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Topic Name: Secrets of red tide
Category: Chemical
Research persons: Timothy F. Jamison,Ivan Vilotijevic
Location: 77 massachusetts avenue,cambridge, ma 02139-4307, United States
Details
In work that could one day help prevent millions of dollars in economic
losses for seaside communities, MIT chemists have demonstrated how tiny marine
organisms likely produce the red tide toxin that periodically shuts down U.S.
beaches and shellfish beds.
In the Aug. 31 cover story of Science, the MIT team describes an elegant
method for synthesizing the lethal components of red tides. The researchers
believe their method approximates the synthesis used by algae, a reaction that
chemists have tried for decades to replicate, without success.
Understanding how and why red tides occur could help scientists figure out
how to prevent the blooms, which cause significant ecological and economic
damage. The New England shellfish industry, for example, lost tens of millions
of dollars during a 2005 outbreak, and red tide killed 30 endangered manatees
off the coast of Florida this spring.
The discovery by MIT Associate Professor Timothy Jamison and graduate student
Ivan Vilotijevic not only could shed light on how algae known as dinoflagellates
generate red tides, but could also help speed up efforts to develop cystic
fibrosis drugs from a compound closely related to the toxin. Red tides, also
known as algal blooms, strike unpredictably and poison shellfish, making them
dangerous for humans to eat. It is unknown what causes dinoflagellates to
produce the red tide toxins, but it may be a defense mechanism, possibly
provoked by changes in the tides, temperature shifts or other environmental
stresses.
One of the primary toxic components of red tide is
brevetoxin, a large and
complex molecule that is very difficult to synthesize.
Twenty-two years ago, chemist
Koji Nakanishi of Columbia University proposed a cascade, or series of
chemical steps, that dinoflagellates could use to produce brevetoxin and other
red tide toxins. However, chemists have been unable to demonstrate such a
cascade in the laboratory, and many came to believe that the "Nakanishi
Hypothesis" would never be proven.
"A lot of people thought that this type of cascade may be impossible," said
Jamison. "Because Nakanishi's hypothesis accounts for so much of the complexity
in these toxins, it makes a lot of sense, but there hasn't really been any
evidence for it since it was first proposed."
Jamison and Vilotijevic's work offers the first evidence that Nakanishi's
hypothesis is feasible. Their work could also help accelerate drug discovery
efforts. Brevenal, another dinoflagellate product related to the red tide
toxins, has shown potential as a powerful treatment for cystic fibrosis (CF). It
can also protect against the effects of the toxins.
"Now that we can make these complex molecules quickly, we can hopefully
facilitate the search for even better protective agents and even more effective
CF therapies," said Jamison.
Until now, synthesizing just a few milligrams of red tide toxin or related
compounds, using a non-cascade method, required dozens of person-years of
effort.
The new synthesis depends on two critical factors-giving the reaction a jump
start and conducting the reaction in water.
Many red tide toxins possess a long chain of six-membered rings. However, the
starting materials for the cascades, epoxy alcohols, tend to form five-membered
rings. To overcome that, the researchers attached a "template" six-membered ring
to one end of the epoxy alcohol. That simple step effectively launches the
cascade of reactions that leads to the toxin chain, known as a ladder polyether.
"The trick is to give it a little push in the right direction and get it
running smoothly," said Jamison.
The researchers speculate that in
dinoflagellates, the
initial jump start is provided by an enzyme instead of a template.
Conducting the reaction in water is also key to a successful synthesis. Water
is normally considered a poor solvent for organic reactions, so most laboratory
reactions are performed in organic solvents. However, when Vilotijevic
introduced water into the reaction, he noticed that it proceeded much more
quickly and selectively.
Although it could be a coincidence that these cascades work best in water and
that dinoflagellates are marine organisms, water may nevertheless be directly
involved in the biosynthesis of the toxins or emulating an important part of it,
said Jamison. Because of this result, the researchers now believe that organic
chemists should routinely try certain reactions in water as well as organic
solvents
"This is an elegant piece of work with multiple levels of impact," said John
Schwab, who manages organic chemistry research for the National Institute of
General Medical Sciences. "Not only will it allow chemists to synthesize this
important class of complex molecules much more easily, but it also provides key
insights into how nature may make these same molecules. This is terrific bang
for the taxpayers' buck!"
About Researchers:
Timothy F. Jamison
Associate Professor of Chemistry
Room: 18-492
(617) 253-2135
Fax: (617) 258-7500
tfj@mit.edu
B. S. University of California, Berkeley 1990
Ph. D. Harvard University 1997
Ivan Vilotijevic
Education:
Massachusetts Institute of Technology, 2005 - present
Ph.D. candidate with Prof. Timothy F. Jamison
B.Sc. University of Belgrade, 2005
with Prof. Rado Markovic
research with Prof. Leo A. Paquette, Ohio State University
research with Prof. David Y. Gin, University of Illinois, Urbana
Current research:
Current research interests include development of epoxide opening cascade
reactions directed towards the synthesis of ladder polyether natural products.
Funded :
The research was funded by the National
Institute of General Medical Sciences, Merck
Research Laboratories,
Boehringer Ingelheim, and MIT.
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