Fatty Acid Degradation- 27

Overview of Fatty Acid Synthesis

• Lecture focused on the biochemical process of fatty acid synthesis, highlighting significance in metabolism and cellular function.

• Key precursor: Acetyl CoA (two-carbon molecule) is essential for fatty acid formation.

Key Stages in Fatty Acid Synthesis

1. Transfer of Acetyl CoA

   • Acetyl CoA is produced in mitochondria, but synthesis occurs in cytoplasm.

   • Transferred as citrate via mitochondrial condensation with oxaloacetate.

   • Cleaved by ATP-citrate lyase in cytoplasm to regenerate acetyl CoA and oxaloacetate.

2. Activation of Acetyl CoA

   • Conversion of acetyl CoA to malonyl CoA via a carboxylation reaction.

   • Catalyzed by acetyl CoA carboxylase I, a biotin-dependent enzyme.

   • This step commits the acetyl CoA to fatty acid synthesis.

3. Elongation

   • Acetyl CoA and malonyl CoA react with acyl carrier protein (ACP) to form new fatty acid chains.

   • Key steps repeated include:

   1. Condensation (carbon chain lengthens)

   2. Reduction (using NADPH)

   3. Dehydration

   4. Reduction again

   • Results in a 16-carbon fatty acid (palmitate).

   • Further extension requires different enzymes beyond 16 carbons.

Requirements for Fatty Acid Synthesis

• In addition to acetyl CoA and ATP, synthesis requires NADPH for reduction.

• Sources of NADPH:

  • Oxaloacetate conversion to malate (leading to NADPH generation).

  • The pentose phosphate pathway also contributes to NADPH supply.

Energetic Accounting

• Basic stoichiometry for palmitate synthesis includes inputs of acetyl CoA, malonyl CoA, NADPH, and ATP.

• Energetic balance is critical for understanding metabolic flux in synthesis pathways.

Enzymatic Equipment

• Fatty acid synthesis enzymes are highly conserved across organisms.

• In animals, components exist in a single polypeptide chain, termed fatty acid synthase (a homodimer setup).

• Enzymatic compartments include:

  • Selecting and condensing compartment: Activation and condensation.

  • Modification compartment: Reduction and dehydration.

Regulation of Fatty Acid Synthesis

• Critical regulatory enzyme: Acetyl CoA carboxylase 1

  • Activity affected by phosphorylation through AMP-dependent kinase (AMPK).

  • High AMPK activity inactivates carboxylase, indicating low energy (high AMP, low ATP).

  • Hormonal effects:

    • Insulin stimulates activity of carboxylase.

    • Glucagon and epinephrine inhibit it.

Variations in Fatty Acid Production

• Unsaturated fatty acids: Synthesized with the introduction of double bonds by specific ER enzymes.

  • Humans cannot synthesize double bonds beyond C-9, making some fatty acids essential (linoleate, linolenate).

• Arachidonic acid: A key 20-carbon fatty acid, precursor for eicosanoids which act as local hormones regulating cellular activities (e.g., inflammation).

Clinical Insights

• Beta-hydroxybutyric acid is an intermediate in fatty acid synthesis and degradation, while its isomer, gamma-hydroxybutyric acid, has different effects (e.g., neurotransmitter).

• Ethanol metabolism affects fatty acid metabolism, leading to increased NADH, altering normal synthesis and degradation pathways, and affecting overall metabolic health.

Important Questions

• What is the key precursor in fatty acid synthesis? The primary precursor in fatty acid synthesis is acetyl-CoA, which is derived from carbohydrates, fats, and proteins.

• Into what compartments does fatty acid chain extension occur? Fatty acid chain extension occurs primarily in the cytoplasm and the endoplasmic reticulum, where enzymes involved in elongation and desaturation processes are located.

• What enzymes are critical for the activation of acetyl CoA? The critical enzymes for the activation of acetyl-CoA include acetyl-CoA carboxylase, which converts acetyl-CoA to malonyl-CoA, and fatty acid synthase, which catalyzes the subsequent steps of fatty acid synthesis.

• How is fatty acid synthesis regulated in response to energy status and hormonal signals? Fatty acid synthesis is regulated by several mechanisms, including allosteric modifications, covalent modifications of key enzymes, and changes in the expression of enzymes in response to hormonal signals such as insulin and glucagon.

• What variations exist for synthesizing unsaturated and longer fatty acids? The synthesis of unsaturated and longer fatty acids involves distinct enzymes and pathways, such as the action of fatty acid desaturases, which introduce double bonds into fatty acid chains, and elongases, which extend the carbon chain length by adding two-carbon units.