section 18 4

Synthesis of Long-Chain Saturated Fatty Acids

383

FIGURE 18-12

Diagram of a fatty acid synthase dimer with its head-to-tail association of the two multifunctional polypeptides.

KS = /S-Ketoacyl synthase; MT = malonyl transacylase; AT = acetyl transacylase; DH = dehydratase; ER = enoyl

reductase; KR = /3-ketoacyl reductase; ACP = acyl carrier site; TE = thioesterase. [Reproduced with permission from

S. J. Wakil, J. K. Stoops, and V. C. Joshi, Fatty acid synthesis and its regulation.

A n n u . Rev. B io ch em .

52,

537 (1983).

© 1983 by Annual Reviews Inc.]

Thioester hydrolase catalyzes the removal of palmitate

from the 4'-phosphopantetheine arm of the acyl carrier site.

O

II

CH3(CH2),4C— S— ACP + H20 -----►

CH3(CH2),4COOH + ACP— SH

The enzyme has an active serine residue and is specific for

long-chain acyl derivatives.

Functional Organization of Fatty Acid Synthase

In animal cells, fatty acid synthase (FAS) consists of two

subunits, each having a molecular weight of 250,000.

Evidence from negative-stain electron microscopy indi-

cates that FAS is a linear polypeptide with a series of

globular domains representing areas of catalytic activity.

Fatty acid synthase mRNA is large enough to code for the

~2300 amino acids required. Animal FAS is the largest

known multifunctional protein. Although each subunit

contains all of the catalytic activities required to synthesize

palmitate, the monomer lacks

-ketoacyl synthase activity.

The two subunits must be juxtaposed head to tail to bring

the cysteine-SH of the

/3

-ketoacyl synthase of one close

to the 4'-phosphopantetheine-SH of the acyl carrier site of

the other to obtain a fully functional dimer.

Figure 18-12 presents schematically the active FAS ho-

modimer complex. Synthesis may proceed from either end

of the active complex.

The assembly of rat liver FAS involves three stages: syn-

thesis of the multifunctional polypeptide chains, formation

of the dimer, and attachment of a 4'-phosphopantetheinc

group by an enzyme-catalyzed reaction. This assembly

process is influenced by changes in developmental, hor-

monal, and nutritional states. The FAS complex provides

considerable catalytic efficiency, since free intermediates

do not accumulate and the individual activities are present

in equal amounts.

The central role of the acyl carrier domain is to carry

acyl groups from one catalytic site to the next. The