Scripps Scientists Discover How Sea Microbe Makes Cancer-Fighting “Warhead”

Researchers from the Scripps Institution of Oceanography at the University of California (UC) San Diego have shown how a molecule made by a sea bacterium turns into a potent cancer-fighting weapon.

Brain Tumors

Brain Tumors

These scientists have been on the research for decades. For the first time, they have a good understanding of the process leading to the activation of the molecule called salinosporamide A.

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The team discovered that an enzyme known as SalC is responsible for building what researchers tag as the molecule’s “warhead.”

The study unravels a mystery that researchers have been contending with for almost two decades. It appeared in the journal Nature Chemical Biology, with Scripps Ph.D. student Kate Bauman as the lead author.

“This has been a very challenging 10-year project,” said co-author Bradley Moore, Bauman’s advisor and a Distinguished Professor at Scripps Oceanography. “Kate’s been able to bring together 10 years’ worth of earlier work to get us across the finish line.”

The findings could help in guiding the development of new anticancer treatments in the future.

This anticancer agent, also known under the name Marizomb, is undergoing Phase III clinical trials for the treatment of glioblastoma.

The anticancer molecule

Salinosporamide is a protective agent for the bacterium that makes it. Salinispora tropica produces the molecule to keep itself from being eaten by predators. But scientists have also found that salinosporamide A can combat cancer.

Apart from this particular molecule, scientists have also isolated other salinosporamides. None of the others have the ability to kill cancer cells, however.

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Researchers at UC San Diego and Scripps have been studying this molecule for a long time. Paul Jensen, a microbiologist, and Bill Fenical, a marine chemist, discovered it alongside the bacterium making it after collecting tropical Atlantic Ocean sediments back in 1990.

Salinosporamide A displays an impressive ability to traverse the blood-brain barrier. This explains the promising results it has been showing in clinical trials for treating the brain cancer glioblastoma.

Starting as a linear molecule, salinosporamide develops into a complex ring structure over time.

How the drug is activated

Researchers thought that multiple enzymes were involved in the intricate folding that makes the molecule active. But they were surprised to find that only SalC played a part.

This enzyme is not a new one. Scientists have known it to play a role in fatty acid production in human beings. It is also used for the production of antibiotics in microbes.

Bauman said the SalC enzyme drives a reaction that is quite different from a regular ketosynthase that produces a linear chain. It instead forms a pair of complex and reactive ring structures – a feat that chemists cannot easily pull off.

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This discovery could aid scientists in creating enzyme mutations that may help fight diverse diseases. Moore stated that enzymes could be used to produce salinosporamides for fighting parasitic infections and immune-related disorders one day.

“That’s the idea behind generating some of these other salinosoporamides,” Bauman explained. “And access to this enzyme SalC that installs the complicated ring structure opens the door to that in the future.”

Researchers made use of the Advanced Light Source, a strong particle accelerator, to uncover the SalC enzyme’s molecular structure.

Several other researchers have been involved in this project, which has been on for more than 10 years. A number of trials in the course of developing the anticancer drug were done at UC San Diego Health’s Moores Cancer Center.

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References

Enzymatic assembly of the salinosporamide γ-lactam-β-lactone anticancer warhead

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