20
Bioorganic Chemistry
such enzymes by arranging key catalytic
groups on an appropriate scaffold. A clas-
sic example of this is the development
of small molecules that mimic the en-
zymatic action of ribonuclease (described
above) by Breslow and coworkers. Using
cyclodextran as a scaffold, they covalently
attached two imidazole rings positioned
to mimic the key catalytic side chains of
the two histidines involved in catalysis by
ribonuclease. This molecule showed activ-
ity in hydrolyzing a model phosphodiester
in a manner analogous to ribonuclease
(Fig. 15).
4.3
Transition-state Analogs and Catalytic
Antibodies
Transition-state analogs are molecules that
closely resemble a reaction’s transition
state (i.e. the highest energy species in the
reaction pathway, more accurately known
as an activated complex) in shape and
charge. Enzymes are observed to bind
tightly
not to
the substrates
and the
products of the reaction that they catalyze
but rather to the transition state, the
highest energy species that forms during
O
O
O
O
O
O
O
O
O
O
O
O
HOH
2
C
HOH
2
C
CH
2
OH
CH
2
OH
OH
HO
HO
HO
OH
HO
OH
OH
OH
OH
HO
HO
N
N
N
N
O
P
O
O
O
HO
P
O
HO
O
Imidazole moieties mimic
catalytic histidines of
ribonuclease
Model substrate complexed
in interior of cyclodextran
Model phosphodiester
substrate hydrolyzed by
cyclodextran derivative
O
Fig. 15
Small-molecule mimic of RNase A, incorporating cyclodextran as a substrate binding site,
and two imidazole moieties for catalyzing hydrolysis of the indicated model substrate.
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