Retrobiosynthesis of unnatural lactams via reprogrammed polyketide synthase
Abstract Engineered polyketide synthases (PKSs) have great potential as biocatalysts. These unnatural enzymes are capable of synthesizing molecules that are either not amenable to biosynthesis or are extremely challenging to access chemically. PKSs can thus be a powerful platform to expand the chemical landscape beyond the limits of conventional metabolic engineering. Here we employ a retrobiosynthesis approach to design and construct PKSs to produce δ-valerolactam (VL) and three enantiopure α-substituted VL analogues that have no known biosynthetic route. We introduce the engineered PKSs and pathways for various malonyl-CoA derivatives into Pseudomonas putida and use proteomics, metabolomics and culture condition optimization to improve the production of our target compounds. These α-substituted VLs are polymerized into polyamides (nylon-5) or converted into their N -acryloyl derivatives. RAFT polymerization produces bio-derived polymers with potential biomedical applications. Overall, this interdisciplinary effort highlights the versatility and effectiveness of a PKS-based retrobiosynthesis approach in exploring and developing innovative biomaterials.
Authors
- Philip D. Laible (ORCID: https://orcid.org/0000-0003-2600-7991)
- Sarah H. Klass (ORCID: https://orcid.org/0000-0002-1021-5342)
- Jennifer W. Gin (ORCID: https://orcid.org/0000-0001-5636-7563)
- Christopher J. Petzold (ORCID: https://orcid.org/0000-0002-8270-5228)
- William E. Michener (ORCID: https://orcid.org/0000-0001-6023-7286)
- Davinia Salvachúa (ORCID: https://orcid.org/0000-0003-0799-061X)
- Meagan Burnet (ORCID: https://orcid.org/0000-0001-6747-468X)
- Allison Yaguchi
- Tyler W. H. Backman (ORCID: https://orcid.org/0000-0002-6056-353X)
- Woojoo E. Kim (ORCID: https://orcid.org/0000-0001-9818-2356)
- Edward E. K. Baidoo (ORCID: https://orcid.org/0000-0001-5787-1219)
- Namil Lee (ORCID: https://orcid.org/0009-0000-0382-8741)
- Christine A. Singer (ORCID: https://orcid.org/0000-0002-7791-6389)
- G. Babnigg (ORCID: https://orcid.org/0000-0002-9838-1803)
- Chenyi Li (ORCID: https://orcid.org/0000-0001-8294-1880)
- Hector Garcia Martin (ORCID: https://orcid.org/0000-0001-8474-6712)
- Brooks A. Abel (ORCID: https://orcid.org/0000-0002-2288-1975)
- Anna Lisa Fear
- Jesus F. Barajas (ORCID: https://orcid.org/0000-0002-4910-2222)
- Christopher W. Johnson (ORCID: https://orcid.org/0000-0002-2979-4751)
- Robert W. Haushalter
- Yan Chen (ORCID: https://orcid.org/0000-0002-1125-313X)
- Young‐Mo Kim (ORCID: https://orcid.org/0000-0002-8972-7593)
- Matthias Schmidt (ORCID: https://orcid.org/0000-0002-3363-4777)
- Yuqian Gao (ORCID: https://orcid.org/0000-0002-2956-2096)
- Connor J. Filbin
Institutions
- QB3 (US)
- Argonne National Laboratory (US)
- National Laboratory of the Rockies (US)
- Pacific Northwest National Laboratory (US)
- Lawrence Berkeley National Laboratory (US)
- Novo Nordisk Foundation (DK)
- Basque Center for Applied Mathematics (ES)
- Joint BioEnergy Institute (US)
- RWTH Aachen University (DE)
- University of California, Berkeley (US)
- Technical University of Denmark (DK)
Publication Details
- Journal
- Nature Catalysis
- Published
- 2025-04-18
- DOI
- https://doi.org/10.1038/s41929-025-01325-6
- Citations
- 12
- Primary Topic
- Microbial Natural Products and Biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 16.73
Funders
- U.S. Department of Energy
- Battelle
- Eusko Jaurlaritza
- Ministerio de Ciencia e Innovación
- Basque Center for Applied Mathematics
- Office of Science
- Office of Energy Efficiency and Renewable Energy
- Agencia Estatal de Investigación
- Biological and Environmental Research
- Bioenergy Technologies Office
- Office of Energy Efficiency
- Lawrence Berkeley National Laboratory
- Pacific Northwest National Laboratory