Generation of noncanonical fumagillin derivatives with a twisted cyclohexane conformation through engineered biosynthesis
Fumagillin-class natural products, known as methionine aminopeptidase 2 inhibitors, have been explored as drug candidates for cancer, obesity, and infectious diseases such as amoebiasis. However, clinical development has been hindered by adverse effects. Here, we identified 2 fumagillin analogues via engineered biosynthesis in Saccharomyces cerevisiae, coupled with metabolomics and activity-guided isolation. Spectroscopic analysis revealed unique 6-oxabicyclo[3.2.1]octane scaffolds that are unprecedented among naturally occurring fumagillins. The compounds exhibited selective antiamoebic activity without cytotoxicity to human lung cells. Stereochemical and computational studies suggested that the unique bicyclic system arises from a twist-boat conformer that enables intramolecular ether formation. These findings demonstrate that biosynthetic pathway engineering can expand the chemical diversity of fumagillin-related molecules and provide new leads for antiparasitic drug discovery.
Authors
- Mihoko Mori (ORCID: https://orcid.org/0009-0009-1229-584X)
- Michio Sato (ORCID: https://orcid.org/0000-0002-6026-8426)
- Yuji Ogata
- Takuma Matsushita (ORCID: https://orcid.org/0009-0008-0946-1299)
- Kouichi Yoshinari (ORCID: https://orcid.org/0000-0002-2027-2017)
- Yumiko Saito‐Nakano (ORCID: https://orcid.org/0000-0002-7132-194X)
- Tomoyoshi Nozaki (ORCID: https://orcid.org/0000-0003-1354-5133)
- Kenji Watanabe (ORCID: https://orcid.org/0000-0002-0463-4831)
- Yuta Tsunematsu (ORCID: https://orcid.org/0000-0001-6750-8034)
- Kanji Niwa
- Ryota Shizu (ORCID: https://orcid.org/0000-0002-0465-5077)
- Seiki Kobayashi
- Noboru Ogata
Institutions
- University of Shizuoka (JP)
- Mitsubishi Chemical (Japan) (JP)
- National Institute of Infectious Diseases (JP)
- Mitsubishi Chemical (Germany) (DE)
- Nagoya University (JP)
- The University of Tokyo (JP)
- Tokyo University of Agriculture and Technology (JP)
Publication Details
- Journal
- Bioscience Biotechnology and Biochemistry
- Published
- 2025-06-17
- DOI
- https://doi.org/10.1093/bbb/zbaf091
- Citations
- 1
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 1.05
Funders
- Japan Agency for Medical Research and Development
- Academia Sinica
- University of California, Los Angeles
- Japan Society for the Promotion of Science