Biosynthesis of Fatty Acids and Eicosanoids:- Fatty Acid Synthase Receives the Acetyl and Malonyl Groups
Before the condensation reactions that build up the fatty acid chain can begin, the two thiol groups on the enzyme complex must be charged with the correct acyl groups (Fig. 21–5, top). First, the acetyl group of acetyl CoA is transferred to the Cys -SH group of the β ketoacyl-ACP synthase. This reaction is catalyzed by acetyl-CoA–ACP transacetylase (AT in Fig. 21–5). The second reaction, transfer of the malonyl group from malonyl-CoA to the OSH group of ACP, is catalyzed by malonyl-CoA–ACP transferase (MT), also part of the complex. In the charged synthase complex, the acetyl and malonyl groups are very close to each other and are activated for the chain-lengthening process. The first four steps of this process are now considered in some detail; all step numbers refer to Figure 21–5.
Step 1 Condensation The first reaction in the formation of a fatty acid chain is condensation of the activated acetyl and malonyl groups to form acetoacetyl-ACP, an acetoacetyl group bound to ACP through the phosphopantetheine -SH group; simultaneously, a molecule of CO2 is produced. In this reaction, catalyzed by β-ketoacyl-ACP synthase (KS), the acetyl group is transferred from the Cys -SH group of the enzyme to the malonyl group on the -SH of ACP, becoming the methyl-terminal two-carbon unit of the new acetoacetyl group.
The carbon atom of the CO2 formed in this reaction is the same carbon originally introduced into malonyl CoA from HCO3- by the acetyl-CoA carboxylase reaction (Fig. 21–1). Thus CO2 is only transiently in covalent linkage during fatty acid biosynthesis; it is removed as each two-carbon unit is added.
Why do cells go to the trouble of adding CO2 to make a malonyl group from an acetyl group, only to lose the CO2 during the formation of acetoacetate? Recall that in the β oxidation of fatty acids (see Fig. 17–8), cleav age of the bond between two acyl groups (cleavage of an acetyl unit from the acyl chain) is highly exergonic, so the simple condensation of two acyl groups (two acetyl-CoA molecules, for example) is highly ender gonic. The use of activated malonyl groups rather than acetyl groups is what makes the condensation reactions thermodynamically favorable. The methylene carbon (C-2) of the malonyl group, sandwiched between car bonyl and carboxyl carbons, is chemically situated to act as a good nucleophile. In the condensation step (step 1 ), decarboxylation of the malonyl group facilitates the nucleophilic attack of the methylene carbon on the thioester linking the acetyl group to β-ketoacyl-ACP synthase, displacing the enzyme’s OSH group. Coupling the condensation to the decarboxylation of the malonyl group renders the overall process highly exergonic. A similar carboxylation-decarboxylation sequence facilitates the formation of phosphoenolpyruvate from pyruvate in gluconeogenesis (see Fig. 14–17). By using activated malonyl groups in the synthesis of fatty acids and activated acetate in their degradation, the cell makes both processes energetically favorable, although one is effectively the reversal of the other. The extra energy required to make fatty acid synthesis favorable is provided by the ATP used to synthesize malonyl-CoA from acetyl-CoA and HCO3 (Fig. 21–1).
Step 2 Reduction of the Carbonyl Group The acetoacetyl ACP formed in the condensation step now undergoes reduction of the carbonyl group at C-3 to form D-β- hydroxybutyryl-ACP. This reaction is catalyzed by β- ketoacyl-ACP reductase (KR) and the electron donor is NADPH. Notice that the D--hydroxybutyryl group does not have the same stereoisomeric form as the L- β - hydroxyacyl intermediate in fatty acid oxidation (see Fig. 17–8).
Step 3 Dehydration The elements of water are now re moved from C-2 and C-3 of D- β -hydroxybutyryl-ACP to yield a double bond in the product, trans- Δ2- butenoyl ACP. The enzyme that catalyzes this dehydration is hydroxyacyl-ACP dehydratase (HD).
Step 4 Reduction of the Double Bond Finally, the double bond of trans- Δ2-butenoyl-ACP is reduced (saturated) to form butyryl-ACP by the action of enoyl-ACP reductase (ER); again, NADPH is the electron donor.
