Years of depreciation in the laboratory have shown how a marine bacteria transforms a powerful anti-cancer drug.
Salinosporamide A, the anti-cancer molecule known as Marizomb, has been developed in Phase III clinical trials to treat glioblastoma, a brain cancer. Researchers today for the first time understand the enzyme-driven process that activates the molecule.
Researchers at the Scripps Institute of Oceanography (UC San Diego) discovered that an enzyme called SalC assembled what the team called the salinosporamide anti-cancer warhead. Katherine Bauman, a graduate student at Scripps, is the author of a research that detailes the assembly process in the March 21 issue of Natural Chemical Biology.
The project solves a nearly 20-year puzzle about how the marine bacterium makes the warhead that is identical to the salinosporamide molecule and opens the way for future biotechnology to produce new anti-cancer agents.
Researchers have discovered how this enzyme makes the salinosporamide A warhead in the future. Researchers should also employ enzymes to produce other types of salinosporamides that could combat non-cancer but also anti-cancer diseases and infections caused by parasites, according to 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. Both Paul Jensen and marine chemist Bill Fenical of Scripps Oceanography discovered both salinosporamide A and the marine organism that produces the molecule after collecting the microbe from the tropical Atlantic Oceanin 1990. Some clinical trials over the course of the drugs development took place at the Moores Cancer Center at UC San Diego Health.
According to Moore, who is Baumans'' advisor, this 10-year project has been quite challenging. Kates have been able to assemble ten years worth of previous work to help us clear the line.
Bauman''s major question was to understand how many enzymes were responsible for forming the molecule into its active shape. Is there a variety of enzymes involved or one?
I''d have guessed money on more than one. It was ultimately SalC. That was surprising, according to the author.
Moore claims that the salinosporamide molecule has a special ability to cross the blood-brain barrier, which contributes to its development in clinical trials for glioblastoma. It starts as a linear molecule that folds into a more complex circular shape.
The way nature makes it very simple. He said that we as chemists cant do what nature has done to make this molecule, but nature does it with a single enzyme.
The enzyme involved is common in biology, and it is one that participates in the production of fatty acids in humans, as well as antibiotics, like erythromycin in microbes.
At the Lawrence Berkeley National Laboratory, Bauman, Percival Yang-Ting Chen of Morphic Therapeutics in Waltham, Mass., and Daniella Trivella of Brazil''s National Center for Research in Energy and Materials, determined the molecular structure of SalC. For this purpose, they utilized the Advanced Light Source, a powerful particle accelerator that generates x-ray light.
According to Bauman, the SalC enzyme performs a very different reaction than a normal ketosynthase. A normal ketosynthase is an enzyme that helps a substance form a linear chain. SalC, by contrast, is able to create two complex, reactive, ring structures.
Both of these ring structures that are difficult for synthetic chemists to construct in the lab are formed by a single enzyme. Now, scientists have the potential to mutate the enzyme until they have discovered forms that are effective in suppressing many types of disease.
The marine pest calledSalinispora tropica reduces consumption by its predators. However, scientists have discovered that salinosporamide A also works to treat cancer. Others have found that salinosporamide A contains biological properties that make it dangerous to cancer cells.
Prohibiting that proteasome makes it a powerful anti-cancer agent, according to Bauman, because to the protein complex that degrades useless or impaired proteins. But there is another type of proteasome found in immune cells. What if scientists could devise a slightly different salinosporamide than salinosporamide A, instead of removing the immunoproteasome? The type that causes the immune system to turn upon the very body it should protect.
And access to this enzyme SalC that installs the complicated ring structure opens the way for future development, according to Bauman.