An Unexpected Pathway

Two discoveries reveal clues about cancer-fighting marine product

Scripps Institution of Oceanography at UC San Diego Professor Brad Moore and postdoctoral researcher Alessandra Eustáquio have made an intriguing two-part discovery in the search for beneficial drugs that originate in the oceans.

First, they recently identified a key, previously unknown enzyme within Salinispora tropica, an ocean-dwelling bacteria species that produces chemicals with potential value in cancer drugs or antibiotics.

After uncovering the new enzyme, which they called "SalL," part two of their search turned to how the organism incorporates chlorine, the key ingredient for triggering the organism's potent cancer-fighting products.

Eustáquio examined four processes, or "biological pathways," that similar natural products use for incorporating chlorine. To the team's surprise, none of them worked. This led to the realization that Eustáquio had discovered a novel mechanism for chlorine incorporation, a new fifth biological pathway.

"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."

According to Moore, the two discoveries offer a road map that could boost Salinispora's prospects as a source of disease treatment. Knowing the pathway for how the compounds are produced in nature may help biotechnologists manipulate key molecules to engineer new versions of Salinispora-based drugs. Genetic engineers may now be able to make 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.

Salinispora, a microbe discovered by Scripps researchers 17 years ago in shallow sediment off the Bahamas, produces natural compounds that have shown promise in marine-based drug development. Salinispora's derivative, "salinosporamide A," is in phase 1 human clinical trials for treating multiple myeloma and other cancers.

The discoveries also help marine chemists understand more about the prevalence of chlorine, a major component of seawater and a fundamental component of Salinispora's cancer-fighting properties, in the ocean. For example, salinosporamide A is some 500 times more potent than salinosporamide B, its chlorine-free analog.

Eustáquio believes the new discoveries also carry implications for understanding evolutionary development, including how and why related enzymes are activated differently.

Both discoveries were described in Nature Chemical Biology. Moore and Eustáquio were joined in the research by Florence Pojer and Joseph Noel of the Howard Hughes Medical Institute of the Salk Institute for Biological Studies. The National Oceanic and Atmospheric Administration, the National Institutes of Health and the National Science Foundation supported the research.

Mario C. Aguilera