Fatty acids can be synthesized from excess carbohydrates and proteins obtained from the diet. This process mainly occurs in the liver and lactating mammary glands, with a smaller contribution from adipose tissue. The synthesis takes place in the cytosol and requires ATP and NADPH. Acetyl coenzyme A (CoA) provides the carbon source for the growing fatty acid chain. Additionally, dietary triacylglycerols (TAG) also supply fatty acids for this process.

The initial step in fatty acid synthesis involves the transfer of acetate units from mitochondrial acetyl CoA to the cytosol. Although the CoA portion of acetyl CoA cannot cross the inner mitochondrial membrane, the acetyl portion can enter the cytosol as part of citrate. Citrate is formed by the condensation of acetyl CoA with oxaloacetate through the action of citrate synthase. The transport of citrate to the cytosol occurs when there is a high concentration of mitochondrial citrate, which is caused by the inhibition of isocitrate dehydrogenase in the tricarboxylic acid (TCA) cycle. In the cytosol, citrate is cleaved to oxaloacetate and acetyl CoA by ATP citrate lyase.

The energy required for the carbon-to-carbon condensations in fatty acid synthesis is provided by the carboxylation and subsequent decarboxylation of acyl groups in the cytosol. Acetyl CoA carboxylase (ACC) catalyzes the carboxylation of acetyl CoA to malonyl CoA. This reaction involves the transfer of carbon dioxide from bicarbonate in an ATP-dependent manner. Biotin, a coenzyme bound to a lysyl residue of the carboxylase, facilitates the carboxylation reaction by transferring the activated carboxyl group to acetyl CoA. ACC plays a crucial role in supplying the activated carboxyl groups for fatty acid synthesis.

acetyl CoA carboxylase, malonyl CoA, ATP citrate lyase, TCA cycle
Carbohydrates and proteins obtained from the diet in excess of the body’s needs for these nutrients can be converted to fatty acids. In adults, de novo fatty acid synthesis occurs primarily in the liver and lactating mammary glands and, to a lesser extent, in adipose tissue. This cytosolic process is endergonic (see p. 70) and reductive. It incorporates carbons from acetyl coenzyme A (CoA) into the growing fatty acid chain, using ATP and reduced nicotinamide adenine dinucleotide phosphate (NADPH). [Note: Dietary TAG also supply fatty acids. See p. 321 for a discussion of the metabolism of dietary nutrients in the well-fed state.]
A. Cytosolic acetyl CoA production
The first step in fatty acid synthesis is the transfer of acetate units from mitochondrial acetyl CoA to the cytosol. Mitochondrial acetyl CoA is produced by the oxidation of pyruvate (see p. 109) and by the catabolism of certain amino acids (see p. 266). However, the CoA portion of acetyl CoA cannot cross the inner mitochondrial membrane, and only the acetyl portion enters the cytosol. It does so as part of citrate produced by the condensation of acetyl CoA with oxaloacetate (OAA) by citrate synthase (Fig. 16.6). [Note: The transport of citrate to the cytosol occurs when the mitochondrial citrate concentration is high. This is observed when isocitrate dehydrogenase of the tricarboxylic acid (TCA) cycle is inhibited by the presence of large amounts of ATP, causing citrate and isocitrate to accumulate (see p. 112). Therefore, cytosolic citrate may be viewed as a high-energy signal. Because a large amount of ATP is needed for fatty acid synthesis, the increase in both ATP and citrate enhances this pathway.] In the cytosol, citrate is cleaved to OAA and acetyl CoA by ATP citrate lyase.
B. Acetyl CoA carboxylation to malonyl CoA
The energy for the carbon-to-carbon condensations in fatty acid synthesis is supplied by the carboxylation and then decarboxylation of acyl groups in the cytosol. The carboxylation of acetyl CoA to malonyl CoA is catalyzed by acetyl CoA carboxylase (ACC ) (Fig. 16.7). ACC transfers carbon dioxide (CO2) from bicarbonate ( ) in an ATP-requiring reaction. The coenzyme is biotin (vitamin B7), which is covalently bound to a lysyl residue of the carboxylase (see Fig. 28.16, p. 385). ACC carboxylates the bound biotin, which transfers the activated carboxyl group to acetyl CoA.
acetylCoAcarboxylase.
diphosphate.