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Biotechnology
50 June 2009 Speciality Chemicals Magazine
Using biological catalysts
for chemical synthesis
Dr Marc Struhalla, managing director of c-LEcta, looks at how biocatalysis has emerged as a key
technology for the manufacture of speciality chemicals
B
iotechnology is one of today's
most rapidly developing tech-
nology areas, leading to new
products being developed in many
different industries. One very
dynamic application area is the use
of biotechnological processes for the
production of speciality chemicals.
The use of enzymes or microor-
ganisms for the synthesis of chemical
products is referred to as biocatalysis.
These products range from high-
value chiral intermediates for the
pharmaceuticals industry to fine and
speciality chemicals for agrochemical,
cosmetic and food applications. Figure
1 shows the number of biocatalytic
processes implemented in industry
since 1960. About 65-70% of these
have been used in pharmaceutical
and agrochemical applications.
The use of biocatalysis in chemical
synthesis can be highly advanta-
geous by comparison with chemical
syntheses. Very often biocatalytic
processes make use of the high
stereo- and enantio-selectivity of the
enzymes, which can act in a highly
specific way on defined chemical
molecules, for instances allowing
direct chiral synthesis of high value
compounds.
Some very successful examples of
the direct use of enzymes for chiral
syntheses have been the use of
ketone reductases and transaminases
to transform ketones into high-value
chiral alcohols and chiral amines
respectively. In such applications, the
formation of the undesired enan-
tiomer is often undetectable, so very
high chiral purities are being
achieved.
In addition to high specificity, bio-
catalytic transformations also offer
the advantage of being run in very
moderate reaction conditions.
Usually they run at atmospheric
pressure, at low temperatures
(<100�C) and in aqueous reaction
systems. Toxic substances can be
avoided and solvent use reduced.
Finally, the use of biocatalysis often
allows a significant reduction in raw
material costs and of the number of
total synthesis steps needed within a
specific route.
Unfortunately, making use of the
potential advantages of biocatalysis
in practise is not that simple. Finding
the right biocatalyst for the desired
applications is a challenge, especially
when the relevant industries have
short development times.
All biocatalytic processes, whether
they use microorganism as biocata-
lysts in whole-cell transformations or
isolated enzymes, depend on the
provision of suitable enzymes with
defined properties. This search for
the ideal enzyme is a multi-parame-
ter process, depending on a number
of enzyme properties.
Enzymes have complex three-
dimensional protein structures, which
might be unstable under certain cir-
cumstances. Thus, parameters like
temperature, pH and the presence of
solvents, additives and by-products
must all be considered. Enzyme effi-
ciency with respect to space/time-
yields, inhibition effects and the eco-
nomics of producing the enzyme
itself is likewise of great importance.
Enzyme activity, in terms of its
specific activity, turnover rates, pH
and temperature profile, also plays a
crucial role. And, last but not least,
enzyme specificity with regard to its
substrate spectrum, enantio- and
regioselectivity needs to be consid-
ered. This complex matrix of enzyme
properties consisting of activity,
specificity, stability and efficiency
parameters makes the search for the
ideal enzyme for defined biocatalytic
applications a challenging task.
The enzymes used in industrial
biocatalysis are usually recombinant
enzymes produced in microorgan-
isms. These organisms are genetical-
ly modified in a way that they pro-
duce the desired enzyme with high
efficiency and large yields. Very
often, relatively crude enzyme prepa-
rations derived from microbial fer-
mentations are applied in the synthe-
sis processes. Work-up needs to be
simple in order to limit the enzyme
costs in the application.
The most straightforward way of
developing a biocatalytic process is to
make use initially of enzymes already
known to be available. Technology
companies focusing on the develop-
ment of biocatalytic processes are
building up large enzyme collections
in order to secure rapid access to fast
feasibility evaluations.
Nonetheless, the available
enzymes are not often adapted to
the specific needs of specific industri-
al applications. They might not show
the necessary turnover on the
desired substrate molecule or they
might bring along insufficient stere-
oselectivities.
At the end of the day, enzymes
are usually catalysts doing a very
specific job in their natural surround-
ings; they were not evolved by
nature to serve the demands of
industrial chemical synthesis. In these
instances, technologies are needed
to develop a new enzyme in a cus-
tomised way. One option, of course,
is to screen natural biodiversity for
new enzyme activities.
As shown in Figure 2, when
searching for adapted enzymes for
defined biocatalytic processes, fast
and efficient screening processes are
needed. Here, beginning with a
library stored as frozen cultures, the
candidate enzymes are produced by
cultivation in a micro-titreplate for-
mat, screened for interesting activi-
ties with a photometric assay, then
further characterised in a secondary
screen based on gas chromatogra-
phy analytics.
One commonly applied strategy is
to use microbial strain collections. In
these, microbial strain candidates are
0
50
100
150
200
250
300
1960 1970 1980 1990 2002 2008 2020
Year
Numberofimplemented
biocatalysisprocesses
?
Figure 1 - Biocatatalytics process implemented in industry, 1960-2020
Figure 2 - Screening natural biodiversity for new enzyme activities

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