This system is present in many tissues, including liver, kidney, brain, lung, mammary gland, and adipose tissue. Its cofactor requirements include NADPH, ATP, Mn²⁺, biotin, and HCO₃⁻ (as a source of CO₂). Acetyl-CoA is the immediate substrate, and free palmitate is the end product.

Production of Malonyl-CoA Is the Initial & Controlling Step in Fatty Acid Synthesis

The initial step in fatty acid synthesis is the carboxylation of acetyl-CoA to form malonyl-CoA byacetyl-CoA carboxylase. The reaction requires ATP and the B vitamin biotin. Acetyl CoA carboxylase is a multienzyme protein containing biotin carboxylase, and a carboxyl transferase as well as biotin carrier protein (which binds biotin), and a regulatory allosteric site. The reaction takes place in two steps: Step 1 catalyzed by biotin carboxylase results in the carboxylation of biotin and uses ATP and Step 2 catalyzed by carboxyl transferase results in the transfer of the carboxyl group to acetyl-CoA forming the product, malonyl-CoA (Figure 1). Acetyl-CoA carboxylase has a major role in the regulation of fatty acid synthesis (see following discussion).

Fig1. Biosynthesis of malonyl-CoA by acetyl-CoA carboxylase. Acetyl carboxylase is a multienzyme complex containing two enzymes, biotin carboxylase (E1) and a carboxyltransferase (E2), and the biotin carrier protein (BCP). Biotin is covalently linked to the BCP. The reaction proceeds in two steps. In step 1, catalyzed by E1, biotin is carboxylated as it accepts a COO⁻ group from HCO3⁻ and ATP is used. In step 2, catalyzed by E2, the COO⁻ is transferred to acetyl-CoA forming malonyl-CoA.

The Fatty Acid Synthase Complex Is a Homodimer of Two Polypeptide Chains Containing Six Enzyme Activities & the Acyl Carrier Protein

After the formation of malonyl-CoA, fatty acids are formed by the fatty acid synthase enzyme complex. The individual enzymes required for fatty acid synthesis are linked in this multienzyme polypeptide complex that incorporates the acyl carrier protein (ACP), which has a similar function to that of CoA in the β-oxidation pathway. It contains the vitamin pantothenic acid in the form of 4′-phosphopantetheine. In the primary structure of the protein, the enzyme domains are believed to be linked in the sequence as shown in Figure 2. X-ray crystallography of the three-dimensional structure, however, has shown that the complex is a homodimer, with two identical subunits, each containing six enzymes and an ACP, arranged in an X shape (see Figure 2). The use of one multienzyme functional unit has the advantages of achieving compartmentalization of the process within the cell without the necessity for permeability barriers, and synthesis of all enzymes in the complex is coordinated since it is encoded by a single gene.

Fig2. Fatty acid synthase multienzyme complex. The complex is a dimer of two identical polypeptide monomers in which six enzymes and the acyl carrier protein (ACP) are linked in the primary structure in the sequence shown. X-ray crystallography of the three dimensional structure has demonstrated that the two monomers in the complex are arranged in an X-shape.

Initially, a priming molecule of acetyl-CoA combines with a cysteine —SH group on the ACP of one monomer of the fatty acid synthase complex (Figure 3, reaction 1a), while malonyl-CoA combines with the adjacent —SH on the 4′ phosphopantetheine of ACP of the other monomer (reaction 1b). These reactions are catalyzed by malonyl acetyl transacylase, to formacetyl (acyl)-malonyl enzyme. The acetyl group attacks the methylene group of the malonyl residue, catalyzed by 3-ketoacyl synthase, and liberates CO2, forming 3-ketoacyl enzyme(acetoacetyl enzyme) (reaction 2), freeing the cysteine —SH group. Decarboxylation allows the reaction to go to completion, pulling the whole sequence of reactions in the forward direction. The 3-ketoacyl group is reduced (3-ketoacylreductase), dehydrated (dehydratase), and reduced again (enoyl reductase) (reactions 3-5) to form the corresponding saturated acyl enzyme (product of reaction 5). The saturated acyl residue now transfers from the —SH of the 4′ phosphopantetheine to the free cysteine —SH group as it is displaced by a new malonyl-CoA. The sequence of reactions is repeated six more times until a saturated 16-carbon acyl radical (palmitoyl) has been assembled. It is liberated from the enzyme complex by the activity of the sixth enzyme in the complex,thioesterase(deacylase). The free palmitate must be activated to acyl-CoA before it can proceed via any other metabolic pathway. Its possible fates are esterification into acylglycerols, chain elongation, desaturation, or esterification into cholesteryl ester. In mammary gland, there is a separate thioesterase specific for acyl residues of C₈ , C₁₀ , or C₁₂ , which are subsequently found in milk lipids.

Fig3. Biosynthesis of long-chain fatty acids. After the initial priming step in which acetyl-CoA is bound to a cysteine-SH group on the fatty acid synthase enzyme (reaction 1a), the addition of a malonyl residue causes the acyl chain to grow by two carbon atoms in each cycle. (Cys, cysteine residue; Pan, 4′-phosphopantetheine.) The blocks highlighted in blue contain the C2 unit derived from acetyl-CoA initially (as illustrated) and subsequently the Cn unit formed in reaction 5.

C₁₂ , which are subsequently found in milk lipids.

The equation for the overall synthesis of palmitate from acetyl-CoA and malonyl-CoA is

The acetyl-CoA used as a primer forms carbon atoms 15 and 16 of palmitate. The addition of all the subsequent C2 units is via malonyl-CoA. Propionyl-CoA instead of acetyl CoA is used as the primer for the synthesis of long-chain fatty acids with an odd number of carbon atoms, which are found particularly in ruminant fat and milk.

The Main Source of NADPH for Lipogenesis Is the Pentose Phosphate Pathway

NADPH is involved as a donor of reducing equivalents in the reduction of the 3-ketoacyl and the 2,3-unsaturated acyl derivatives (see Figure 3, reactions 3 and 5). The oxidative reactions of the pentose phosphate pathway are the chief source of the hydrogen required for the synthesis of fatty acids. Significantly, tissues specializing in active lipogenesis that is, liver, adipose tissue, and the lactating mammary gland also possess an active pentose phosphate pathway. Moreover, both metabolic pathways are found in the cytosol of the cell, so there are no membranes or permeability barriers against the transfer of NADPH. Other sources of NADPH include the reaction that converts malate to pyruvate catalyzed by the NADP malate dehydrogenase (malic enzyme) (Figure 4) and the extramitochondrial isocitrate dehydrogenase reaction (a substantial source in ruminants).

Fig4. The provision of acetyl-CoA and NADPH for lipogenesis. (K, α-ketoglutarate transporter; P, pyruvate transporter; PPP, pentose phosphate pathway; T, tricarboxylate transporter.)

Acetyl-CoA Is the Principal Building Block of Fatty Acids

 Acetyl-CoA is formed from glucose via the oxidation of pyruvate in the matrix of the mitochondria. However, as it does not diffuse readily across the mitochondrial membranes, its transport into the cytosol, the principal site of fatty acid synthesis, requires a special mechanism involving citrate. After condensation of acetyl-CoA with oxaloacetate in the citric acid cycle within mitochondria, the citrate produced can be translocated into the extramitochondrial compartment via the tricarboxylate transporter, where in the presence of CoA and ATP, it undergoes cleavage to acetyl CoA and oxaloacetate by ATP-citrate lyase, which increases in activity in the well-fed state. The acetyl-CoA is then available for malonyl-CoA formation and synthesis of fatty acids (see Figures 1 and 3), and the oxaloacetate can form malate via NADH-linked malate dehydrogenase, followed by the generation of NADPH and pyruvate via the malic enzyme. The NADPH becomes available in the cytosol for lipogenesis, and the pyruvate can be used to regenerate acetyl-CoA after transport into the mitochondrion (see Figure 4). This pathway is a means of transferring reducing equivalents from extramitochondrial NADH to NADP to form NADPH.

As the citrate (tricarboxylate) transporter in the mitochondrial membrane requires malate to exchange with citrate, malate itself can be transported into the mitochondrion, where it is able to reform oxaloacetate. There is little ATP-citrate lyase or malic enzyme in ruminants, probably because in these species acetate (derived from carbohydrate digestion in the rumen and activated to acetyl-CoA extra mitochondrially) is the main source of acetyl-CoA.

Elongation of Fatty Acid Chains Occurs in the Endoplasmic Reticulum

This pathway (the “microsomal system”) elongates saturated and unsaturated fatty acyl-CoAs (from C₁₀ upward) by two carbons, using malonyl-CoA as the acetyl donor and NADPH as the reductant, and is catalyzed by the microsomal fatty acid elongase system of enzymes (Figure 5). Elongation of stearyl-CoA in brain increases rapidly during myelination in order to provide C₂₂ and C₂₄ fatty acids for sphingolipids.

Fig5. Microsomal elongase system for fatty acid chain elongation. NADH may also be used by the reductases, but NADPH is preferred.

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مواضيع ذات صلة

Some polyunsaturated fatty acids cannot be synthesized by mammals and are nutritionally essential

Short- & Long-Term Mechanisms Regulate Lipogenesis

Impaired Oxidation of Fatty Acids Gives Rise to Diseases Often Associated With Hypoglycemia

Ketogenesis Occurs When There is a High Rate of Fatty Acid Oxidation in The Liver

β -Oxidation of Fatty Acids Involves Successive Cleavage with Release OF Acetyl-CoA

Oxidation of Fatty Acids Occurs in Mitochondria

Amphipathic Lipids Self - Orient at Oil: Water Interfaces

Lipid Peroxidation is A Source of Free Radicals

Steroids Play Many Physiologically Important Roles

Glycolipids (Glycosphingolipids) are Important in Nerve Tissue & in the Cell Membrane

Phospholipids are The Main Lipid Constituents of Membranes

Fatty Acids are Aliphatic Carboxylic Acids