596
THE ORGANIC CHEMISTRY OF INTERMEDIARY METABOLISM
Claisen
reaction
E
NADPH
NADPH
– H 2 O
malonyl-CoA
malonyl−SEnz
Enz−SH
acetyl-CoA
stereospecific
reduction of
carbonyl
E2 elimination
of H 2 O
reduction of
double bond
fatty acyl−SEnz
fatty acyl-CoA
fatty acid
each turn of the cycle extends
the chain length of the acyl
group by two carbons
β-hydroxyacyl−SEnz
β-ketoacyl−SEnz
α,β-unsaturated acyl−SEnz
acyl-enzyme thioester
O
CH 3
SCoA
O
SCoA
CO 2 H
O
SEnz
CO 2 H
O
RCH 2
SEnz
O
SEnz
RCH 2
O
O
SEnz
RCH 2
OH
H
O
SEnz
RCH 2
O
SEnz
RCH 2
O
SCoA
RCH 2
O
OH
RCH 2
Enz−SH
R
HSCoA
H 2 O
The Claisen reaction follows, giving the acetoacetyl thioester (β-ketoacyl–SEnz; R=H), which
is reduced stereospecifically to the corresponding βhydroxy ester, consuming NADPH in the reaction.
Then follows elimination of water, giving the E
(trans) α,β-unsaturated ester. Reduction of the double
bond again utilizes NADPH and generates a saturated
acyl–SEnz (fatty acyl–SEnz; R=H) that is two carbons longer than the starting material. This can feed
back into the system, condensing again with malonyl
thioester, and going through successive reduction,
dehydration and reduction steps, gradually increasing
the chain length by two carbons for each cycle, until
the required chain length is obtained. At that point,
the fatty acyl chain can be released as a fatty acylCoA or as the free acid. The chain length actually
elaborated is probably controlled by the specificity
of the thioesterase enzymes that subsequently catalyse release from the enzyme. Note that the reduction, dehydration, reduction steps are essentially the
reverse of the oxidation, hydration, oxidation steps
in fatty acid metabolism, though the enzymes and
coenzymes involved are different.
Box 15.2
Fatty acid synthase
Fatty acid synthesis is catalysed in animals by the enzyme fatty acid synthase, which is a multifunctional protein
containing all of the catalytic activities required. Bearing in mind the necessity to provide a specific binding site
for the various substrates involved, and then the fairly complex sequence of reactions carried out, it raises the
question of just how it is possible for this process to be achieved at the enzymic level. Nature has devised an
elaborate but satisfyingly simple answer to this problem.
THE ORGANIC CHEMISTRY OF INTERMEDIARY METABOLISM
Claisen
reaction
E
NADPH
NADPH
– H 2 O
malonyl-CoA
malonyl−SEnz
Enz−SH
acetyl-CoA
stereospecific
reduction of
carbonyl
E2 elimination
of H 2 O
reduction of
double bond
fatty acyl−SEnz
fatty acyl-CoA
fatty acid
each turn of the cycle extends
the chain length of the acyl
group by two carbons
β-hydroxyacyl−SEnz
β-ketoacyl−SEnz
α,β-unsaturated acyl−SEnz
acyl-enzyme thioester
O
CH 3
SCoA
O
SCoA
CO 2 H
O
SEnz
CO 2 H
O
RCH 2
SEnz
O
SEnz
RCH 2
O
O
SEnz
RCH 2
OH
H
O
SEnz
RCH 2
O
SEnz
RCH 2
O
SCoA
RCH 2
O
OH
RCH 2
Enz−SH
R
HSCoA
H 2 O
The Claisen reaction follows, giving the acetoacetyl thioester (β-ketoacyl–SEnz; R=H), which
is reduced stereospecifically to the corresponding βhydroxy ester, consuming NADPH in the reaction.
Then follows elimination of water, giving the E
(trans) α,β-unsaturated ester. Reduction of the double
bond again utilizes NADPH and generates a saturated
acyl–SEnz (fatty acyl–SEnz; R=H) that is two carbons longer than the starting material. This can feed
back into the system, condensing again with malonyl
thioester, and going through successive reduction,
dehydration and reduction steps, gradually increasing
the chain length by two carbons for each cycle, until
the required chain length is obtained. At that point,
the fatty acyl chain can be released as a fatty acylCoA or as the free acid. The chain length actually
elaborated is probably controlled by the specificity
of the thioesterase enzymes that subsequently catalyse release from the enzyme. Note that the reduction, dehydration, reduction steps are essentially the
reverse of the oxidation, hydration, oxidation steps
in fatty acid metabolism, though the enzymes and
coenzymes involved are different.
Box 15.2
Fatty acid synthase
Fatty acid synthesis is catalysed in animals by the enzyme fatty acid synthase, which is a multifunctional protein
containing all of the catalytic activities required. Bearing in mind the necessity to provide a specific binding site
for the various substrates involved, and then the fairly complex sequence of reactions carried out, it raises the
question of just how it is possible for this process to be achieved at the enzymic level. Nature has devised an
elaborate but satisfyingly simple answer to this problem.