SYNTHESIS OF FATTY ACIDS
597
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.
SH
Cys
ACP
SH
S
Cys
CH 3
O
H
O
O
O
SH
Cys
O
O
SH
Cys
O
S
Cys
O
acetyl-CoA malonyl-CoA
Claisen reaction
(β-ketoacyl synthase)
reduction
dehydration
reduction
transfer
fatty acid synthase
(acetyl/malonyl transacylases)
(β-ketoacyl reductase;
β-hydroxyacyl dehydratase;
enoyl reductase)
ACP
S
ACP
S
ACP
S
ACP
SH
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.
S
N
H
N
H
O
O
O
OH
R
O
P
O
OH
O
CH 2 Ser ACP
phosphopantetheine
pantothenic acid
cysteamine
pantetheine bound to serine
group of ACP through phosphate
growing fatty
acyl chain
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.
TE ACP KR ER
DH MAT KS
dotted lines indicate two sites for
fatty acid synthesis, utilizing enzyme
activities from both subunits
SH
SH
dimeric fatty acid synthase
SH
SH
ACP: acyl carrier protein
DH: dehydratase
ER: enoylreductase
KR: β-ketoacylreductase
KS: β-ketoacylsynthase
MAT: malonyl/acetyltransferase
TE: thioesterase
KS MAT DH
ER KR ACP TE
subunit-1
subunit-2
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
597
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.
SH
Cys
ACP
SH
S
Cys
CH 3
O
H
O
O
O
SH
Cys
O
O
SH
Cys
O
S
Cys
O
acetyl-CoA malonyl-CoA
Claisen reaction
(β-ketoacyl synthase)
reduction
dehydration
reduction
transfer
fatty acid synthase
(acetyl/malonyl transacylases)
(β-ketoacyl reductase;
β-hydroxyacyl dehydratase;
enoyl reductase)
ACP
S
ACP
S
ACP
S
ACP
SH
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.
S
N
H
N
H
O
O
O
OH
R
O
P
O
OH
O
CH 2 Ser ACP
phosphopantetheine
pantothenic acid
cysteamine
pantetheine bound to serine
group of ACP through phosphate
growing fatty
acyl chain
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.
TE ACP KR ER
DH MAT KS
dotted lines indicate two sites for
fatty acid synthesis, utilizing enzyme
activities from both subunits
SH
SH
dimeric fatty acid synthase
SH
SH
ACP: acyl carrier protein
DH: dehydratase
ER: enoylreductase
KR: β-ketoacylreductase
KS: β-ketoacylsynthase
MAT: malonyl/acetyltransferase
TE: thioesterase
KS MAT DH
ER KR ACP TE
subunit-1
subunit-2
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