Principles of Biochemistry Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Lipid Biosynthesis
The synthase system catalyzing fatty acid formation features seven active sites

In animal Tissues, the seven Enzymes involved in FATTY ACID Biosynthesis are organized into a cluster, or complex, known as the fatty acid synthase system; the total Molecular Weight of this cytoplasmic complex is approximately 400,000. This association of seven enzymes likely evolved to accelerate the sequential steps of fatty acid synthesis.

Central to this system is the acyl carrier protein (ACP), to which the intermediates of fatty acid biosynthesis are covalently bound. ACP is a relatively small, heat-stable protein with a molecular weight of 9,000. Its prosthetic group is 4'-phosphopantetheine (Fig. 21-5), which is also a component of coenzyme A. The phosphopantetheine molecule contains the vitamin pantothenic acid (Sec. 10.7) and a sulfhydryl group. Phosphopantetheine is attached via a phosphate ester bond to the hydroxyl group of a Serine residue in the ACP molecule.

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Fig. 21-5. The prosthetic group of the acyl carrier protein is 4'-phosphopantetheine, covalently linked to the hydroxyl group of a serine residue in the polypeptide chain. Phosphopantetheine, which contains the vitamin pantothenic acid, is also present in the CoA molecule (Sec. 10.7). During fatty acid synthesis, the SH group of phosphopantetheine serves as the binding site for malonyl groups.

The function of ACP in fatty acid biosynthesis is analogous to that of coenzyme A in Fatty acid oxidation. Throughout the assembly of the fatty acid chain, intermediates form thioester bonds with ACP, whereas during fatty acid oxidation, intermediates form thioester bonds with coenzyme A. It is hypothesized that the 4'-phosphopantetheine prosthetic group of ACP, together with its attachment serine residue, acts as a "swivel arm" that sequentially transfers covalently bound fatty acid residues from one Active Site of the enzyme complex to another (Fig. 21-6), much like the mechanism operating in the mitochondrial Pyruvate dehydrogenase complex (Sec. 16.2). Fatty acid synthase contains Two Types of sulfhydryl groups essential for its catalytic activity (Fig. 21-7). One SH group belongs to the 4'-phosphopantetheine prosthetic group of ACP, and the other belongs to a specific Cysteine residue within the 3-ketoacyl-ACP synthase domain (Sec. 21.5, a). Both of these SH groups participate directly in fatty acid biosynthesis.

Fig. 21-6. Schematic representation of the fatty acid synthase complex. In animal tissues, the enzymes catalyzing fatty acid synthesis are clustered around the acyl carrier protein (ACP). The 4'-phosphopantetheine prosthetic group (Pp) is linked to a serine residue (Fig. 21-5) and Functions as a flexible "swivel arm" (about 2.0 nm long) that transfers fatty acid residues from the active site of one enzyme to that of the next (moving counterclockwise in the diagram). In bacterial and plant Cells, the Enzymes of the fatty acid synthase system do not form a cluster but exist as separate, individual Polypeptides.

Fig. 21-7. The fatty acid synthase molecule contains two catalytic SH groups essential for activity. One SH group belongs to the 4'-phosphopantetheine prosthetic group (Pp), and the other belongs to an active cysteine residue (Cys).

Both SH groups are involved in fatty acid synthesis. The sulfhydryl group of phosphopantetheine in ACP serves as the binding site for malonyl groups. The letter E designates the entire fatty acid synthase complex.