section 18 4
Synthesis of Long-Chain Saturated Fatty Acids
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 .
© 1983 by Annual Reviews Inc.]
Thioester hydrolase catalyzes the removal of palmitate
from the 4'-phosphopantetheine arm of the acyl carrier site.
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
-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