Deep-sea microbes provide a rich source of medicinally effective drugs.
Years of work in the lab has shown how a marine bacterium makes a potent anti-cancer molecule.
The anti-cancer molecule salinosporamide A, also known as marizomb, is in Phase III clinical trials for the treatment of glioblastoma, a brain tumor. Scientists now understand for the first time the enzyme-driven process that activates the molecule.
Researchers at UC San Diego’s Scripps Institution of Oceanography found that an enzyme called SalC assembles what the team calls the salinosporamide anticancer “warhead.” Scripps student Katherine Bauman is the lead author of an article that explains the assembly process in the March 21 issue natural chemical biology.
The work solves a nearly 20-year-old mystery about how the marine bacterium makes the warhead unique to the salinosporamide molecule and opens the door to future biotechnology to create new anti-cancer drugs.
“Now that scientists understand how this enzyme makes the salinosporamide A warhead, this discovery could be used in the future to use enzymes to make other types of salinosporamides that not only kill cancer, but also diseases of the immune system and infections caused by parasites.” could attack,” said co-author Bradley Moore, a distinguished professor at Scripps Oceanography and the Skaggs School of Pharmacy and Pharmaceutical Sciences.
Salisporamide has a long history at Scripps and UC San Diego. Microbiologist Paul Jensen and marine chemist Bill Fenical of Scripps Oceanography discovered both salinosporamide A and the marine organism that produces the molecule after collecting it the microbe from sediments of the tropical Atlantic in 1990. Some of the clinical trials over the course of the drug’s development took place at UC San Diego Health’s Moores Cancer Center.
“This has been a very challenging 10-year project,” said Moore, who is a consultant to Bauman. “Kate was able to pull together 10 years of previous work to get us across the finish line.”
A big question for Bauman was figuring out how many enzymes are responsible for folding the molecule into its active form. Are multiple enzymes involved or just one?
“I would have bet money on more than one. In the end it was just SalC. That was surprising,” she said.
According to Moore, the salinosporamide molecule has a special ability to cross the blood-brain barrier, which accounts for its advances in clinical trials for glioblastoma. The molecule has a small but complex ring structure. It starts out as a linear molecule that folds into a more complex circular shape.
“The way nature does it is wonderfully simple. We as chemists can’t do what nature did to make this molecule, but nature does it with a single enzyme,” he said.
The enzyme involved is widespread in biology; it is one involved in the production of fatty acids in humans and antibiotics such as erythromycin in microbes.
Bauman, Percival Yang-Ting Chen of Morphic Therapeutics in Waltham, Massachusetts, and Daniella Trivella of Brazil’s National Center for Energy and Materials Research determined the molecular structure of SalC. To do this, they used the Advanced Light Source, a powerful particle accelerator that produces X-rays, at the US Department of Energy’s Lawrence Berkeley National Laboratory.
“The SalC enzyme performs a reaction that is very different from a normal ketosynthase,” Bauman said. A normal ketosynthase is an enzyme that helps a molecule form a linear chain. In contrast, SalC produces salinosporamide by forming two complex, reactive ring structures.
A single enzyme can form both ring structures, which are difficult for synthetic chemists to make in the laboratory. Armed with this information, scientists can now mutate the enzyme until they find forms that show promise for suppressing different types of diseases.
The marine bacterium involved, called Salinispora tropica, makes salinosporamide to avoid being eaten by its predators. But scientists have found that salinosporamide A can also treat cancer. They have isolated other salinosporamides, but salinosporamide A has properties the others lack – including a biological activity that makes it dangerous to cancer cells.
“Inhibiting this proteasome makes it a great anti-cancer agent,” Bauman said, speaking of the protein complex breaking down useless or impaired proteins. But there is another type of proteasome found in immune cells. What if scientists could create a slightly different salinosporamide than salinosporamide A? One that weakly inhibits the cancer-prone proteasome but is excellent at inhibiting the immune proteasome? Such a salinosporamide could be a highly selective treatment for autoimmune diseases, the kind that causes the immune system to turn against the body it’s supposed to protect.
“That’s the idea behind making some of these other salinosoporamides. And access to this enzyme, SalC, which installs the complicated ring structure, opens the door to that in the future,” Bauman said.
As confirmed by Bauman’s list of co-authors, Moore’s group began work on this project more than a decade ago. Former Moore Lab postdocs who have contributed are Tobias Gulder from Technische Universität Dresden; Daniela Trivella from the Brazilian National Center for Energy and Materials Research; and Percival Yang-Ting Chen of Morphic Therapeutics in Waltham, Massachusetts. Vikram V. Shende is currently a postdoctoral fellow at the Moore Lab. The other two co-authors are long-time collaborators on the project: Sreekumar Vellaath and Daniel Romo from Baylor University.
Reference: “Enzymatic assembly of the salinosporamide γ-lactam-ß-lactone anticancer warhead” March 21, 2022, natural chemical biology.
Bauman’s work is funded by a National Research Service Award from the National Institutes of Health. Additional funding was provided by the Robert A. Welch Foundation and the São Paulo Research Foundation.
https://scitechdaily.com/scientists-discover-how-molecule-from-deep-sea-microbe-becomes-potent-anticancer-weapon/ Scientists discover how a molecule from a deep-sea microbe becomes a powerful weapon against cancer