Biosynthesis of Fatty Acids
1. General Overview
- Fatty acid synthesis is the anabolic (building) process that forms fatty acids from Acetyl-CoA.
- Occurs mainly in:
- Liver (primary site)
- Adipose tissue
- Lactating mammary gland
- Takes place in the cytosol (in contrast to β-oxidation → mitochondria)
2. Substrates Required
- Acetyl-CoA (initial 2-carbon donor).
- Malonyl-CoA (provides 2-carbon units for chain elongation).
- NADPH (reducing power).
- ATP (required for preparation steps).
- Citrate is the transporter that carries Acetyl-CoA from mitochondria → cytosol.
3. Formation of Malonyl-CoA (Committed Step)
- Acetyl-CoA → Malonyl-CoA
- Enzyme: Acetyl-CoA Carboxylase (ACC)
- Requires:
- ATP
- Biotin (Vitamin B7) as a coenzyme.
- This is the rate-limiting step of fatty acid synthesis.
4. Fatty Acid Synthase (FAS) Complex
- A large multi-enzyme complex in cytosol.
- Uses:
- Acetyl-CoA (starting molecule)
- Repeated addition of Malonyl-CoA units.
- Produces:
- Palmitic Acid (16-carbon fatty acid) as the final product.
- Each cycle of elongation includes:
- Condensation
- Reduction
- Dehydration
- Reduction → Uses NADPH in the reduction steps.
5. Examples of Reductive Synthesis & Role of NADPH
- Fatty acid synthesis is a reductive process.
- NADPH supplies the electrons needed to reduce carbon atoms.
- Sources of NADPH:
- Pentose Phosphate Pathway (main source)
- Malic Enzyme (Oxaloacetate → Malate → Pyruvate + NADPH)
- NADPH is necessary for:
- Reduction of keto groups to alcohols
- Reduction of double bonds to single bonds
- This builds fully saturated fatty acids
6. Regulation of Fatty Acid Synthesis
A) Hormonal Regulation
- Insulin stimulates fatty acid synthesis:
- Activates Acetyl-CoA Carboxylase.
- Promotes glucose entry → increases citrate and NADPH.
- Glucagon and Epinephrine inhibit synthesis:
- Inhibit ACC via phosphorylation.
B) Metabolic Regulation
- Citrate activates ACC → When energy is abundant.
- Palmitoyl-CoA inhibits ACC → Feedback inhibition (end-product control).
- Malonyl-CoA inhibits Carnitine Shuttle
- Prevents β-oxidation during fatty acid synthesis.
Key idea: Cell does not synthesize and oxidize fatty acids at the same time.
7. Energetic and Metabolic Balance
- 1 cycle of addition requires:
- 1 Acetyl-CoA + 7 Malonyl-CoA
- 14 NADPH
- Formation of Palmitate (C16) requires:
- 8 Acetyl-CoA total
- 7 ATP (for carboxylation to malonyl)
- 14 NADPH (for reduction steps)
- Energetically expensive, therefore it occurs when ATP and glucose levels are high.
8. Extension and Modification of Fatty Acids
- Elongation beyond 16 carbons occurs in:
- ER and mitochondria
- Desaturation (introduction of double bonds) occurs in:
- ER
- Humans cannot introduce double bonds past C9.
- Therefore Linoleic and Linolenic acid are essential fatty acids (must be taken from diet).