Key Trigger Discovered for Cancer-Fighting Marine Bacterium

This discovery could lead to new applications of the natural compounds in treating human diseases.

A research team led by Dr. Bradley Moore, a professor with marine biomedical laboratories at Scripps Institution of Oceanography at University of California, San Diego (UCSD; USA) and UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences, and postdoctoral researcher Alessandra Eustáquio, along with their colleagues at the Salk Institute for Biological Studies (San Diego, CA, USA), discovered an enzyme called SalL inside Salinispora tropica, a promising marine bacterium identified in 1991 by Scripps researchers.

As described in the January 2008 issue of the journal Nature Chemical Biology, the researchers also identified a unique process--a pathway--for the way the marine bacterium incorporates a chlorine atom, the vital ingredient for triggering its powerful cancer-fighting natural compound. Previously known methods for activating chlorine were processed through oxygen-based approaches. The new method, however, employs a substitution strategy that utilizes non-oxidized chlorine as it is found in nature, as with common table salt.

"This was a totally unexpected pathway,” said Dr. 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.”

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 Drs. Moore and Scripps' Daniel Udwary solved the genome of S. tropica in June 2007, an accomplishment that helped pave the way for the new discoveries.

Dr. Moore believes these 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 cannot 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 Dr. Moore.

At this point, it is unclear how pervasively SalL and its unique biologic activation pathway exist in the ocean environment. Chlorine is a major component of seawater and according to Dr. Moore, an essential 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 Dr. Moore.

According to Dr. 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.


Related Links:
Scripps Institution of Oceanography at University of California, San Diego
Salk Institute for Biological Studies