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The newly
discovered SalL enzyme.
Researchers uncover key trigger for potent Cancer-Fighting Marine product
Newswise — An
unexpected discovery in marine biomedical
laboratories at Scripps Institution of
Oceanography at UC San Diego has led to new,
key information about the fundamental
biological processes inside a marine
organism that creates a natural product
currently being tested to treat cancer in
humans.
The finding could lead
to new applications of the natural product
in treating human diseases.
A research team led by
Bradley Moore, a professor with UCSD’s
Scripps Oceanography Center for Marine
Biotechnology and Biomedicine and Skaggs
School of Pharmacy and Pharmaceutical
Sciences, and postdoctoral researcher
Alessandra Eustáquio, along with their
colleagues at the Salk Institute for
Biological Studies, discovered an enzyme
called SalL inside Salinispora tropica, a
promising marine bacterium identified in
1991 by Scripps researchers.
As they describe in the
most recent issue of Nature Chemical
Biology, the researchers also identified a
novel process—a “pathway”—for the way the
marine bacterium incorporates a chlorine
atom, the key ingredient for triggering its
potent cancer-fighting natural product.
Previously known methods for activating
chlorine were processed through oxygen-based
approaches. The new method, on the other
hand, employs a substitution strategy that
uses non-oxidized chlorine as it is found in
nature, as with common table salt.
“This was a totally
unexpected pathway,” said Moore. “There are
well over 2,000 chlorinated natural products
and this is the first example in which
chlorine is assimilated by this kind of
pathway,” said Moore.
The Salinispora
derivative “salinosporamide A” is currently
in phase I human clinical trials for the
treatment of multiple myeloma and other
cancers.
A team led by Moore and
Scripps’ Daniel Udwary solved the genome of
S. tropica in June, an achievement that
helped pave the way for the new discoveries.
Moore believes the
discoveries provide a new “road map” for
furthering S. tropica’s potential for drug
development. Knowing the pathway of how the
natural product is made biologically may
give biotechnology and pharmaceutical
scientists the ability to manipulate key
molecules to engineer new versions of
Salinispora-derived drugs. Genetic
engineering may allow the development of
second-generation compounds that can’t be
found in nature.
“It’s possible that
drug companies could manufacture this type
of drug in greater quantities now that we
know how nature makes it,” said Moore.
At this point it is
unclear how pervasively SalL and its unique
biological activation pathway exist in the
ocean environment. Chlorine is a major
component of seawater, and, according to
Moore, a fundamental component of
Salinispora’s disease-inhibiting abilities.
Salinosporamide A, for example, is 500 times
more potent than its chlorine-free analog
salinosporamide B.
“The chlorine atom in
salinosporamide A is key to the drug’s
irreversible binding to its biological
target and one of the reasons the drug is so
effective against cancer,” said Moore.
According to Eustáquio,
finding the enzyme and its new pathway also
carries implications for understanding
evolutionary developments, including clues
for how and why related enzymes are
activated in different ways.
Also joining Moore and
Eustáquio in the research were coauthors
Florence Pojer and Joseph Noel (of the
Howard Hughes Medical Institute, Jack H.
Skirball Center for Chemical Biology and
Proteomics, The Salk Institute for
Biological Studies), who developed
high-resolution X-ray structures and other
aspects of the research.
The work was supported
by the National Oceanic and Atmospheric
Administration, the National Institutes of
Health and the National Science Foundation.
Scripps Institution of
Oceanography at UC San Diego Center for
Marine Biotechnology and Biomedicine:
http://cmbb.ucsd.edu/
# # #
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Scripps Institution of
Oceanography: scripps.ucsd.edu
Scripps Institution of
Oceanography, at UC San Diego, is one of the
oldest, largest and most important centers
for global science research and graduate
training in the world.
The National Research
Council has ranked Scripps first in faculty
quality among oceanography programs
nationwide.
Now in its second
century of discovery, the scientific scope
of the institution has grown to include
biological, physical, chemical, geological,
geophysical and atmospheric studies of the
earth as a system.
Hundreds of research
programs covering a wide range of scientific
areas are under way today in 65 countries.
The institution has a
staff of about 1,300, and annual
expenditures of approximately $140 million
from federal, state and private sources.
Scripps operates one of the largest U.S.
academic fleets with four oceanographic
research ships and one research platform for
worldwide exploration.
