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MGH researchers describe new way to
identify, evolve novel enzymes
First technique that does not depend
on prior knowledge of enzyme's mechanism
BOSTON - August 15, 2007 - The intricate interplay of proteins
and other chemicals that underlies most biological activities requires
the participation of enzymes, specialized molecules that accelerate
chemical reactions between molecules. The creation of totally new
enzymes can help improve the synthesis of chemicals and pharmaceuticals,
devise new tools for molecular biology research, and develop new
therapies. In the August 16 issue of Nature, two Massachusetts
General Hospital (MGH) researchers describe a way of creating novel
enzymes that, for the first time, does not require prior understanding
of exactly how the enzymes work.
"To date, the only source of enzymes has been biology,"
says Jack Szostak, PhD, of the MGH Department of Molecular Biology,
the report's senior author. "Great efforts are going into modifying
and improving these natural enzymes, and our work demonstrates the
potential of evolving completely new enzymes in the laboratory."
Szostak and his co-author Burckhard Seelig, PhD, used a technique
called mRNA display -previously developed in Szostak's lab - that
allows the identification and amplification of proteins that fit
particular criteria. In order to create an enzyme that would stimulate
or catalyze the joining of two segments of RNA in a way that does
not occur naturally, they began by generating a library of 4 trillion
small proteins with slight variations in their sequences. Each protein
was then brought together with the RNA segments to be joined, called
substrates.
If a particular protein induced the RNA substrates to join, resulting
in a significantly larger molecule, that signified the protein was
an active enzyme. The investigators could select out the larger
RNA strands, generate more of the enzymes, and repeat the experiment.
The induction of random mutations to produce different forms of
the enzymes and reducing the time allowed for the splicing reaction
enabled the development of more efficient versions by means of guided
evolution.
Szostak notes that the final version of the enzyme they created
is quite small and still not very stable, but it is a starting point
to discovering additional strategies that may help improve its activity.
The same mRNA-display technique can also identify enzymes that break
down or otherwise modify their substrate molecules.
"We hope our work on optimizing this enzyme will demonstrate
that we can evolve catalysts with activity as good as that of naturally
occurring enzymes," Szostak explains. "We'd also like
to determine the 3D structure of our new enzyme to understand how
it binds to its relatively larger substrates and catalyzes the joining
of the two RNA strands." The Alex Rich Distinguished Investigator
in Molecular Biology at MGH, Szostak also is a professor of Genetics
at Harvard Medical School, a Howard Hughes Medical Institute investigator
and a member of the MGH Center for Computational and Integrative
Biology. This study was supported by a grant from the NASA Astrobiology
Institute, and Seelig's work was supported in part by the Emmy Noether-Program
of the Deutsche Forschungsgemeinschaft.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of nearly $500 million and
major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, systems biology, transplantation biology and photomedicine.
MGH and Brigham and Women's Hospital are founding members of Partners
HealthCare HealthCare System, a Boston-based integrated health care
delivery system.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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