier Protein (ACP)

  Function: ACP serves as the carrier of the growing fatty acid chain.

  Attachment: Malonyl-CoA and acetyl-CoA are transferred to ACP.

  3. Elongation Cycle

  Step 1: Condensation:

  Enzyme: β-ketoacyl synthase.

  Reaction: Condensation of acetyl-ACP and malonyl-ACP, releasing CO₂ and forming β-ketoacyl-ACP.

  Mechanism: Decarboxylation facilitates the condensation reaction.

  Result: Acyl chain grows by two carbons.

  Step 2: Reduction:

  Enzyme: β-ketoacyl reductase.

  Reaction: Reduces the β-keto group to a hydroxyl group.

  Cofactor: NADPH provides the reducing power.

  Result: Formation of β-hydroxyacyl-ACP.

  Step 3: Dehydration:

  Enzyme: Dehydratase.

  Reaction: Removes water, creating a double bond.

  Result: Formation of enoyl-ACP.

  Step 4: Reduction:

  Enzyme: Enoyl reductase.

  Reaction: Reduces the double bond, forming a saturated fatty acyl group.

  Cofactor: NADPH provides the reducing power.

  Result: Formation of acyl-ACP.
• Example: Palmitate Synthesis


  Overall Reaction:Acetyl-CoA+7Malonyl-CoA+14NADPH+14H+→Palmitate+7CO2+8CoA+14NADP++6H2O

  Process: The fatty acyl chain grows by two-carbon units donated by malonyl-ACP, with the loss of CO₂ at each step. The final product is palmitate (16:0).
• Availability of Substrates


  Acetyl-CoA: Provided by the transfer of acetyl groups from mitochondria to the cytosol via the citrate shuttle.

  NADPH: Generated by the pentose phosphate pathway and malic enzyme.
• Acetyl-CoA Carboxylase (ACC) Regulation

  Activated by dephosphorylation (insulin promotes this state)

  Inhibited by phosphorylation (glucagon and epinephrine promote this state)

  Allosteric Regulators: Citrate activates ACC; palmitoyl-CoA inhibits ACC
• Malonyl-CoA Regulation


  Inhibits carnitine acyltransferase I, preventing the entry of fatty acids into mitochondria for β-oxidation
• Insulin


  Promotes glucose uptake and glycolysis, increasing acetyl-CoA levels

  Activates ACC, enhancing fatty acid biosynthesis
• Glucagon


  Inhibits ACC via phosphorylation, reducing fatty acid biosynthesis

  Promotes fatty acid oxidation by activating AMPK
• Citrate Shuttle


  Transports acetyl-CoA from mitochondria to the cytosol

  Citrate is converted back to acetyl-CoA in the cytosol, providing substrate for fatty acid synthesis
• Pentose Phosphate Pathway


  Provides NADPH for reductive biosynthesis, including fatty acid synthesis
• Summary


  • Biosynthesis:

  Location: Cytoplasm.

  Key Enzymes: Acetyl-CoA carboxylase, fatty acid synthase.

  Regulation: Activated by insulin, citrate; inhibited by glucagon, palmitoyl-CoA.

  End Product: Palmitate (16:0).

  Oxidation:

  Location: Mitochondrial matrix.

  Key Enzymes: Acyl-CoA dehydrogenase, enoyl-CoA hydratase, β-hydroxyacyl-CoA dehydrogenase, thiolase.

  Regulation: Inhibited by malonyl-CoA.

  End Products: Acetyl-CoA, NADH, FADH₂.