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Most biological processes depend on enzymes, which are proteins that
speed up chemical reactions, but the function of many enzymes remains
a mystery.
�There are thousands of molecules that could be substrates [for a
specific enzyme], and it would take too long to physically test them
all,� Raushel said. �So we decided there was a need for a new method
to determine the function of enzymes.�
The team started with the three-dimensional X-ray structure of an
enzyme and then used a computer to try to fit different smaller
molecules into the active site of the enzyme like pieces in a puzzle.
�Each enzyme has a specific size and shape,� Raushel said, �and you
can use a computer to take small molecules and fit them into the
active site of an enzyme one by one and score them on how well they
fit. It�s more or less like fitting a key into a lock, but a lot more
difficult since both the enzyme and the substrate are conformationally
flexible.�
After the computer scores the molecules on how well they fit the
enzyme, it ranks their order, and the researchers can then use the
prioritized list to decide which molecules to physically test.
�As far as we know, this is the first time anybody has used molecular
docking to predict the function of an enzyme,� Raushel said. �And it
was verified by both experiment and X-ray crystallography.�
Other methods researchers use to try to determine an enzyme�s function
or substrate specificity include physically testing thousands of
possible molecules, gathering information from the nearby genes, and
comparing the structure of the enzyme to that of other enzymes with
known functions. �I think that in the end, we�ll have to use all of
these methods together,� Raushel said. �One single method just won�t
suffice.�
Raushel and his team plan to continue using their molecular docking
method to find the function of other enzymes.
�We�re looking at other X-ray structures of proteins that have unknown
functions, and we�re working to fill the gap,� Raushel said. �We�re
trying to see how general this method is going to be or if we were
just lucky in this particular case.�
Raushel and Texas A&M post-doctoral associate Ricardo Marti-Arbona
work in conjunction with Brian Shoichet at the University of
California, San Francisco, and Steven Almo from the Albert Einstein
College of Medicine in New York.
Raushel hopes that over the next five years, the team can start to use
its findings to locate potential targets for new drugs.
�Understanding the substrate specificity of certain enzymes could
allow researchers to differentiate enzymes that catalyze one reaction
in pathogenic organisms and a slightly different reaction in human
systems,� Raushel said. �This would allow scientists to design [drugs]
that would specifically target a pathogenic organism while not
affecting the human enzyme.�
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