Introduction:
When dietary carbohydrates and amino acids are consumed in excess, the body converts them into fatty acids and stores them as triacylglycerols. The de novo synthesis of fatty acids occurs mainly in the liver, kidney, adipose tissue, and lactating mammary glands.
The enzyme system for fatty acid biosynthesis is located in the cytosol. The carbon atoms for fatty acid synthesis come from acetyl-CoA, while NADPH provides reducing power and ATP supplies energy.
The process of fatty acid synthesis occurs in three major stages:
- Production of Acetyl-CoA and NADPH
- Conversion of Acetyl-CoA to Malonyl-CoA
- Reactions of the Fatty Acid Synthase (FAS) Complex
1. Production of Acetyl-CoA and NADPH
Acetyl-CoA and NADPH are essential precursors for fatty acid synthesis. Acetyl-CoA is generated inside mitochondria from several sources:
- Oxidation of pyruvate
- β-oxidation of fatty acids
- Degradation of certain amino acids
- Metabolism of ketone bodies
Since the mitochondrial membrane is impermeable to acetyl-CoA, it is transported to the cytosol as citrate. Acetyl-CoA combines with oxaloacetate to form citrate in the mitochondria, which then moves to the cytosol where citrate lyase cleaves it to release acetyl-CoA and oxaloacetate.
In the cytosol, oxaloacetate is converted to malate, which is further converted to pyruvate by the malic enzyme, producing NADPH and CO₂. Both products are essential for fatty acid synthesis.
Advantage of Coupled Transport:
This citrate–malate shuttle provides both acetyl-CoA for fatty acid synthesis and NADPH as a reducing equivalent in the cytosol — an efficient arrangement for lipid biosynthesis.
2. Formation of Malonyl-CoA
The second stage of fatty acid synthesis involves the carboxylation of acetyl-CoA to form malonyl-CoA, catalyzed by acetyl-CoA carboxylase (ACC). This is an ATP-dependent and biotin-requiring enzyme.
Reaction:
Acetyl-CoA + CO₂ + ATP → Malonyl-CoA + ADP + Pi
This step is the committed and rate-limiting step in fatty acid biosynthesis and is the key regulatory point of the process.
3. Reactions of the Fatty Acid Synthase (FAS) Complex
Fatty acid synthesis beyond malonyl-CoA formation is catalyzed by a multifunctional enzyme system called the Fatty Acid Synthase (FAS) complex. In eukaryotes, this complex exists as a dimer, each monomer possessing seven enzymatic activities and an acyl carrier protein (ACP) containing 4’-phosphopantetheine.
Steps of Fatty Acid Synthesis (Palmitate Formation):
- Transfer of acetyl group: Acetyl-CoA transfers its two-carbon fragment to ACP via acetyl-CoA-ACP transacylase. The acetyl group then moves to a cysteine residue on the enzyme.
- Transfer of malonyl group: Malonyl-CoA-ACP transacylase transfers the malonyl group to ACP.
- Condensation: The acetyl group (on cysteine) condenses with the malonyl group (on ACP), releasing CO₂. The reaction is catalyzed by β-ketoacyl-ACP synthase.
- First Reduction: The β-keto group is reduced to a hydroxyl group by β-ketoacyl-ACP reductase using NADPH.
- Dehydration: β-Hydroxyacyl-ACP dehydratase removes water, forming a double bond between α and β carbons.
- Second Reduction: The double bond is reduced by enoyl-ACP reductase using NADPH to form a saturated acyl-ACP chain (butyryl-ACP).
These reactions are repeated in cycles, each time adding a two-carbon unit from malonyl-CoA. After seven cycles, a 16-carbon fatty acid — palmitate — is formed, which is then released by palmitoyl thioesterase.
Overall Reaction of Palmitate Synthesis:
8 Acetyl-CoA + 7 ATP + 14 NADPH + 14 H⁺ → Palmitate + 8 CoA + 7 ADP + 7 Pi + 6 H₂O
Fatty Acid Synthase (FAS) Complex
The FAS complex is a dimer with each monomer having a molecular weight of about 240,000. It includes all seven enzyme activities and an ACP with a reactive –SH group. Only the dimeric form is active, as both monomers work cooperatively in antiparallel (head-to-tail) orientation to synthesize two fatty acids simultaneously.
Functional Advantages of FAS Complex:
- Ensures high efficiency by confining all reactions within a single complex.
- Prevents loss or interference of intermediates with other cellular reactions.
- All enzyme activities are encoded by a single gene, ensuring coordinated synthesis and regulation.
Regulation of Fatty Acid Synthesis
Fatty acid synthesis is tightly controlled by multiple mechanisms involving enzymes, hormones, and dietary factors.
1. Allosteric Regulation:
Acetyl-CoA carboxylase (ACC) is the key regulatory enzyme:
- Citrate activates ACC by promoting polymerization (active form), enhancing fatty acid synthesis.
- Palmitoyl-CoA and malonyl-CoA inhibit ACC by causing depolymerization (inactive form).
2. Hormonal Regulation:
- Insulin activates ACC by dephosphorylation and promotes fatty acid synthesis.
- Glucagon, epinephrine, and norepinephrine inhibit ACC via cAMP-dependent phosphorylation, reducing fatty acid synthesis.
- Insulin also increases glucose uptake and conversion of pyruvate to acetyl-CoA, thereby enhancing fatty acid formation.
3. Dietary Regulation:
- A high-carbohydrate or fat-free diet increases ACC and FAS synthesis, promoting fatty acid formation.
- Fasting or high-fat diet decreases the production of these enzymes, reducing fatty acid synthesis.
4. Availability of NADPH:
About 50–60% of the NADPH required for fatty acid synthesis is produced by the hexose monophosphate (HMP) shunt and the citrate-malate-pyruvate shuttle.
Synthesis of Long-Chain Fatty Acids from Palmitate
Palmitate (C16) is the primary product of fatty acid synthase activity. Longer-chain fatty acids are produced through chain elongation in the endoplasmic reticulum (microsomal system) and mitochondria.
Microsomal Elongation:
- Involves addition of two-carbon units from malonyl-CoA using elongase enzymes.
- Uses NADPH as a reducing agent.
Mitochondrial Elongation:
- Occurs by reversal of β-oxidation reactions.
- Uses acetyl-CoA as the carbon donor and NADPH for reduction.
Detailed Notes:
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