Researchers discover how a marine molecule becomes a powerful weapon against cancer

The salinosporamide A molecule, also called Marizomb, is in phase III clinical trials to treat glioblastoma, an aggressive brain cancer, in hospitals around the world. This drug was developed by researchers at Scripps Institution of Oceanography at UC San Diego (USA), from a marine microorganism.

Now, a team from the same institution has deciphered, for the first time, the enzymatic process that activates this molecule. The paper describes how an enzyme called SalC assembles what researchers call the anticancer ‘warhead’ of salinosporamide A. The study was published in Nature Chemical Biology.

“Our study solves a nearly 20-year-old puzzle about how this marine bacterium produces the warhead, which is unique to the salinosporamide molecule, and opens the door to future biotechnology to make new anticancer agents,” says Katherine Bauman, lead author of the study.

For his part, Bradley Moore, co-author and advisor to Bauman, highlights that “the fact that this mechanism is already known may serve in the future to use the enzymes in the production of other types of salinosporamides capable of attacking not only cancer, but also diseases of the immune system and infections caused by parasites.”

A marine bacterium discovered in 1990

Salinosporamide has a long history at Scripps and UC San Diego. The microbiologist Paul Jensen and the marine chemist Bill Fenical of Scripps discovered both salinosporamide A and the marine organism that produces the molecule, after collecting the microbe from tropical Atlantic Ocean sediments in 1990. Some of the clinical trials carried out over the course of the drug’s development took place at the Cancer Center at UC San Diego Health.

For Bauman, one of the big unknowns to be resolved was how many enzymes were responsible for folding the molecule into its active form. “I would bet on several enzymes involved. In the end, it was just SalC, which is surprising,” she adds.

Cultures to produce salinosporamide A, a potent anticancer agent currently in clinical trials to treat glioblastoma. /Erik Jepsen/UC San Diego

Moore points out that “the salinosporamide molecule has a special ability to cross the blood-brain barrier, which explains its progress in clinical trials for glioblastoma.” The expert details that its structure begins as a linear molecule that folds into a more complex circular shape.

The salinosporamide molecule has a special ability to cross the blood-brain barrier, which explains its progress in clinical trials for glioblastoma.

Bradley Moore, co-author

“We as chemists can’t do that, but nature made this molecule with a single enzyme, which is just wonderful,” says Moore.

Harmful to cancer cells

The enzyme involved is common in biology as it is involved in the production of fatty acids in humans and of antibiotics such as erythromycin in microbes.

The team determined the molecular structure of SalC. For that, they used the Advanced Light Source, a powerful particle accelerator that generates X-ray light, at Lawrence Berkeley National Laboratory.

The marine bacterium involved, called Salinispora tropica, manufactures salinosporamide to avoid being eaten by predators. But researchers have found that salinosporamide A can also treat cancer.

Other salinosporamides have been isolated previously, but salinosporamide A has characteristics that the others lack, including a biological activity that makes it harmful to cancer cells, the authors conclude.