Fatty Acid Synthesis Part 2

Introduction

• Recap of Part 1: Discussed the basics of fatty acid synthesis and necessary substrates.
• Objective: Dive into detailed steps of fatty acid synthesis.

Key Substrates for Fatty Acid Synthesis

1. NADPH
   • Generated from:
     • Malic enzyme (converting Malate to Pyruvate)
     • Pentose Phosphate Pathway (converting Glucose 6-phosphate to Ribose 5-phosphate)
   • Function: Provides reducing power.
2. Malonyl-CoA
   • Formed by carboxylation of Acetyl-CoA via Acetyl-CoA Carboxylase.
   • Role: Building block for fatty acid chain.
   • Regulation:
     • Stimulated by Insulin and Citrate.
     • Inhibited by Glucagon, Norepinephrine, Epinephrine, and Long-chain fatty acids.
   • Also inhibits CPT1, preventing fatty acid oxidation.
3. Fatty Acid Synthase Type 1 (FAS1)
   • Two components:
     • Cysteine residue with thiol group.
     • ACP (Acyl Carrier Protein) with phosphopantetheine.
   • Function: Catalyzes the synthesis of fatty acids.

Step-by-step Fatty Acid Synthesis

Initial Steps

1. Add Acetyl-CoA to ACP

   • Enzyme: Acetyl Transacylase.
   • Removes CoA component.

2. Transfer Acetyl Group to Cysteine End

   • Enzyme: Acyl Transacylase.

3. Add Malonyl-CoA to ACP

   • Enzyme: Malonyl Transacylase.
   • Removes CoA component.

Chain Elongation

4. Condensation of Malonyl-CoA and Acetyl Group

   • Enzyme: Acyl-Malonyl ACP Condensing Enzyme.
   • Carbon dioxide removal (Decarboxylation).
   • Forms a four-carbon beta-ketone structure.

5. Reduction of Beta-Ketone to Hydroxyl Group

   • Enzyme: Beta-Keto-ACP Reductase.
   • NADPH donates electrons.

6. Dehydration to Form Double Bond

   • Enzyme: 3-Hydroxyacyl Dehydratase.

7. Reduction of Double Bond

   • Enzyme: Enoyl-ACP Reductase.
   • Converts to saturated acyl group.
   • NADPH used.

Continuing the Cycle

• Transfer the growing chain to the Cysteine end.
• Add another Malonyl-CoA and repeat the cycle.
• Each cycle adds two carbons.

Final Steps

• Continue cycle until a 16-carbon palmitate is formed.
• Enzyme: Thioesterase cleaves palmitate from ACP.

Conclusion

• Total of 7 cycles for complete synthesis of a 16-carbon fatty acid.
• Regulatory pathways ensure that synthesis and oxidation are balanced based on cellular energy needs.