Chemistry Reference
In-Depth Information
Therefore,
we
could
consider
using
the
Claisen
reaction
in fatty acid synthesis.
Claisen reaction
O
O
O
O
O
O
H
3
C
SCoA
H
3
C
SCoA
H
3
C
SCoA
H
2
C
SCoA
SCoA
However, a more favourable pathway is used,
employing a more reactive nucleophile. Rather than
using the enolate anion derived from
acetyl-CoA
,
nature uses the enolate anion derived from malonyl-
CoA.
Malonyl-CoA
is obtained from acetyl-CoA
by means of an enzymic carboxylation reaction,
incorporating CO
2
(usually from the soluble form
bicarbonate). Now CO
2
is a particularly unreactive
material, so this reaction requires the input of energy
(from ATP) and the presence of a suitable coenzyme,
biotin
, as the carrier of CO
2
(see Section 15.9). The
conversion
of
acetyl-CoA
into
malonyl-CoA
in-
creases the acidity of the
-hydrogens, since the
acidic protons are flanked by two carbonyl groups,
and thus it is easier to generate a nucleophile for the
Claisen condensation. We should relate this to the
use of diethyl malonate rather than ethyl acetate as a
nucleophile in Section 10.9.
The Claisen reaction can now proceed smoothly,
but nature introduces another little twist. The car-
boxyl group introduced into malonyl-CoA is simul-
taneously lost by a decarboxylation reaction during
the Claisen condensation. Accordingly, we now see
that the carboxylation step helps to activate the
α
CO
2
O
-
carbon and facilitate Claisen condensation, and the
carboxyl is immediately removed on completion of
this task. An alternative rationalization is that decar-
boxylation of the malonyl ester is used to generate
the acetyl enolate anion without any requirement for
a strong base (see Box 10.17).
α
O
SCoA
ATP
CH
3
SCoA
CO
2
H
malonyl-CoA
biotin
acetyl-CoA
acetyl-CoA
carboxylase
O
O
O
O
CH
3
SCoA
CH
3
SCoA
CH
3
SCoA
CO
2
lost in
concerted
reaction
O
O
acetoacetyl-CoA
SCoA
SCoA
CO
2
repeat
malonyl-CoA
O
O
H
fatty acids
O
O
alternatively, enzyme
generates transient
enolate anion
SCoA
CH
2
SCoA
O
O
H
B
Enz
The processes of fatty acid biosynthesis are
catalysed by the enzyme
fatty acid synthase
.In
animals, this is a multifunctional protein containing
all of the catalytic activities required, whereas in
bacteria and plants it is an assembly of enzymes
that can be separated. Acetyl-CoA and malonyl-CoA
themselves are not involved in the condensation step:
they are converted into enzyme-bound
thioesters
.
