Chemistry Reference
In-Depth Information
The fatty acid synthase protein is known to contain an
acyl carrier protein
(ACP) binding site, and also
an active-site cysteine residue in the
β
-ketoacyl synthase domain. Acetyl and malonyl groups are successively
transferred from coenzyme A esters and attached to the thiol groups of Cys and ACP.
O
O
O
SH
malonyl-CoA
acetyl-CoA
S
CH
3
H
SH
S
O
Cys
Cys
ACP
ACP
(acetyl/malonyl transacylases)
fatty acid synthase
Claisen reaction
(
O
β
-ketoacyl synthase)
O
O
O
reduction
dehydration
reduction
S
SH
SH
SH
S
transfer
S
Cys
Cys
Cys
ACP
ACP
ACP
(β
-ketoacyl reductase;
β
-hydroxyacyl dehydratase;
enoyl reductase)
The Claisen condensation occurs, and the processes of reduction, dehydration, and reduction then occur whilst
the growing chain is attached to ACP. The ACP carries a
phosphopantetheine
group exactly analogous to that
in coenzyme A (pantothenic acid: vitamin B
5
). This phosphopantetheine group provides a long flexible arm,
enabling the growing fatty acid chain to reach the active site of each enzyme in the complex, and allowing the
different chemical reactions to be performed without releasing intermediates from the enzyme. The chain is then
transferred to the thiol of Cys, and the process can continue.
O
O
O
P
R
S
growing fatty
acyl chain
H
H
O
O
CH
2
Ser
ACP
OH
O
OH
pantetheine bound to serine
group of ACP through phosphate
cysteamine
pantothenic acid
phosphopantetheine
Making the process even more efficient, animal fatty acid synthase is a dimeric protein containing two catalytic
centres, and it is able to generate two growing chains at the same time. The monomeric subunits are also arranged
head to tail, so that the acyl group of one unit actually picks up a malonyl extender from the other unit. It
is interesting that the sequence of enzyme activities along the protein chain of the enzyme complex does not
correspond with the order in which they are employed.
dotted lines indicate two sites for
fatty acid synthesis, utilizing enzyme
activities from both subunits
KS MAT DH ER KR ACP TE
subunit-1
SH
SH
ACP: acyl carrier protein
DH: dehydratase
ER: enoylreductase
KR:
SH
SH
β
-ketoacylreductase
TE ACP KR ER DH MAT KS
subunit-2
KS:
-ketoacylsynthase
MAT: malonyl/acetyltransferase
TE: thioesterase
β
dimeric fatty acid synthase
A similar approach is employed in the formation of peptides such as peptide antibiotics (see Box 13.11). In
marked contrast to the ribosomal biosynthesis of proteins, where a biological production line interprets the genetic
