The discovery of a multidomain enzyme increases the potential for drug development

Pharmaceutical scientists at the National University of Singapore (NUS) have identified and characterized a unique multi-domain enzyme capable of catalyzing two different types of reactions, both crucial for the production of drug molecules.

Natural products produced by living organisms such as plants, animals and microorganisms control various survival and defense purposes. However, these compounds can be further used as medicines and medicines. Many well-known medications, including ibuprofen and penicillin, are derived from these natural substances. The biosynthetic enzymes responsible for producing natural products create unique molecules that are often difficult for humans to reproduce. The discovery of new biosynthetic enzymes opens the possibility of developing innovative drug molecules that could provide new therapeutics to treat life-threatening infections and cancer.

Led by Assistant Professor Brandon I. Morinaka from the Department of Pharmacy and Pharmaceutical Sciences, NUS Faculty of Science, the researchers have identified multidomain enzymes that catalyze two reactions – cyclization and hydroxylation – on a single peptide substrate. These bacterial biosynthetic enzymes could potentially provide new opportunities for producing drug molecules, as both transformations are difficult to achieve through chemical synthesis. In these systems, the enzyme contains two distinct domains: a radical SAM domain responsible for catalyzing cyclization and a hydroxylase domain for catalyzing hydroxylation. Interestingly, although the hydroxylase domain was originally predicted to be a protease due to its structural similarity to metalloproteases, the researchers discovered that it belongs to a new type of oxygenase family called αKG-HExxH. This research was conducted in collaboration with Professor Zhang Qi of Fudan University, China, and Professor Yvain Nicolet of the University of Grenoble-Alps, France.

The results were published in the journal Natural chemistry.

Assistant Professor Morinaka said: “The combination of a multi-domain protein for peptide modification and the discovery of a new oxygenase family will open new avenues in natural product discovery and enzymology.”

These enzymes are notable because they represent a new protein design capable of modifying peptides with two different domains simultaneously within a single protein. While previous enzymes have been shown to catalyze interconnected transformations, the reactions in this study are separate reactions. These findings represent a new strategy for developing peptide drugs that could serve as next-generation treatments for infections and cancer.

We are always amazed at the chemistry that nature has developed. These reactions are difficult, if not impossible, for humans to plan or imagine.

Brandon I. Morinaka, Assistant Professor, Department of Pharmacy and Pharmaceutical Sciences, NUS Faculty of Science

In the future, the researchers want to explore the potential therapeutic applications of the enzyme products, investigate how the enzymes catalyze such complex reaction sequences, and engineer the systems in such a way that an even broader range of new products are created.