Fatty Acid Synthesis Overview

Fatty Acid Synthesis Overview

• Fatty acid synthesis, also known as lipogenesis, primarily creates triacylglycerols (TAGs) from carbohydrates.
• Starting materials include fatty acids (acyl CoA) and glycerol (glycerol-3-P).
• The process involves multiple steps.

Fatty Acid Synthesis Steps

• Biosynthesis of fatty acid: This is a critical initial step.
• Activation of fatty acid: This prepares fatty acids for incorporation.
• Biosynthesis of glycerol-3-P: Another necessary step for TAG formation.
• Combination of steps 2 and 3: This combines activated fatty acids and glycerol-3-P to form TAGs.

Biosynthesis of Fatty Acids: Systems

• There are three main systems for fatty acid synthesis:
  • De novo synthesis in the cytoplasm
  • Chain elongation in mitochondria
  • Chain elongation in microsomes

De Novo Synthesis of Fatty Acids (FA)

• This process is the opposite of beta-oxidation.
• It occurs in the cytoplasm.
• It uses 2-carbon acetate units to build even-chain, saturated fatty acids.
• It differs from fatty acid degradation, utilizing acyl carrier protein (ACP) instead of CoA.
• It employs enzymes linked in a complex.
• It uses NADPH as its reducing power.
• Unique pathways (unlike glycolysis/gluconeogenesis) occur.
• In mammals, this process mainly takes place in the cytosol of liver and adipose tissue, and mammary glands during lactation.
• Acetyl-CoA is the primary starting material for FA synthesis, though most acetyl-CoA comes from carbohydrate metabolism in mitochondria.

Acetyl-CoA Sources

• Acetyl-CoA comes from various sources:
  • Carbohydrates (glycogen, glucose)
  • Fats (fatty acid oxidation)
  • Proteins (amino acid deamination)

1-Acetyl-CoA from Carbohydrates

• Excess carbohydrates are transported to the cytosol as citrate.
• The citrate is then converted to acetyl-CoA within the cytosol.
• This is a critical process to provide acetyl-CoA from the mitochondria to the cytosol for fatty acid synthesis.

2-Acetyl-CoA from Proteins

• Amino acid degradation leads to acetyl-CoA or citrate.
• Citrate is exported to the cytosol.
• Resulting in acetyl-CoA in the cytosol.

3-Acetyl-CoA from Lipids

• The end product of fatty acid oxidation is acetyl-CoA.

Acetyl-CoA Transport

• Acetyl-CoA cannot pass directly from the mitochondria to the cytosol.
• Instead, acetyl-CoA is converted to citrate, then transported to the cytosol.
• In the cytosol, citrate is converted back to acetyl-CoA and oxaloacetate.

Sources of NADPH

• These molecules are crucial for fatty acid synthesis. Sources include:
  • Pentose shunt (HMP) pathway
  • Malic enzyme
  • UDP-glucose dehydrogenase
  • Cytoplasmic isocitrate dehydrogenase
  • NAD/NADP transhydrogenase
  • Glutamate dehydrogenase

Enzymes for Fatty Acid Synthesis

• Acetyl-CoA carboxylase: Catalyzes the committed, rate-limiting, step in fatty acid synthesis.
• Fatty acid synthase: Multi-enzyme complex consisting of 7 enzymes linked together in a polypeptide chain.  Contains acyl carrier protein (ACP), which uses pantothenic acid (vitamin B5) to carry acyl groups during synthesis.

Steps of Extramitochondrial Pathway (De Novo Synthesis)

• Condensation
• Reduction
• Dehydration
• Additional reduction
• Formation of Malonyl CoA is the rate-limiting step.

Regulation of FA Synthesis

• Allosteric regulation:
  • Regulated by citrate (activator)
  • Inhibited by long-chain acyl-CoA (product)
• Key enzyme: Acetyl-CoA carboxylase, the rate-limiting step.
• Hormonal regulation (covalent modification):
  • Activated by dephosphorylation (insulin)
  • Inactivated by phosphorylation (glucagon)

Fate of Palmitate

• Estrification: Incorporation into triacylglycerols (TAGs)
• Elongation: Extending the fatty acid chain
• Desaturation: Introducing double bonds

Chain Elongation in Microsomes

• The reactions mirror cytosolic fatty acid synthase.
• The primary source for 2-carbon units is malonyl-CoA.
• NADPH is used as the reducing agent.
• Site for lengthening pre-existing fatty acid chains (particularly useful for sphingolipid synthesis).
• Active during nerve myelination.

Chain Elongation in Mitochondria

• Acetyl-CoA is the new 2-carbon precursor.
• NADH and NADPH play roles as reducing agents.
• This pathway operates almost as a reverse form of fatty acid oxidation.
• It's important in situations with high NADH/NAD+ ratios (like in anaerobic conditions).

Biosynthesis of Unsaturated Fatty Acids

• Desaturases introduce double bonds in fatty acid chains.
• Mammals lack the ability to insert double bonds in specific locations.
• Certain polyunsaturated fatty acids (PUFAs) are essential components of the diet. 

Biosynthesis of Triacylglycerols (TAGs)

• Glycerol and fatty acids must be activated by ATP before incorporation.
• Occurs primarily in microsomes of tissues like liver, kidney, intestine, and lactating mammary glands.
• Glycerol activation involves a specific enzyme (glycerol kinase).
• Fatty acid activation uses acyl CoA synthetase enzymes.