Introduction to Enzyme and Coenzyme Chemistry - E-Library Home

266 Chapter 12
(1) Selective substrate binding. The catalyst must be able to bind its substrate
eVectively and speciWcally via a combination of electrostatic, hydrogenbonding
and hydrophobic interactions.
(2) Pre-organisation. The catalyst must have a rigid, well-deWned threedimensional
structure, so that when it binds its substrate there is little loss
of entropy in going to the transition state of the reaction.
(3) Catalytic groups. There must be suitably positioned catalytic groups arranged
convergently (i.e. pointing inwards towards the substrate), implying
that quite a large cavity is required.
(4) Physical properties. If the catalyst is to be useful in aqueous solution, it
should be water soluble, be able to bind its substrate in water, and be active
at close to pH 7.
These requirements turn out to be extremely demanding in practice, so there are
only a fairly small number of synthetic enzyme-like catalysts which have been
developed to date. However, this is a rapidly emerging area of research, so I will
give a few examples of current models and advise the interested reader to watch
this space!
Historically, the Wrst type of enzyme models developed by Cram used
cationic binding sites provided by ‘crown ethers’, a family of cyclic polyether
molecules with a high aYnity for metal ions. As well as binding metal ions,
crown ethers could bind substituted ammonium cations, which was exploited in
the design of the model shown in Figure 12.13. This model contains pendant
thiol groups that can act as catalytic groups for ester hydrolysis, analogous to
the cysteine proteases. This catalyst was found to accelerate the hydrolysis of
amino acid p-nitrophenyl esters in ethanol by 10 2 --10 3 -fold compared with an
acyclic version, showing the importance of pre-organisation of the catalyst.
This system also showed some enantioselectivity, being selective for d-amino
acid esters by 5–10-fold.
More recently, binding sites have been developed for anionic substrates.
One example developed by Hamilton is a small molecule containing two
gaunidinium side chains which is able to bind phosphodiesters via electrostatic
and hydrogen-bonding interactions. This system was able to accelerate the rate
of an intramolecular phosphodiester hydrolysis reaction shown in Figure 12.14
by 700-fold, presumably by a combination of transition state stabilisation and
protonation of the leaving group.
The most versatile family of enzyme models in current use are the cyclodextrins
developed by Breslow. These are a family of cyclic oligosaccharide molecules
which form a bucket-shaped cavity capable of forming tight complexes
with aromatic molecules. These systems oVer the advantages that the size of the
central cavity is quite large, the binding is eVective, they are water soluble, and
they contain pendant hydroxyl groups around the rim of the ‘bucket’ which can
be functionalised with catalytic groups.