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Topic Name: Researchers reveil key information about the fundamental biological processes inside a marine organism

Category: Biomedical

Research persons: Bradley Moore, Alessandra Eustáquio

Location: Scripps Institution of Oceanography, University of California, United States

Details

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.

Note for Marine biology

Marine biology is the scientific study of living organisms in the ocean or other marine or brackish bodies of water. Given that in biology many phyla, families and genera have some species that live in the sea and others that live on land, marine biology classifies species based on the environment rather than on taxonomy.
Marine life represents a vast resource, providing food, medicine, and raw materials, in addition to helping to support recreation and tourism all over the world. At a fundamental level, marine life helps determine the very nature of our planet. Marine organisms contribute significantly to the oxygen cycle, and are involved in the regulation of the earth's climate. Shorelines are in part shaped and protected by marine life, and some marine organisms even help create new land.

Note for Salinosporamide A

Salinosporamide A is a potent proteasome inhibitor used as an anticancer agent that recently entered phase I human clinical trials for the treatment of multiple myeloma only three years after its discovery. This novel marine natural product is produced by the recently described obligate marine bacterium Salinispora tropica which is found in ocean sediment. Salinosporamide A belongs to a family of compounds possessing a densely functionalized γ-lactam-β-lactone bicycle. In preliminary screening, a high percentage of the organic extracts of cultured Salinospora strains possessed antibiotic and anticancer activities, which suggests that these bacteria are an excellent resource for drug discovery. Salinospora strain CNB-392 was isolated from a heat-treated marine sediment sample and cytotoxicity-guided fractionation of the crude extract led to the isolation of salinosporamide A. Although salinosporamide A shares an identical bicyclic ring structure with omuralide, it is uniquely functionalized. Salinosporamide A displayed potent in vitro cytotoxicity against HCT-116 human colon carcinoma with an IC50 value of 11 ng mL-1.

In figure 1, A high-resolution X-ray representation of the new enzyme's structure.

In figure 2, Salinispora tropica

In figure 3, Alessandra Eustáquio and her colleagues in Brad Moore's laboratory discoverd a new enzyme and biological pathway in Salinispora tropica, a promising marine organism that creates a natural product being tested to treat cancer.