Chemists from the University of California - Los Angeles (UCLA) and the
University of Washington (UW) have succeeded in creating
designer enzymes for
reactions not normally catalyzed in nature, opening the
door for scientists to control the very reactions that sustain life.
Reporting their results in the journal Nature,
the
researchers said the designer enzymes will have applications in
biological warfare and for creating more effective medications. The
work to date has been funded by DARPA, the U.S. Defense Department''s
central research and development organization.
"The
design of new enzymes for reactions not normally catalyzed in
nature is finally feasible," said UCLA team leader Kendall Houk. "The
goal of our research is to use computational methods to design the
arrangement of groups inside a protein to cause any desired reaction to
occur." To demonstrate the feasibility of this approach, the
researchers created designer enzymes for a
chemical reaction known as
the Kemp elimination, a non-natural chemical transformation in which
hydrogen is pulled off a carbon atom.
"Enzymes are such potent catalysts; we want to harness that catalytic
ability," said UCLA co-researcher Jason DeChancie. "We want to design
enzymes for reactions that naturally occurring enzymes don''t do. There
are limits on the reactions that natural enzymes carry out, compared
with what we can dream up that enzymes can potentially do."
The researchers also reported another successful chemical reaction that
used designer enzymes to catalyze a retro-aldol reaction, which
involves breaking a carbon-carbon bond. The
aldol reaction is a key
process in living organisms associated with the processing and
synthesis of carbohydrates. This reaction is also widely used in the
large-scale production of commodity chemicals and in the pharmaceutical
industry.
The implementation of the aldol reaction was an important challenge,
according to Houk, as the reaction involves at least six chemical
transformations, requiring UCLA scientists to compute all six chemical
steps with their corresponding transition states. The structures were
then combined in such a way to allow all six steps to occur.
Houk''s group uses computational methods based on the physical laws of
quantum mechanics to study in detail the mechanisms of chemical
reactions. By exploring multiple combinations of chemical groups, they
can determine those that are most suitable to facilitate any given
chemical transformation. Then, they determine the precise
three-dimensional arrangement of these chemical groups, which is
critical for the specificity and activity of the enzyme.
The UCLA researchers then provide a blueprint for the active site to
their UW colleagues, headed up by biochemist David Baker, who then
design a sequence of amino acids that fold to produce an active site
like the one designed by Houk''s group.
How far off are designer enzymes with important applications? "I think
we''re there," said UCLA''s DeChancie. "These papers are showing the
technology is now in place."
More abstracts about the Roll-Your-Own Enzymes A Reality