Scientists discover how molecule becomes anticancer weapon

A marine bacterium makes a potent anti-cancer molecule.

The anti-cancer molecule salinosporamide A, also called Marizomb, is in Phase III clinical trials to treat a brain cancer. For the first time, scientists understand the process that causes the molecule to be activated.

The team at the UC San Diego's Scripps Institution of Oceanography found that an enzyme called SalC assembles what they call the salinosporamide anti-cancer drug.

The work solved a 20-year-old mystery about how the marine bacterium makes the warhead that is unique to the salinosporamide molecule.

The discovery of how the salinosporamide A warhead is made could lead to the creation of other types of salinosporamides that could be used to attack cancer and other diseases.

There is a long history of silisporamide at UC San Diego. Microbiologist Paul Jensen and marine chemist Bill Fenical discovered salinosporamide A and the marine organisms that produce it after collecting the microbe from the tropical Atlantic Ocean in 1990. Moores Cancer Center at UC San Diego Health is where some of the clinical trials over the course of the drug's development took place.

Moore said that the 10-year project has been very challenging.

Bauman wanted to know how many of the enzymes were involved in folding the molecule into its active shape. Is there more than one enzymes involved?

I would have bet on more than one. In the end, it was just SalC. She said that it was surprising.

Moore says the salinosporamide molecule has a special ability to cross the blood-brain barrier, which accounts for its progress in clinical trials. The molecule has a ring structure. It is a linear molecule that folds into a circular shape.

The way nature makes it simple is beautiful. He said that nature does it with a singleidase, but that we as chemists cannot do what nature has done to make this molecule.

The production of antibiotics like erythromycin and the production of fatty acids in humans is a result of the activity of theidase involved.

Bauman, Chen, and Trivella of Brazil's National Center for Research in Energy and Materials determined the structure of the molecule. They used the Advanced Light Source at the Lawrence Berkeley National Laboratory.

Bauman said that the reaction performed by the SalC is very different from a normal one. A linear chain is formed by a molecule that is aided by a normal ketosis. salinosporamide is manufactured by forming two ring structures.

Synthetic chemists can't make those ring structures in the lab because a singleidase can form them. Scientists now have the information they need to modify the enzyme until they find a form that will suppress disease.

salinosporamide is made by the marine bacterium to avoid being eaten. Scientists have found that salinosporamide A can be used to treat cancer. salinosporamide A has features that the others lack, including biological activity that makes it hazardous to cancer cells.

Bauman said that the inhibition of the proteasome makes it a great anti-cancer agent. There is another type of proteasome found in immune cells. What if scientists could come up with a different salinosporamide? Is it possible that one that doesn't work against the cancer-prone proteasome but works against the immunoproteasome? A salinosporamide that causes the immune system to turn on the very body it should protect could be a highlyselective treatment for autoimmune diseases.

That is the idea behind generating some of these other salinosoporamides. Bauman said that access to the SalC that installs the complicated ring structure opens the door to that in the future.

Moore's group began working on this project more than a decade ago, according to Bauman's list of co-authors. Three former Moore Lab scientists contributed to the project, including a German scientist, a Brazilian scientist, and a Massachusetts scientist. There is a scientist in the Moore Lab. The other two co-authors have been collaborating on the project for a long time.

More information: Bradley Moore, Enzymatic assembly of the salinosporamide γ-lactam-β-lactone anticancer warhead, Nature Chemical Biology (2022). DOI: 10.1038/s41589-022-00993-w. www.nature.com/articles/s41589-022-00993-w Journal information: Nature Chemical Biology Citation: Scientists discover how molecule becomes anticancer weapon (2022, March 21) retrieved 21 March 2022 from https://phys.org/news/2022-03-scientists-molecule-anticancer-weapon.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.