Bioorganic Chemistry
21
the reaction. Enzymes have evolved to
use this strategy for catalysis. By forming
an
active
site
that
is
complementary
in shape and charge to the transition
state,
enzymes can stabilize
or lower
the energy of this species. The effect
of
this
is
to
accelerate
the
reaction
because the activation barrier is more
easily overcome. This complementarity
in charge and shape to the transition
state
is
readily
demonstrated
by
the
effectiveness of transition-state analogs as
enzyme inhibitors. A classic example of a
transition-state analog is a phosphonate-
containing
molecule
that
mimics
the
transition state of the hydrolysis of the
corresponding acyl
derivative
(Fig. 16).
When an ester is hydrolyzed, the central
carbonyl group changes from being planer
(sp
2
hybridization of the carbonyl carbon)
to being tetrahedral (sp
3
hybridization).
The
phosphonate-containing
analog
is
able
to
reproduce
the
shape
of
the
transition state as well as the partially
negatively charged oxygens. In addition,
it is chemically stable, whereas the actual
transition state exists only fleetingly. In
this example, an enzyme that catalyzed
the hydrolysis of this ester would also
bind tightly to the phosphonate analog.
Transition-state analogs are a successful
strategy for enzyme inhibition, one that
forms the basis of several drugs.
In addition to generating effective en-
zyme inhibitors, transition-state analogs
can be used to generate antibodies that
are capable of catalyzing chemical re-
actions (so-called ‘‘catalytic antibodies’’).
The theory underlying this approach is
that antibodies that are elicited against a
transition-state analog, and therefore have
the ability to bind them, will be chemi-
cally and sterically complementary to the
transition state and will therefore be po-
tentially capable of catalyzing the reaction.
The general strategy behind the produc-
tion of a catalytic antibody is to (1) design
and synthesize a molecule whose shape
and charge closely resemble that of the
transition state of the reaction one wishes
to catalyze, (2) tether this molecule to a
larger molecule, (3) elicit an immune re-
sponse to this conjugate, and (4) screen
the resultant monoclonal antibodies for
R
O
R
O
O
H
H
R
O
O
OH
R
dd
R
O
HO
OH
R
R
OH
O
HO
R
R
P
O
O
O
R
d
d
Transition state
Transition state analog:
mimics both charge and shape
of true transition state
Fig. 16
Comparison of transition-state structure and transition-state analog structure for an
ester hydrolysis.
previous page 695 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 697 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off