Describe the de novo synthesis of fatty acids. Explain the citrate shuttle, the role of acetyl-CoA carboxylase, and compare it with β-oxidation.

Definition and Site

Transport of Acetyl-coa — the Citrate Shuttle

• Acetyl-CoA is made in the mitochondrion but needed in the cytosol, and cannot cross the inner membrane

Acetyl-CoA + oxaloacetate → citrate (citrate synthase) → Citrate crosses via the tricarboxylate carrier → In cytosol: ATP-citrate lyase → Acetyl-CoA + oxaloacetate → OAA → malate → malic enzyme → pyruvate + NADPH → Pyruvate returns to the mitochondrion

• The shuttle also generates NADPH through the malic enzyme — a second purpose
• Citrate accumulates only when the cell has plenty of energy, so it is a natural signal that lipogenesis is appropriate

The Committed Step — Acetyl-coa Carboxylase

• This is the rate-limiting and committed step of fatty acid synthesis
• Malonyl-CoA inhibits CPT-I, shutting down β-oxidation at the same time — reciprocal control from a single molecule

Fatty Acid Synthase Complex

• A dimer, each monomer carrying seven enzyme activities plus acyl carrier protein (ACP)
• ACP contains phosphopantetheine, derived from pantothenic acid (B5)
• The growing chain remains bound throughout — no free intermediates escape

The repeating sequence

Condensation — acetyl + malonyl, CO2 released → Reduction — NADPH → Dehydration → Reduction — NADPH → Chain now 2 carbons longer; repeat 7 times

• After 7 cycles, thioesterase releases palmitate
• The CO2 fixed by carboxylase is released again at condensation — it is catalytic, driving the reaction forward

Stoichiometry and Sources of Nadph

Comparison with Β-oxidation

Elongation and Desaturation

• Elongation occurs in the endoplasmic reticulum (malonyl-CoA, NADPH) and in mitochondria (acetyl-CoA)
• Desaturation by Δ9, Δ6 and Δ5 desaturases in the ER
• Man cannot introduce a double bond beyond carbon 9 — which is why linoleic and α-linolenic acids are essential and must come from the diet

Applied Aspects

• Excess carbohydrate is converted to fat — the biochemical basis of obesity from a high-carbohydrate diet
• Non-alcoholic fatty liver disease — excess hepatic lipogenesis, driven by insulin resistance and fructose, is central to its pathogenesis
• Biotin deficiency impairs acetyl-CoA carboxylase and therefore lipogenesis
• Metformin activates AMPK → inhibits acetyl-CoA carboxylase → ↓ lipogenesis and ↑ fat oxidation
• Fatty acid synthase is over-expressed in many tumours and is being explored as a drug target