Fatty Acid Synthesis

Fatty Acid Synthesis - Cytosol's Carbon Convoy

• Primary Site: Cytosol (📌 Cytosol for Carbon chain creation).
• Core Challenge: Acetyl-CoA, the 2-carbon building block, is mainly produced in mitochondria (e.g., from pyruvate via PDH, β-oxidation). However, the inner mitochondrial membrane is impermeable to Acetyl-CoA.
• The "Carbon Convoy" - Citrate Shuttle:
  • Step 1 (Mitochondria): Acetyl-CoA + Oxaloacetate → Citrate (via Citrate Synthase).
  • Step 2 (Transport): Citrate is transported from mitochondria to the cytosol via a specific citrate transporter.
  • Step 3 (Cytosol): Citrate → Acetyl-CoA (cytosolic) + Oxaloacetate (via ATP Citrate Lyase).

    ⭐ ATP Citrate Lyase is a rate-limiting, inducible enzyme; crucial for supplying cytosolic Acetyl-CoA for FA synthesis and cholesterol synthesis.

• Essential Reductant: NADPH, primarily from HMP Shunt (PPP) and malic enzyme (conversion of malate to pyruvate in cytosol).

Fatty Acid Synthesis - Power Up & Commit

• NADPH Supply (Power Up):
  • Major: HMP Shunt (Pentose Phosphate Pathway).
  • Minor: Malic enzyme (Malate $\rightarrow$ Pyruvate, produces NADPH).
• Commitment Step (Rate-Limiting):
  • Enzyme: Acetyl-CoA Carboxylase (ACC).
  • Substrate: Cytosolic Acetyl-CoA (from citrate shuttle).
  • Reaction: Acetyl-CoA + $CO_2$ + ATP $\xrightarrow{ACC, Biotin}$ Malonyl-CoA.
  • Cofactor: Biotin.
• ACC Regulation:
  • Allosteric: (+) Citrate; (-) Palmitoyl-CoA.
  • Hormonal: (+) Insulin (deP $\rightarrow$ active); (-) Glucagon/Epinephrine (P $\rightarrow$ inactive via PKA).
  • Energy status: (-) AMP (via AMPK).

⭐ Malonyl-CoA, product of ACC, inhibits Carnitine Palmitoyltransferase I (CPT-I), preventing futile cycling with β-oxidation.

Fatty Acid Synthesis - The Palmitate Machine

• Site: Cytosol.
• Enzyme: Fatty Acid Synthase (FAS) complex - large dimeric multi-enzyme.
• Product: Palmitate ($C_{16:0}$), a 16-C saturated FA.
• Substrates: Acetyl-CoA (primer), Malonyl-CoA (2-C unit donor).

FAS Domains (per monomer):

• Acyl Carrier Protein (ACP): carries growing chain.
• Ketoacyl Synthase (KS): condensation.
• Malonyl/Acetyl-CoA Transferase (MAT): loads substrates.
• Dehydratase (DH): removes $H_2O$.
• Enoyl Reductase (ER): reduces double bond.
• Ketoacyl Reductase (KR): reduces keto group.
• Thioesterase (TE): releases Palmitate.

Cycle (7 repeats of 4 steps): 📌 CRDR: Condensation, Reduction, Dehydration, Reduction.

• Stoichiometry (Palmitate synthesis by FAS): $1 \text{ Acetyl-CoA} + 7 \text{ Malonyl-CoA} + 14 \text{ NADPH} + 14H^+ \rightarrow \text{Palmitate} + 7 CO_2 + 8 \text{ CoA} + 14 \text{ NADP}^+ + 6 H_2O$

• Requires: NADPH (from HMP shunt), ATP & Biotin (for Acetyl-CoA Carboxylase to form Malonyl-CoA).

⭐ Exam Favourite: The FAS complex is a homodimer; each monomer has all 7 enzyme activities. The two subunits work in a "head-to-tail" manner, with the growing chain on one ACP interacting with enzymatic domains on both subunits.

Fatty Acid Synthesis - Metabolic Modulators

• Acetyl-CoA Carboxylase (ACC) - Rate-Limiting Step:

  • Allosteric:
    • ↑ Citrate: Activates (high energy signal)
    • ↑ Long-chain fatty acyl-CoA: Inhibits (feedback)
  • Hormonal:
    • Insulin: Activates (dephosphorylates) → ↑ FA synthesis
    • Glucagon/Epinephrine: Inactivates (phosphorylates) → ↓ FA synthesis
    • AMPK: Inactivates (phosphorylates) → ↓ FA synthesis (low energy)

  ⭐ Citrate allosterically activates ACC, promoting its polymerization.

• Fatty Acid Synthase (FAS) Complex:

  • Regulation: Mainly by substrate availability (Malonyl-CoA, NADPH).
  • Insulin: ↑ FAS gene expression.

• Fate of Palmitate ($C_{16:0}$):

  • Elongation: ER & mitochondria (adds 2C units from Malonyl-CoA).
  • Desaturation: ER by desaturases (e.g., $\Delta^9$); needs $O_2$, NADH. Humans: no double bonds beyond $\Delta^9$.

📌 Cross-Reference: For the detailed ACC mechanism, see the "Power Up & Commit" section above.

High‑Yield Points - ⚡ Biggest Takeaways

• Primary sites: Cytosol of liver, adipose tissue, and lactating mammary glands.
• Rate-limiting step: Catalyzed by Acetyl-CoA Carboxylase (ACC), which requires biotin.
• ACC regulation: Allosterically activated by citrate, hormonally by insulin; inhibited by palmitoyl-CoA, glucagon.
• End product: Predominantly Palmitate (C16:0), a saturated fatty acid.
• NADPH source: Essential reducing power primarily from the Pentose Phosphate Pathway (PPP).
• Citrate shuttle: Transports mitochondrial acetyl-CoA to the cytosol for synthesis.
• Fatty Acid Synthase (FAS) complex: A large, multi-functional enzyme catalyzing multiple steps.