De Novo Fatty Acid Synthesis Overview
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ammuDe Novo Fatty Acid Synthesis Overview
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Powered by AIEssential fatty acids, such as linoleic acid and α-linolenic acid, are precursors for the synthesis of bioactive compounds like prostaglandins, thromboxanes, leukotrienes, and lipoxins. They are crucial for maintaining the physical properties of cell membranes, particularly in phospholipids, and are vital for brain and retinal development. Mammals lack the enzymatic capability to introduce double bonds between carbon 10 and the terminal methyl end, thus necessitating dietary intake from plants .
The introduction of double bonds at specific positions among fatty acids affects fluidity and function of cell membranes. Mammals can introduce double bonds at the Δ4, Δ5, Δ6, and Δ9 positions, crucial for forming important unsaturated fats like oleate (18:1Δ9) from stearate. However, they cannot introduce double bonds beyond C10 from the methyl-terminal end, making linoleic and α-linolenic acids, with double bonds beyond this point, essential in the diet. These dietary essential fatty acids are precursors for bioactive molecules necessary for proper cellular function .
The acyl carrier protein (ACP) is crucial in fatty acid synthesis as it acts as a flexible shuttle that carries intermediates between catalytic sites of the synthase complex. Its structure, featuring a prosthetic group known as 4'-phosphopantetheine, provides this flexibility. The hydroxyl group of the serine residue in ACP facilitates the attachment of acyl groups through thioester linkage, allowing the transfer of reaction intermediates effectively during the synthesis process .
The fatty acid synthase complex consists of three domains each housing specific enzymes: the first domain contains acetyl transacylase (AT), malonyl transacylase (MT), and condensing enzyme (CE); the second includes acyl carrier protein (ACP), β-ketoacyl reductase (KR), dehydratase (DH), and enoyl reductase (ER), while the third houses thioesterase (TE). These enzyme domains facilitate the respective steps in fatty acid synthesis from initiation, through elongation and reduction of the growing fatty acid chain, to the release of the final product .
In fatty acid elongation, palmitic acid (16-carbon) is extended by adding two-carbon units derived from malonyl-CoA. This process is similar to its initial synthesis, involving reduction, dehydration, and another reduction step. However, the elongation of very long-chain fatty acids occurs in the brain during myelination and requires a different set of enzymes in the endoplasmic reticulum or mitochondria. The brain-specific elongation also necessitates fatty acid elongase, a multienzyme complex that facilitates this process .
Increased dietary intake of polyunsaturated fatty acids (PUFAs) inhibits lipogenesis. This occurs through multiple pathways; one significant mechanism is the reduction in the concentration of enzymes involved in fatty acid synthesis, as PUFAs suppress the expression of genes encoding these enzymes. Additionally, PUFAs affect the covalent modifications, leading to decreased activity of acetyl-CoA carboxylase and other key enzymes in the lipogenic pathway, thus reducing fat synthesis .
Acetyl-CoA carboxylase is regulated allosterically by citrate, which activates the enzyme, and by palmitoyl-CoA, which serves as a feedback inhibitor. Covalent modification involves hormonal regulation, where insulin increases enzyme activity, whereas glucagon and epinephrine decrease it. This modulation is crucial as acetyl-CoA carboxylase catalyzes the rate-limiting step in fatty acid synthesis, determining the overall rate of lipogenesis .
Acetyl-CoA generated in the mitochondria must be transferred to the cytoplasm for fatty acid synthesis, as this biosynthesis occurs in the cytoplasmic compartment. The transport mechanism involves the conversion of acetyl-CoA to citrate, which is then transported across the mitochondrial membrane. Once in the cytoplasm, citrate is converted back to acetyl-CoA and oxaloacetate. This process is crucial as it ensures a supply of acetyl-CoA needed for initiating lipogenesis in the cytoplasm where synthesis enzymes and conditions are favorable .
In vertebrates, the fatty acid synthase complex functions as a homodimer, meaning it consists of two identical subunits, each having seven active sites responsible for multiple reaction steps. The homodimeric nature allows for an efficient sequential progression of the synthesis reactions as the intermediates remain covalently attached and passed from one active site to another within the complex. This structural arrangement greatly enhances the catalytic efficiency and coordination of the biosynthesis of fatty acids such as palmitate .
The primary cofactors required for fatty acid synthesis are NADPH, ATP, biotin, and HCO3-. NADPH serves as the reductant, providing the necessary reducing power for the reduction steps in the synthesis. ATP is needed for the activation of acetyl-CoA to malonyl-CoA, an energy-dependent process. Biotin acts as a carrier for the active CO2 unit in the carboxylation of acetyl-CoA, while HCO3- is the source of CO2 in the carboxylation reaction that forms malonyl-CoA .