Revealing Nature’s Hidden Power: Groundbreaking Discovery of Enzymes for Advanced Cancer Treatment

Researchers at the UF Scripps Institute have identified two extraordinary enzymes, potentially transforming the generation of natural substances for healthcare, including innovative cancer therapies. This breakthrough also enhances our understanding of powerful compounds such as tiancimycin A.

Discovery of Unique Enzymes in Natural Products

In a vast collection of natural specimens at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, hidden among numerous bacterial strains, were a few delicate vials containing something surprising and possibly highly beneficial.

Uncovering New Enzymes

Reported in Nature Chemical Biology, a team under the guidance of chemist Ben Shen, Ph.D., unveiled two enzymes with exceptional properties beneficial in battling diseases like cancer. This revelation, announced recently, could simplify the study and production of intricate natural chemicals, potentially leading to new pharmaceuticals.

Role of Ben Shen, Ph.D., in Natural Products Research

Ben Shen, Ph.D., a chemistry professor, heads the Natural Products Discovery Center at the institute, which boasts one of the globe’s most extensive microbial natural chemical collections. Scott Wiseman credits this center.

Influence on Pharmaceutical Research

Shen emphasized the significant role bacterial chemicals play in drug development. He directs the Natural Products Discovery Center, renowned for its extensive microbial natural product assortment.

Shen remarked, “Nearly half of the FDA-approved antibiotics and anticancer drugs are derived from natural products or inspired by them. We’re using advanced genomic and computational techniques to decode their complex chemistry and enzymology, leading to rapid progress. These newly found enzymes are a prime example.”

Discovery of Beneficial Enzymes at the Natural Products Discovery Center

Scientists at the Natural Products Discovery Center, part of The Herbert Wertheim UF Scripps Institute, discovered two novel enzymes, which could aid in developing medicines for cancer and other diseases. Scott Wiseman acknowledges this discovery.

Characteristics of the Newly Discovered Enzymes

The research team identified enzymes termed “cofactorless oxygenases,” which uniquely integrate oxygen into new compounds without needing typical metals or cofactors.

This innovative synthesis method offers survival benefits to organisms, aiding them in combating infections or threats. For chemists, these enzymes provide new avenues for creating beneficial materials, explain the study’s primary authors, postdoctoral researchers Chun Gui, Ph.D., and Edward Kalkreuter, Ph.D.

Resolving a Persistent Puzzle

The discovery of enzymes TnmJ and TnmK2 clarifies the potency of tiancimycin A, a potential antibiotic and anticancer compound, initially identified by the Shen lab in 2016, as noted by Gui and Kalkreuter.

These enzymes allow bacteria to produce DNA-targeting compounds, potentially valuable in combating viruses or cancer.

Tiancimycin A: A Powerful Compound

Tiancimycin A, under development for cancer-targeted antibody therapy, represents a new wave in cancer treatment. However, producing sufficient quantities for large-scale study has been challenging.

“Identifying the genes responsible for tiancimycin A was just a part of the challenge. The synthesis steps were unpredictable,” stated Gui, highlighting the uniqueness of the two enzymes.

Origin and Chemical Challenges of Tiancimycin A

Tiancimycin A was initially discovered in soil-based Streptomyces bacteria from the institute’s strain collection. To generate its potent chemical weapon, the organism had to overcome the challenge of replacing stable carbon-carbon bonds with more reactive carbon-oxygen bonds, a process long puzzling scientists.

Exploring the Collection’s Richness

The solution involved examining other bacteria producing similar natural products within the institute’s collection of 125,000 strains. The collection, initially stored in a pharmaceutical company’s basement and rich in historically significant drugs, was relatively unexplored until Shen’s team won a competition in 2018 to fully research it in an academic environment.

Shen’s team is now developing methods to study these strains, sequence their genomes, and create a searchable database for scientific use. Modern sequencing and bioinformatics reveal numerous uncharted natural products in each bacterial strain, says Shen, a member of the UF Health Cancer Center.

Future Prospects and Significance

The discovery of these cofactorless enzymes highlights the chemical wealth within The Wertheim UF Scripps Institute’s collection. This finding reinvigorates interest in understanding the unique chemistry’s evolutionary reasons and potential applications.

“This publication underlines the numerous surprises nature holds,” Shen stated, “It can enlighten us about fundamental chemistry and biology, offering tools and inspiration for transforming lab discoveries into impactful medicines.”

Reference: “Cofactorless oxygenases guide anthraquinone-fused enediyne biosynthesis” by Chun Gui, Edward Kalkreuter, Yu-Chen Liu, Gengnan Li, Andrew D. Steele, Dong Yang, Changsoo Chang, and Ben Shen, 9 November 2023, Nature Chemical Biology.
DOI: 10.1038/s41589-023-01476

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• UF Scripps Institute
• Nature Chemical Biology
• Natural Products Discovery Center
• UF Health Cancer Center