Biosynthesis of Fatty Acids and Eicosanoids:- Fatty Acid Synthesis Proceeds in a Repeating Reaction Sequence
The long carbon chains of fatty acids are assembled in a repeating four-step sequence (Fig. 21–2). A saturated acyl group produced by this set of reactions becomes the substrate for subsequent condensation with an activated malonyl group. With each passage through the cycle, the fatty acyl chain is extended by two carbons. When the chain length reaches 16 carbons, the product (palmitate, 16:0; see Table 10–1) leaves the cycle. Car bons C-16 and C-15 of the palmitate are derived from the methyl and carboxyl carbon atoms, respectively, of an acetyl-CoA used directly to prime the system at the outset (Fig. 21–3); the rest of the carbon atoms in the chain are derived from acetyl-CoA via malonyl-CoA. Both the electron-carrying cofactor and the activating groups in the reductive anabolic sequence differ from those in the oxidative catabolic process. Recall that in β oxidation, NAD+ and FAD serve as electron acceptors and the activating group is the thiol (OSH) group of coenzyme A (see Fig. 17–8). By contrast, the reducing agent in the synthetic sequence is NADPH and the activating groups are two different enzyme-bound OSH groups, as described below.
All the reactions in the synthetic process are cat alyzed by a multienzyme complex, fatty acid synthase. Although the details of enzyme structure differ in prokaryotes such as Escherichia coli and in eukaryotes, the four-step process of fatty acid synthesis is the same in all organisms. We first describe the process as it occurs in E. coli, then consider differences in enzyme structure in other organisms.
FIGURE 21–2 Addition of two carbons to a growing fatty acyl chain: a four-step sequence. Each malonyl group and acetyl (or longer acyl) group is activated by a thioester that links it to fatty acid synthase, a multienzyme complex described later in the text. 1 Condensation of an activated acyl group (an acetyl group from acetyl-CoA is the first acyl group) and two carbons derived from malonyl-CoA, with elimination of CO2 from the malonyl group, extends the acyl chain by two carbons. The mechanism of the first step of this reaction is given to il lustrate the role of decarboxylation in facilitating condensation. The-keto product of this condensation is then reduced in three more steps nearly identical to the reactions of β oxidation, but in the re verse sequence: 2 the -keto group is reduced to an alcohol, 3 elimination of H2O creates a double bond, and 4 the double bond is reduced to form the corresponding saturated fatty acyl group.
