Fatty Acid Synthesis

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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. Acetyl-CoA Carboxylase mechanism

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 Cycle

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.

Practice Questions: Fatty Acid Synthesis

Test your understanding with these related questions

Which two enzymes are required for the beta oxidation of polyunsaturated fatty acids (PUFA)?

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Flashcards: Fatty Acid Synthesis

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Which enzyme of beta oxidation, converts ATP to AMP directly, releasing PPi?_____

TAP TO REVEAL ANSWER

Which enzyme of beta oxidation, converts ATP to AMP directly, releasing PPi?_____

Fatty-acyl coA synthetase

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