Chemical switching offers new control over DNA repair enzymes
Researchers at SciLifeLab and Karolinska Institutet introduce a new way to redirect enzyme activity, with potential for future treatments. In a recent perspective article in ChemBioChem (Wiley, 2025), the team led by Dr. Maurice Michel explains how chemical switching could change how we use small molecules to influence enzyme activity.
The team consists of researchers from SciLifeLab and the Department of Oncology and Pathology at Karolinska Institutet, together with partners in the EUbOPEN consortium. They have developed a method called chemical switching. This approach gives researchers new ways to control how enzymes work in human cells.
What is chemical switching?
Chemical switching is based on small, specially designed molecules called Organocatalytic Switches (ORCAs). These molecules fit into the active site of an enzyme and take part in the reaction itself. Inspired by techniques from biocatalysis and organocatalysis, the switches don’t block the enzyme, they change what it does, or increase its activity. They work together with custom-designed proteins as part of the system.
As SciLifeLab researcher Dr. Maurice Michel explains: “Enzymes have evolved to exceed in one function. These functions are ultimately controlled by physicochemical descriptors, such as pH, temperature, functional groups, charge etc. Influencing chemical descriptors to change enzymatic function is then a logical step to take”.
The key step is doing this inside living cells. The researchers focused on an enzyme called OGG1, which helps repair DNA damage caused by oxidative stress. That kind of damage plays a role in aging, cancer, neurodegenerative diseases, and metabolic conditions. The ORCAs developed by the team boost OGG1’s repair function, helping to reduce inflammation, fix damaged DNA, and reverse fibrosis.
How does it actually work?
The process is simple in principle. The ORCAs are nitrogen-based molecules that enter OGG1’s active site and remove a specific proton from a reaction intermediate called a Schiff base. This starts a different chemical reaction inside the enzyme, one that no longer needs help from another repair protein. The result is faster and more efficient DNA repair. And because Schiff base intermediates are common in many enzymes, the same approach could be used more widely.
“This is the first time we have shown how to comprehensively reprogram an enzyme directly through its chemistry”
“The idea that we can design a molecule or a protein variant to switch enzymatic reactions on or off by participating in the chemistry itself offers profound mechanistic impact in medicine and biotechnology. It was great fun getting our thoughts about this on paper,” says Dr. Maurice Michel.
The research was done within EUbOPEN, a European project focused on making chemical tools freely available to study proteins that haven’t been explored in detail. The ORCAs described in this and other studies are among the first of their kind and represent an important step in the growing fields of chemical enzymology and precision medicine.
Contact
Maurice Michel
SciLifeLab researcher
Department of Oncology and Pathology, Karolinska Institutet
Email: maurice.michel@ki.se
Photo: Stefan Zimmerman.
