Fatty acid synthesis

Fatty Acid Synthesis - The Groundwork

⭐ Fatty acid synthesis is a cytoplasmic process that occurs primarily in the liver and adipose tissue, especially in the well-fed state when insulin is high and there is an excess of acetyl-CoA.

• Process: De novo synthesis of fatty acids from Acetyl-CoA.
• Location: Cytoplasm (📌 Synthesis in the Cytoplasm).
  • Primarily in the liver, lactating mammary glands, and adipose tissue.
• Metabolic State: Fed state (↑ Insulin, ↓ Glucagon).
• Key Substrates: Acetyl-CoA (transported from mitochondria via the citrate shuttle), NADPH.

Citrate Shuttle - The Great Escape

⭐ The citrate shuttle is essential because acetyl-CoA cannot directly cross the inner mitochondrial membrane, but citrate can.

• Function: Transports acetyl-CoA from the mitochondria to the cytoplasm, the site of fatty acid synthesis.
• Process: In the mitochondria, acetyl-CoA combines with oxaloacetate (OAA) to form citrate. Citrate then crosses the inner mitochondrial membrane.
• Key Enzyme: In the cytoplasm, ATP-citrate lyase cleaves citrate.
• Reaction: $Citrate + ATP + CoA \rightarrow Acetyl-CoA + Oxaloacetate + ADP + P_i$

Fatty Acid Synthase - The Assembly Line

Fatty Acid Synthase (FAS) is a large, dimeric multi-enzyme complex responsible for synthesizing fatty acids. Its Acyl Carrier Protein (ACP) domain acts as a mobile arm, shuttling the growing fatty acid chain between catalytic sites.

The synthesis process iteratively adds two-carbon units from Malonyl-CoA via a repeating four-step sequence.

• Substrates: Acetyl-CoA (primer), Malonyl-CoA (2-C donor)
• Cofactor: Requires NADPH as the reducing agent.
• Product: Palmitate (C16), the primary end product.

📌 The four repeating steps are Condensation, Reduction, Dehydration, Reduction (CRDR).

⭐ The synthesis of one molecule of palmitate requires 14 molecules of NADPH, primarily supplied by the pentose phosphate pathway.

Overall reaction: $8 \text{ Acetyl-CoA} + 7 \text{ ATP} + 14 \text{ NADPH} \rightarrow \text{Palmitate} + 8 \text{ CoA} + 7 \text{ ADP} + 7 \text{ P}_i + 14 \text{ NADP}^+ + 6 \text{ H}_2\text{O}$

Regulation - The Control Panel

⭐ Acetyl-CoA carboxylase (ACC), the rate-limiting enzyme, is the key control point. It's allosterically activated by citrate and inhibited by the end-product, palmitoyl-CoA.

• Hormonal Control (Covalent Modification): ACC's activity is regulated by phosphorylation.

  • Insulin (High-energy signal): Promotes dephosphorylation, activating ACC. This favors fat storage.
  • Glucagon & Epinephrine (Low-energy signal): Promote phosphorylation, inactivating ACC. This favors fat breakdown.

• Allosteric Control:

  • Activator: ↑ Citrate signals abundant acetyl-CoA from the mitochondria.
  • Inhibitor: ↑ Palmitoyl-CoA provides feedback inhibition.

📌 Insulin Carefully Activates (Insulin, Citrate = Activation).

• Location: Fatty acid synthesis is a cytosolic process, primarily in the liver, lactating mammary glands, and adipose tissue.
• Rate-Limiting Enzyme: Acetyl-CoA Carboxylase (ACC) is the irreversible, committed step, requiring biotin.
• Key Regulation: Insulin upregulates (dephosphorylates) ACC; glucagon and epinephrine downregulate it. Citrate is a key allosteric activator.
• Transport: Acetyl-CoA is transported from mitochondria to the cytosol via the citrate shuttle.
• Cofactors: Requires NADPH as a reducing agent, primarily from the HMP Shunt.