Lipid Anabolism

Lipid Metabolism II: Anabolism of Lipids

Overview of Lipid Anabolism

• Biosynthesis of Fatty Acids: The process of constructing fatty acid molecules from simpler precursors, primarily acetyl-CoA.

• Biosynthesis of Lipids (Triacylglycerols and Phospholipids): Involves building lipids from fatty acids.

Fatty Acid Synthesis

• Pathway: Distinct from degradation; occurs in the cytosol.

• Starting Material:

  • Acetyl-CoA: Provides the initial two carbons.

  • Malonyl-CoA: Donates two-carbon units for elongation.

• Mechanism:

  • Intermediates are attached to the -SH groups of an Acyl Carrier Protein (ACP).

  • NADPH: Acts as the reductant during synthesis.

• Enzyme Complex:

  • Fatty Acid Synthase: Multi-enzyme complex or single polypeptide in higher organisms.

  • Function: Stops elongation at palmitate (C16).

  • Further elongation and unsaturation occur via different enzyme systems.

Formation of Malonyl Coenzyme A

• Synthesis: The committed step in fatty acid synthesis.

• Regulation:

  • Controlled by acetyl-CoA carboxylase.

  • Enzyme Activity: Inactivated by phosphorylation and activated through dephosphorylation.

• Loading: Acetyl-CoA and Malonyl-CoA are transferred to the ACP.

Fatty Acid Synthesis Steps

• Overall Goal: Attach two-carbon acetate units from malonyl-CoA to a growing fatty acid chain and reduce it.

• Elongation Cycles: Comprise four enzyme-catalyzed steps:

  1. Condensation

  2. Reduction

  3. Dehydration

  4. Reduction

• Enzyme System:

  • Called Fatty Acid Synthase; a complex of distinct enzymes.

  • In bacteria, enzymes are separate; in mammals, they are part of a single polypeptide.

Enzymatic Details in Elongation Cycle

• Condensation: Catalyzed by β-ketoacyl-ACP synthase (KS).

• Reduction: Performed by β-ketoacyl-ACP reductase (KR).

• Dehydration: Catalyzed by β-hydroxyacyl-ACP dehydratase (DH).

• Final Reduction: Performed by enoyl-ACP reductase (ER).

Elongation Cycle Process

• Process: Involves condensation of acetyl-ACP and malonyl-ACP to form acetoacetyl-ACP.

• Similar Steps: The remaining steps mimic those in fatty acid degradation with key differences:

  • Uses NADPH instead of NADH and FADH2.

  • D-enantiomer of Hydroxybutarate is formed instead of L-enantiomer.

• Cycle Repetition: The cycle is completed seven times with malonyl-CoA, producing palmityl-ACP (C16).

• Finalization: A thioesterase cleaves palmityl-CoA from the ACP after reaching palmitate.

• Limitations: Further elongation and unsaturation are managed by enzymes found in the endoplasmic reticulum (ER).

Stoichiometry of Palmitate Synthesis

• Involves the transformation of:

  • Malonyl-CoA into Palmitate

  • Acetyl-CoA into Malonyl-CoA

Differences in Fatty Acid Degeneration vs. Synthesis

• Reversibility: Fatty acid degradation is not reversible; different enzymes are utilized.

• Mitochondrial Isolation: Oxidative processes in mitochondria are distinct, with notable electron balances and limits.

Citrate Shuttle Mechanism

• Transport: Acetyl-CoA is produced in the mitochondrial matrix but fatty acids are synthesized in the cytosol.

• Citration Mechanism: Acetyl-CoA is shuttled as citrate.

  • In cytoplasm, citrate is cleaved by ATP-citrate lyase (utilizing one ATP).

Biosynthesis of Triacylglycerols and Phospholipids

• Fates of Newly Synthesized Fatty Acids:

  • Fate I: Incorporated into triacylglycerols for long-term energy storage.

  • Fate II: Incorporated into membrane phospholipids.

• Glycerol 3-Phosphate: Precursor for the backbones of fats and phospholipids derived from Dihydroxyacetone phosphate (DHAP) in glycolysis.

• Acyl Transferases: Responsible for attaching fatty acids to glycerol 3-phosphate, forming phosphatidic acid.

Formation of Lipids from Phosphatidic Acid

• Task: Phosphatidic acid is modified to produce triacylglycerols and phospholipids.

  • Triacylglycerols: Formed through dephosphorylation and acylation of phosphatidic acid.

  • Phospholipids: Result from head group attachment onto phosphate from phosphatidic acid.