Fatty acids are synthesized by the successive addition of two-carbon units from acetyl CoA, followed by reduction. Like ^-oxidation, fatty acid synthesis is a spiral sequence of reactions, with different enzymes catalysing the reaction sequence for synthesis of short, medium- and long-chain fatty acids.
Unlike ^-oxidation, which occurs in the mitochondrial matrix, fatty acid synthesis occurs in the cytosol. The enzymes required for fatty acid synthesis form a multienzyme complex, arranged in a series of concentric rings around a central acyl carrier protein (ACP), which carries the growing fatty acid chain from one enzyme to the next. The functional group of the acyl carrier protein is the same as that of CoA, derived from the vitamin pantothenic acid and cysteamine (see Figure 11.26). As the chain grows in length, so the middle then outermost rings of enzymes are used. Short- and medium-chain fatty acids are not released from one set of enzymes to bind to the next, as occurs in ^-oxidation.
The only source of acetyl CoA is in the mitochondrial matrix, and, as discussed in section 5.5.1, acetyl CoA cannot cross the inner mitochondrial. For fatty acid synthesis, citrate is formed inside the mitochondria by reaction between acetyl CoA and oxaloacetate (Figure 5.27), and is then transported out of the mitochondria, to undergo cleavage in the cytosol to yield acetyl CoA and oxaloacetate. The acetyl CoA is used for fatty acid synthesis, while the oxaloacetate (indirectly) returns to the mitochondria to maintain citric acid cycle activity.
Fatty acid synthesis can occur only when the rate of formation of citrate is greater than is required for energy-yielding metabolism. Although citrate is a symmetrical molecule, and carbons 1 and 2 are equivalent to carbons 5 and 6, it behaves asymmetrically. The two carbons that are added from acetyl CoA remain in the four carbon intermediates of the citric acid cycle during the first turn. If cells are incubated with [14C]acetate and malonate as an inhibitor of succinate dehydrogenase (see Figure 5.18), no radioactivity is detectable in the carbon dioxide released in the first (partial) turn of the cycle. This is the result of metabolic channelling. Citrate is passed directly from the active site of citrate synthase to that of aconitase. It is only when isocitrate
dehydrogenase is saturated, and hence aconitase is inhibited by its product, that citrate is released from the active site of citrate synthase into free solution, to be available for transport out of the mitochondria.
Oxaloacetate cannot re-enter the mitochondrion directly. As shown in Figure 5.27, it is reduced to malate, which then undergoes oxidative decarboxylation to pyruvate, linked to the reduction of NADP+ to NADPH. This provides about half the NADPH
that is required for fatty acid synthesis. The resultant pyruvate enters the mitochondrion and is carboxylated to oxaloacetate in a reaction catalysed by pyruvate carboxylase.
As shown in Figure 5.28, the first reaction in the synthesis of fatty acids is carboxylation of acetyl CoA to malonyl CoA. This is a biotin-dependent reaction (section 11.12.2) and, as discussed above (section 5.5.1), the activity of acetyl CoA carboxylase is regulated in response to insulin and glucagon. Malonyl CoA is not only the substrate for fatty acid synthesis, but also a potent inhibitor of carnitine palmitoyl transferase, so inhibiting the uptake of fatty acids into the mitochondrion for P-oxidation.
The malonyl group is transferred onto an acyl carrier protein, and then reacts with the growing fatty acid chain, bound to the central acyl carrier protein of the fatty acid synthase complex. The carbon dioxide that was added to form malonyl CoA is lost in this reaction. For the first cycle of reactions, the central acyl carrier protein carries an acetyl group, and the product of reaction with malonyl CoA is acetoacetyl-ACP; in subsequent reaction cycles, it is the growing fatty acid chain that occupies the central ACP, and the product of reaction with malonyl CoA is a ketoacyl-ACP.
The ketoacyl-ACP is then reduced to yield a hydroxyl group. In turn, this is dehydrated to yield a carbon—carbon double bond, which is reduced to yield a saturated fatty acid chain. Thus, the sequence of chemical reactions is the reverse of that in P-oxidation (section 5.5.2). For both reduction reactions in fatty acid synthesis, NADPH is the hydrogen donor. One source of this NADPH is the pentose phosphate pathway (section 5.4.2) and the other is the oxidation of malate (arising from oxaloacetate) to pyruvate, catalysed by the malic enzyme (see Figure 5.27).
The end-product of cytosolic fatty acid synthesis is palmitate (C16:0); longer-chain fatty acids (up to C24) and unsaturated fatty acids are synthesized from palmitate in the endoplasmic reticulum and mitochondria.
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