De novo synthesis of fatty acids is a crucial metabolic process in which acetyl-CoA is converted into fatty acids. This process primarily occurs in the cytoplasm of liver cells (hepatocytes), adipose tissue, and mammary glands during lactation. Palmitic acid (C16:0) is the primary product of this pathway and serves as a precursor for other fatty acids. This note provides a detailed overview of the biochemical steps involved in the de novo synthesis of palmitic acid.
Fatty Acid Synthesis
Fatty acid synthesis involves the creation of long-chain fatty acids from acetyl-CoA and malonyl-CoA. The process is catalyzed by a multi-enzyme complex called fatty acid synthase (FAS). The synthesis involves a repetitive series of reactions that extend the fatty acid chain by two carbon units at a time.
Key Steps in Fatty Acid Synthesis
1. Transfer of Acetyl-CoA to the Cytoplasm
2. Formation of Malonyl-CoA
3. Fatty Acid Chain Elongation
Step-by-Step Breakdown
1. Transfer of Acetyl-CoA to the Cytoplasm
Source of Acetyl-CoA: Acetyl-CoA is primarily generated in the mitochondria from the oxidation of pyruvate, fatty acids, and amino acids.
Transport Mechanism: Acetyl-CoA cannot directly cross the mitochondrial membrane. Instead, it is converted to citrate by condensing with oxaloacetate, catalyzed by citrate synthase.
Citrate Shuttle:
Citrate is transported out of the mitochondria into the cytoplasm.
Enzyme: ATP-citrate lyase
Reaction:
Citrate +ATP + CoA → Acetyl-CoA + Oxaloacetate + ADP + Pi​
Citrate is cleaved back into acetyl-CoA and oxaloacetate in the cytoplasm.
2. Formation of Malonyl-CoA
Enzyme: Acetyl-CoA carboxylase (ACC)
Cofactor: Biotin (vitamin B7)
Regulation: Acetyl-CoA carboxylase is regulated by phosphorylation (inactive) and dephosphorylation (active) and allosterically activated by citrate and inhibited by palmitoyl-CoA.
Reaction:
Acetyl-CoA + CO2​ + ATP → Malonyl-CoA + ADP + Pi​
This carboxylation step is the rate-limiting step in fatty acid synthesis and produces malonyl-CoA.
3. Fatty Acid Chain Elongation
Enzyme Complex: Fatty acid synthase (FAS), a multifunctional enzyme complex.
Initial Loading:
Acetyl Transacylase transfers an acetyl group from acetyl-CoA to the acyl carrier protein (ACP) of FAS.
Malonyl Transacylase transfers a malonyl group from malonyl-CoA to ACP.
Cycle of Reactions:
1. Condensation:
Enzyme: β-Ketoacyl-ACP synthase
Reaction:
Acetyl-ACP + Malonyl-ACP → Acetoacetyl-ACP + CO2​
The acetyl group (2 carbons) and the malonyl group (3 carbons) condense to form acetoacetyl-ACP, releasing CO2.
2. Reduction:
Enzyme: β-Ketoacyl-ACP reductase
 Cofactor: NADPH
Reaction:
Acetoacetyl-ACP + NADPH + H+ → D-β-Hydroxybutyryl-ACP + NADP+
The β-keto group is reduced to a hydroxyl group.
3. Dehydration:
Enzyme: β-Hydroxyacyl-ACP dehydratase
Reaction:
D-β-Hydroxybutyryl-ACP → Crotonyl-ACP + H2​O
The hydroxyl group is removed as water, forming a double bond (crotonyl-ACP).
4. Reduction:
Enzyme: Enoyl-ACP reductase
Cofactor: NADPH
Reaction:
Crotonyl-ACP + NADPH + H+ → Butyryl-ACP + NADP+
The double bond is reduced to a single bond, producing butyryl-ACP.
Repetition: The butyryl-ACP then undergoes successive cycles of condensation, reduction, dehydration, and reduction, each time adding two carbon units from malonyl-CoA, until the fatty acid chain reaches 16 carbons in length, forming palmitoyl-ACP.
Termination:
Enzyme: Thioesterase
Reaction:
Palmitoyl-ACP + H2​O → Palmitate + ACP
The palmitoyl group is cleaved from ACP, releasing free palmitic acid.
Regulation of Fatty Acid Synthesis
Fatty acid synthesis is tightly regulated by hormonal and nutritional signals to ensure balance between energy storage and expenditure.
1. Allosteric Regulation:
Citrate activates acetyl-CoA carboxylase (ACC).
Palmitoyl-CoA inhibits ACC.
2. Hormonal Regulation:
Insulin promotes fatty acid synthesis by activating ACC through dephosphorylation and increasing glucose uptake and metabolism.
Glucagon and Epinephrine inhibit fatty acid synthesis by promoting phosphorylation and inactivation of ACC.
3. Nutritional Regulation:
High carbohydrate and low-fat diets stimulate fatty acid synthesis.
High-fat diets and fasting suppress fatty acid synthesis.
Summary
De novo synthesis of fatty acids is a critical metabolic pathway that converts acetyl-CoA into long-chain fatty acids, primarily palmitic acid, through a series of enzymatic reactions. This process occurs in the cytoplasm and is regulated by hormonal and nutritional factors to maintain energy homeostasis. The synthesized fatty acids are essential for energy storage, membrane synthesis, and production of signaling molecules.
