Mining Natural Products Reveals Nature’s Method for Building a Cancer Killer

Crystal structures of apo-TnmK1. JACS doi/10.1021/jacs.2c08957. Shen lab at UF Scripps Biomedical Research.

In a new paper published in the Journal of the American Chemical Society, a team led by chemistry professor Ben Shen, Ph.D., reveals one way that nature assembles a specific subgroup of chemicals called enediynes, offering hints for how to do the same synthetically.

Enediynes are a class of chemicals originally discovered in microbes that are of great interest to the pharmaceutical and other industries because of their unique properties. For example, they can bind and break DNA, leading to cell death. This makes them potentially useful against cancer and as antibiotics. But chemists have had difficulty working with enediynes in the lab, limiting the ability to study and make use of them in a broader way.

Shen’s team studied an enediyne natural product called tiancimycin. In it, a key carbon-carbon bond formation connects an aromatic segment called anthraquinone, which is mainly responsible for DNA binding, to an enediyne core, which confers the DNA cleavage activity. Using comparative genomics to mine the genome database at the Natural Products Discovery Center, they found an elusive enzyme called TnmK1 that catalyzes a carbon-carbon bond formation. In this way, it builds the characteristic anthraquinone-fused enediyne scaffold.

The discovery could prove useful to synthetic chemists who work to build enediyne natural products in a lab setting so that they can be further studied as drug leads or developed into clinical drugs. 

“The enediyne natural products are phenomenal in chemistry, biology and medicine, with three drugs currently on the market developed from a family of natural products with less than 20 members known to date,” Shen said.

The antibody-drug conjugates Mylotarg®, for acute myeloid leukemia, and Besponsa®,  for B-cell precursor acute lymphoblastic leukemia, as well as SMANCS, used to treat liver cancer, rely on two enediynes, said Chun Gui, Ph.D., co-first author with Edward Kalkreuter, Ph.D.

Shen believes that within the approximately 125,000 actinobacteria strains at the Natural Products Discovery Center at UF Scripps, there are literally thousands more enediyne natural products awaiting discovery.

“Mining the 10,000 genomes sequenced to date from our actinobacterial strain collection alone, we have already discovered nearly 1,000 strains that are predicted to produce new enediyne natural products, including more than 10 predicted to produce variants of the enediyne used in Mylotargâ,” Shen said.

Learn more: Opening nature’s biodiversity to science