[Nature sub-issue] Marine bacteria make "anti-cancer molecules", and scientists understand the mystery for the first time!

This article was originally written by Translational Medicine.
Please indicate the source when reprinting.
Author: Ashley Introduction: Recent research has revealed how marine bacteria can produce effective anti-cancer molecules
.

The anticancer molecule Salinosporamide A is in Phase III clinical trials for the treatment of glioblastoma
.

For the first time, scientists now understand the enzyme-driven process that activates the molecule
.

The research solves a nearly 20-year-old mystery of how marine bacteria make the "warhead" characteristic of salinosporamide, opening the door for future biotechnologies to create novel anticancer agents
.

Years of laboratory work have revealed how marine bacteria make a potent cancer-fighting molecule
.

The marine bacteria involved, called Salinispora tropica, make salinosporamide to avoid being eaten by its predators
.

But scientists have found that salinosporamide A can also treat cancer
.

They isolated other salinosporamides, but salinosporamide A had other features it lacked -- including biological activity that made it harmful to cancer cells
.

The anticancer molecule salinosporamide A, also known as Marizomb, is in Phase III clinical trials for the treatment of a type of brain cancer called glioblastoma
.

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 have discovered that an enzyme called SalC assembles what the team calls a cancer-fighting "warhead" of salinosporamide
.

Scripps graduate student Katherine Bauman is the lead author of a March 21 paper in the journal Nature Chemical Biology, "Enzymatic assembly of the salinosporamide γ-lactam-β-lactone anticancer warhead," explaining the assembly process
.

The work solves a nearly 20-year-old mystery of how marine bacteria make the "warhead" characteristic of salinosporamide, opening the door for future biotechnologies to create novel anticancer agents
.

Co-author Bradley Moore, Distinguished Professor of Scripps Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences, said: "Now that scientists understand how this enzyme makes the salinosporamide A 'warhead', this discovery could be used in the future to harness the enzyme to Produce other types of salinosporamides that attack not only cancer but also diseases of the immune system and infections caused by parasites
.

” Salisporamide has a long history at Scripps and UC San Diego
.

Microbiologist Paul Jensen and marine chemist Bill Fenical of Scripps Oceanography discovered salinosporamide A and the marine organisms that produce the molecule in 1990 after collecting microbes from sediments in the tropical Atlantic
.

Some clinical trials in the drug development process are conducted at Moores Cancer Center
.

"It's been a very challenging 10-year project," said Moore, who is a consultant to Bauman
.

"Kate has brought together 10 years of early work to get us across the finish line
.

" One of Bauman's big problems is figuring out how many enzymes are responsible for folding the molecule into its active shape
.

Are multiple enzymes involved or only one enzyme involved? "I would bet on more than one enzyme," she said.
"
But
in the end, it was surprising that only SalC was involved
.

" Moore said that the salinosporamide molecule has a special ability to cross the blood-brain barrier, which explains its role in glioblastoma cells.
Advances in Oncology Clinical Trials
.

The molecule has a small but complex ring structure
.

It starts as a linear molecule that folds into a more complex circle
.

"Nature makes it beautiful and simple," he said.
"
We
as chemists can't make this molecule the way nature does, but nature can do it with just one enzyme
.

This enzyme is common in biology; it's in It is involved in the production of fatty acids in the human body and in the production of antibiotics such as erythromycin in microorganisms
.

Bauman, Percival Yang-Ting Chen and Daniella Trivella 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 U.
S.
Department of Energy's Lawrence Berkeley National Laboratory
.

"SalC enzymes perform reactions that are very different from normal ketone synthases," Bauman said
.

Normal ketone synthase is an enzyme that helps molecules form linear chains
.

In contrast, SalC produces salinosporamide by forming two complex reactive ring structures
.

A single enzyme can form both ring structures, something synthetic chemists have difficulty making in the lab
.

Armed with this information, scientists can now mutate the enzyme until they find a form that promises to inhibit various types of disease
.

"Inhibiting the proteasome makes it a great anticancer agent," Bauman said of protein complexes that degrade useless or damaged proteins
.

But another type of proteasome is found in immune cells
.

What if scientists could engineer a slightly different salinosporamide from salinosporamide A? A proteasome with poor inhibition of the cancer-prone proteasome, but stronger inhibition of the immunoproteasome? This salinosporamide could be a highly selective treatment for autoimmune diseases that cause the immune system to attack the body it's supposed to protect
.

"That was the idea of ​​generating some other salinosporamides," Bauman said.
"
And
the use of SalC, an enzyme that can install complex ring structures, opens the door to this structure in the future
.

"Reference: https://phys.
org/news/2022-03-scientists-molecule-anticancer-weapon.
html Note: This article is intended to introduce medical research progress and cannot be used as a reference for treatment plans
.

For health guidance, please Go to a regular hospital for treatment
.

Recommendations and activities Click on the text to view the details.
March 24th 19:00-20:30 Online Multiple Myeloma Research Progress and Application of MRD March 30th 19:00-21:00 Online Protein Webinar on Frontier Advances in Omics and Prospects of Innovative Technologies March 31st 19:00-21:00 Online Sharing of Global Technology | Oncology Precision Diagnosis Innovation and Development Webinar (coming soon) April 14th 09:00-18 :00 The 3rd Beijing Single-Cell Sequencing Technology Application Forum (coming soon) April 20, 09:00-18:00 How to improve the efficiency of new macromolecular drug research and development from basic experiments (coming soon)