Page 52 - Visions of the Future Chemistry and Life Science

Enzymology takes a quantum leap forward 41

‘Lock and Key’ mechanism propounded by Emil Fischer – in which the
enzyme accommodates a specific substrate like a lock does a key – opened
the door to our understanding of enzyme catalysis. This has evolved to take
account of protein motion in the ‘Induced Fit’ model of catalysis in which
the enzyme has one conformation in the absence, and another conforma-
tion in the presence, of substrate. The induced fit model of catalysis recog-
nises preferred complementarity to the transition state and has provided a
conceptual framework for transition state theory. Now, moving into the
new Millennium, our understanding has progressed yet further by high-
lighting the role of (i) protein dynamics and (ii) quantum tunnelling in
enzyme catalysis. Thus, the rules underpinning our design and understand-
ing of enzymes have changed significantly. Important areas where these
rules apply include enzyme redesign, the production of catalytic antibod-
ies, design of enzyme inhibitors (drugs and pesticides), enzymatic fine
chemical synthesis and use of enzymes in bulk processing (e.g. paper man-
ufacture, food industry and detergents).
Enzyme redesign strategies currently attempt to reduce the activation
energy (i.e. the barrier height) by seeking maximum complementarity with
the transition state and destabilisation of the ground state. This is the
approach adopted in producing catalytic antibodies. Here, an animal’s
immune system is exposed to a transition state analogue, thus inducing
antibodies with surface complementarity to the transition state. Although
in principle this is an elegant approach to producing novel catalysts, in
practice it is usual for catalytic antibodies to have poor catalytic rates.
These studies imply that knowledge of the transition state alone is not suf-
ficient to develop a good catalyst. Insight into additional factors required
for efficient catalysis has come from recent work. An important determi-
nant of catalytic efficiency is the role of protein dynamics. The structural
plasticity of protein molecules is important in driving both classical and
quantum mechanical transfers. As we have seen, in quantum mechanical
transfers distortion of the enzyme molecule transiently compresses barrier
width and equalises reactant and product energy states. In contrast to clas-
sical models of catalysis, for vibrationally driven ground state tunnelling
maximum complementarity with the ground state should be sought.
Additionally, the exclusion of water will reduce the mass of the transferred
particle (thus increasing tunnelling probability). The challenge will there-
fore be to incorporate these new aspects into programmes of rational
enzyme redesign and to provide a unified theory for enzyme catalysed reac-
tions. Over the past century, our understanding of catalysis has been based