Scripps Institution of Oceanography Ph.D. student Kate Bauman streaks new Salinispora cultures for additional study in a biosafety cabinet with lab director Bradley Moore. These bacterial cultures produce salinosporamide A, a potent anticancer agent currently in stage III clinical trials for glioblastoma. Credit: Erik Jepsen/UC San Diego
Deep-sea microbe provides rich source of medically powerful drugs.
Years of labor in the laboratory have revealed how a marine bacterium makes a potent anti-cancer molecule.
The anti-cancer particle salinosporamide A, likewise called Marizomb, is in Phase III clinical trials to deal with glioblastoma, a brain cancer. Scientists now for the first time understand the enzyme-driven process that activates the particle.
Researchers at UC San Diegos Scripps Institution of Oceanography discovered that an enzyme called SalC assembles what the team calls the salinosporamide anti-cancer “warhead.” Scripps college student Katherine Bauman is the lead author of a paper that discusses the assembly process in the March 21 issue of Nature Chemical Biology.
These bacterial cultures produce salinosporamide A, a powerful anticancer representative currently in phase III scientific trials for glioblastoma. Microbiologist Paul Jensen and marine chemist Bill Fenical of Scripps Oceanography discovered both salinosporamide A and the marine organism that produces the molecule after gathering the microbe from sediments of the tropical Atlantic Ocean in 1990. Moore says the salinosporamide particle has a special capability to cross the blood-brain barrier, which accounts for its development in clinical trials for glioblastoma. They have separated other salinosporamides, however salinosporamide A has features that the others do not have– including biological activity that makes it hazardous to cancer cells.
What if scientists could design a somewhat different salinosporamide than salinosporamide A?
The work resolves an almost 20-year riddle about how the marine germs makes the warhead that is special to the salinosporamide molecule and unlocks to future biotechnology to make brand-new anti-cancer agents.
” Now that scientists comprehend how this enzyme makes the salinosporamide A warhead, that discovery could be used in the future to utilize enzymes to produce other kinds of salinosporamides that could assault not just cancer however diseases of the body immune system and infections caused by parasites,” said co-author Bradley Moore, a Distinguished Professor at Scripps Oceanography and the Skaggs School of Pharmacy and Pharmaceutical Sciences.
Salinispora cultures in the Moore Lab at UC San Diegos Scripps Institution of Oceanography. These bacterial cultures produce salinosporamide A, a powerful anticancer currently in stage III clinical trials to treat glioblastoma. Credit: Erik Jepsen/UC San Diego
Salisporamide has a long history at Scripps and UC San Diego. Microbiologist Paul Jensen and marine chemist Bill Fenical of Scripps Oceanography found both salinosporamide A and the marine organism that produces the particle after gathering the microbe from sediments of the tropical Atlantic Ocean in 1990. Some of the scientific trials throughout the drugs advancement took location at Moores Cancer Center at UC San Diego Health.
” This has actually been a really tough 10-year project,” stated Moore, who is Baumans advisor. “Kates had the ability to unite 10 years worth of earlier work to get us throughout the finish line.”
A huge question for Bauman was to discover how numerous enzymes were accountable for folding the particle into its active shape. Are numerous enzymes included or simply one?
” I would have wager cash on more than one. In the end, it was simply SalC. That was surprising,” she said.
Moore says the salinosporamide particle has a special capability to cross the blood-brain barrier, which represents its development in scientific trials for glioblastoma. The particle has a complex but small ring structure. It starts as a direct molecule that folds into a more complicated circular shape.
” The method nature makes it is perfectly simple. We as chemists cant do what nature has done to make this particle, but nature does it with a single enzyme,” he said.
The enzyme involved prevails in biology; it is one that takes part in the production of fatty acids in humans and antibiotics like erythromycin in microbes.
Bauman, Percival Yang-Ting Chen of Morphic Therapeutics in Waltham, Mass., and Daniella Trivella of Brazils National Center for Research in Energy and Materials, identified the molecular structure of SalC. For this purpose they used the Advanced Light Source, an effective particle accelerator that creates x-ray light, at the U.S. Department of Energys Lawrence Berkeley National Laboratory.
” The SalC enzyme performs a reaction extremely different from a typical ketosynthase,” Bauman stated. A typical ketosynthase is an enzyme that assists a particle form a direct chain. SalC, by contrast, manufactures salinosporamide by forming 2 complex, reactive, ring structures.
A single enzyme can form both of those ring structures that are tough for synthetic chemists to make in the lab. Armed with this information, scientists now can mutate the enzyme till they discover forms that reveal guarantee for reducing various types of disease.
The marine germs included, called Salinispora tropica, makes salinosporamide to prevent being eaten by its predators. However researchers have discovered that salinosporamide An also can deal with cancer. They have actually isolated other salinosporamides, however salinosporamide A has features that the others do not have– consisting of biological activity that makes it dangerous to cancer cells.
What if researchers could devise a somewhat various salinosporamide than salinosporamide A? Such a salinosporamide might be a highly selective treatment for autoimmune illness, the type that triggers the immune system to turn upon the really body it should protect.
” Thats the concept behind producing a few of these other salinosoporamides. And access to this enzyme SalC that sets up the complicated ring structure unlocks to that in the future,” Bauman said.
As Baumans list of co-authors attests, Moores group started working on this project more than a decade earlier. Former Moore Lab postdoctoral scientists who contributed are Tobias Gulder of Germanys Technical University of Dresden; Daniela Trivella of Brazils National Center for Research in Energy and Materials; and Percival Yang-Ting Chen of Morphic Therapeutics in Waltham, Mass.
Reference: “Enzymatic assembly of the salinosporamide γ-lactam-ß-lactone anticancer warhead” 21 March 2022, Nature Chemical Biology.DOI: 10.1038/ s41589-022-00993-w.
Baumans 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.