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Researchers at the University of Bayreuth have, for the first time, deciphered key steps in the biosynthetic mechanism of the potential anti-cancer agent fostriecin. The team led by Prof. Dr. Frank Hahn has succeeded in producing all enzymes involved in the process in the laboratory and examining them individually under controlled conditions. In the long term, the findings may pave the way for more efficient production of the compound and open up new avenues in cancer therapy. The researchers have reported their findings in the renowned journal Nature Communications.
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Why it matters
Cancer cells are characterised by uncontrolled cell division. This is why many cancer drugs aim to inhibit the cells’ ability to divide, for example by blocking specific enzymes that cancer cells require for growth and proliferation. Fostriecin is a promising natural product produced by bacteria that can induce cancer cell death by disrupting signalling pathways. However, earlier clinical trials investigating fostriecin as an anti-cancer agent had to be discontinued because the compound could not be obtained in sufficient quantity and purity. In addition, fostriecin’s instability and certain structural features complicate its development as a drug. The research team in Bayreuth has therefore clarified an important part of the biosynthetic mechanism underlying this potential anti-cancer agent—an advance that could, in the long term, enable more efficient and sustainable production of fostriecin. This increases the likelihood that the natural product may in future serve as the basis for new and effective cancer therapies.
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At the centre of the team’s research, led by Prof. Hahn, head of the Organic Chemistry IV research group at the University of Bayreuth, was the so‑called pharmacophore: the structural components and properties of a molecule that are primarily responsible for its pharmacological activity. “In our study, we have for the first time succeeded in producing several of the enzymes crucial for constructing the fostriecin pharmacophore in the laboratory, and in studying them individually under controlled conditions outside the cell,” says Hahn.
The researchers have also shown for the first time that all these enzymes work together to form the pharmacophore when combined in a single vessel. “This is highly exciting for the development of modern synthesis technologies, because—both for economic and environmental reasons—there is increasing interest in producing complex molecules with as little effort as possible. Enzymatic synthesis offers great potential here,” Hahn explains.
Another remarkable finding of the study was the discovery of previously unknown enzymatic activities: during pharmacophore formation, a thioesterase performs two crucial steps—transferring malonic acid and forming a ring structure. Until now, it was not known that a single enzyme could carry out both functions. A novel demalonylase then cleaves off the malonic acid, generating the part of the pharmacophore that interacts with the target protein in the cancer cell. Essential to pharmacophore formation is the finely tuned interplay between the thioesterase, the demalonylase and a kinase, which incorporates a characteristic phosphate ester into the pharmacophore. “This optimises the formation of the bioactive end product. Without the precise coordination of these three enzymes, the fostriecin biosynthesis pathway in the bacterium would resemble a leaky garden hose: although the bacterium invests considerable resources in producing fostriecin, the process would often fail to yield the desired bioactive molecule, because inactive and unstable intermediates would form and degrade,” Hahn explains.
In further studies, the team aims to extend its insights to the biosynthesis of structurally related natural products and to employ the identified biosynthetic enzymes in targeted chemoenzymatic synthesis. This approach combines the strengths of synthetic chemistry with those of biotechnology, making it especially powerful.
The study was funded through an Exploration Grant from the Boehringer Ingelheim Foundation.
Prof. Dr. Frank Hahn
Organic Chemistry IV
University of Bayreuth
Phone: +49 (0)921 / 55‑3660
E-mail: frank.hahn@uni-bayreuth.de
Source: Lisa N. K. T. Nguyen, Luca Schlotte, Julian Hoffmann, Dominik Betz, Marius Schröder & Frank Hahn. Covalent warhead assembly in fostriecin biosynthesis involves malonylation–lactonisation by a bifunctional thioesterase and enzymatic demalonylation. Nature Communications (2026)
DOI: https://doi.org/10.1038/s41467-026-70144-5
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