FATTY ACID BIOSYNTHESIS
- Occurs in the liver and adipose tissue (cytosol)
- After a carbohydrate-rich meal (high insulin:glucagon ratio)
- Not just reverse of beta-oxidation: distinct enzymes and compartments
Reactions
1. Citrate Shuttle
- Acetyl CoA in mitochondrial matrix transported to cytosol as citrate
- Citrate synthase: citrate from oxaloacetate and acetyl CoA (also first CAC rxn)
- Citrate a marker of high intracellular energy (CAC intermediate)
2. Malonyl CoA Formation
- Acetyl CoA carboxylase: adds 1 carbon to acetyl CoA to form malonyl CoA
- ABC carboxylase reaction
- Citrate activates rxn
- Long-chain fatty acyl CoA (intermed. of FA breakdown): inhibits rxn
ABC carboxylase reactions: consume ATP, require biotin, consume CO2
- Malonyl CoA synthesis in fatty acid biosynthesis
- Gluconeogenesis: pyruvate carboxylase
- Odd chain fatty acid oxidation: propionyl carboxylase
3. Palmitate Synthesis
- Palmitate: 16-carbon fatty acid
- Catalyzed by fatty acid synthase
- ACP is carrier protein component of fatty acid synthase
- Series of 4 reactions:
i. Condensation: acetyl-ACP + malonyl-ACP = 4-C intermediate + CO2
ii. Reduction (NADPH)
iii. Dehydration: water molecule released
iv. Reduction (NADPH)
- First condensation = 4C molecule
- 6 increments x 2C (malonyl-ACP) = 12 C
- Total = 16 C palmitate
4. Palmitate Modification
i. Elongation: in smooth
ER or
mitochondria
- 2-carbon increments using malonyl CoA (NOT malonyl-ACP)
- Each increment includes four rxn's from palmitate synthesis
ii. Desaturation: in smooth ER or peroxisomes
CLINICAL CORRELATION
Essential fatty acids: linoleic acid and linolenic acid cannot be synthesized endogenously.
- Mammals cannot induce double bonds beyond C9