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158 Chapter 7
O
H
− OH
O −
O
H OH
O O − O OH
Figure 7.2 Aldol reaction.
Carbon–carbon bond formation via carbanion
equivalents
7.2 Aldolases
The aldol reaction involves the condensation of two carbonyl compounds via
an enolate intermediate. The reaction is illustrated in Figure 7.2 for the case
of the self-condensation of acetone in alkaline aqueous solution. A wide range
of aldol reactions occur in biological systems that are used for the formation of
carbon–carbon bonds. Cleavage of carbon–carbon bonds by the reverse reaction
is also found.
The enzymes which catalyse these aldol reactions are known as aldolases,
and they are divided into two families based on their mechanism of action. The
class I aldolases function by formation of an imine linkage between one
carbonyl reagent and the e-amino group of an active site lysine residue,
followed by deprotonation of the adjacent carbon to generate an enamine
intermediate. Enamines are well-known enolate equivalents in synthetic organic
chemistry: they can be formed under mild conditions by condensation of the
carbonyl compound with a primary or secondary amine, and they react with
carbonyl compounds also under mild conditions.
The class II aldolases do not proceed through enamine intermediates but
instead use a metal ion to assist catalysis. The metal ion is usually a divalent
metal ion such as Mg 2þ ,Mn 2þ or Zn 2þ . The two classes are exempliWed by the
enzyme fructose-1,6-bisphosphate aldolase, which is found in mammals as a
class I enzyme, and in bacteria as a class II enzyme.
CASE STUDY: Fructose-1,6-bisphosphate aldolase
Fructose-1,6-bisphosphate aldolase catalyses the reversible reaction of dihydroxyacetone
phosphate (DHAP) with glyceraldehyde 3-phosphate (G3P) to
give fructose-1,6-bisphosphate, shown in Figure 7.3.
O OH
fructose-1,6-bisphosphate
O
2− aldolase
O 3 PO
2− O 3 PO
2−
OPO +
3
OH OH
OH
fructose-1,6-bisphosphate
dihydroxyacetone-1-phosphate
Figure 7.3 Reaction catalysed by fructose-1,6-bisphosphate aldolase.
O
2−
OPO 3
OH
glyceraldehyde-3-phosphate