Retrobiosynthesis of Unnatural Lactams via Reprogrammed Polyketide Synthase

Namil Lee; Matthias Schmidt; Chenyi Li; Connor Filbin; Sarah Klass; Allison Yaguchi; Anna Lisa Fear; Tyler Backman; Brooks Abel; Young-Mo Kim; Woojoo Kim; Christopher Johnson; Yan Chen; Jennifer Gin; Christopher Petzold; Edward Baidoo; Yuqian Gao; Meagan Burnet; Gyorgy Babnigg; Philip Laible; Christine Singer; William Michener; Davinia Salvachua; Hector Garcia Martin; Robert Haushalter; Jay Keasling

doi:10.1038/s41929-025-01325-6

Retrobiosynthesis of Unnatural Lactams via Reprogrammed Polyketide Synthase

Namil Lee, Matthias Schmidt, Chenyi Li, Connor Filbin, Sarah Klass, Allison Yaguchi, Anna Lisa Fear, Tyler Backman, Brooks Abel, Young-Mo Kim, Woojoo Kim, Christopher Johnson, Yan Chen, Jennifer Gin, Christopher Petzold, Edward Baidoo, Yuqian Gao, Meagan Burnet, Gyorgy Babnigg, Philip LaibleChristine Singer, William Michener, Davinia Salvachua, Hector Garcia Martin, Robert Haushalter, Jay Keasling

Renewable Resources and Enabling Sciences Center

Research output: Contribution to journal › Article › peer-review

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 ..delta..-valerolactam (VL) and three enantiopure ..alpha..-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 ..alpha..-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.

Original language	American English
Pages (from-to)	389-402
Number of pages	14
Journal	Nature Catalysis
Volume	8
Issue number	4
DOIs	https://doi.org/10.1038/s41929-025-01325-6
State	Published - 2025

NREL Publication Number

NREL/JA-2800-89531

Keywords

biomolecule
lactam
nylon-6 replacement
polyketide synthase
Pseudomonas putida

Access to Document

10.1038/s41929-025-01325-6

https://www.nrel.gov/docs/fy25osti/89531.pdf

Cite this

Lee, N., Schmidt, M., Li, C., Filbin, C., Klass, S., Yaguchi, A., Fear, A. L., Backman, T., Abel, B., Kim, Y.-M., Kim, W., Johnson, C., Chen, Y., Gin, J., Petzold, C., Baidoo, E., Gao, Y., Burnet, M., Babnigg, G., ... Keasling, J. (2025). Retrobiosynthesis of Unnatural Lactams via Reprogrammed Polyketide Synthase. Nature Catalysis, 8(4), 389-402. https://doi.org/10.1038/s41929-025-01325-6

@article{fa64c1a91cde466ab77b11f0d59b393b,

title = "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 ..delta..-valerolactam (VL) and three enantiopure ..alpha..-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 ..alpha..-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.",

keywords = "biomolecule, lactam, nylon-6 replacement, polyketide synthase, Pseudomonas putida",

author = "Namil Lee and Matthias Schmidt and Chenyi Li and Connor Filbin and Sarah Klass and Allison Yaguchi and Fear, {Anna Lisa} and Tyler Backman and Brooks Abel and Young-Mo Kim and Woojoo Kim and Christopher Johnson and Yan Chen and Jennifer Gin and Christopher Petzold and Edward Baidoo and Yuqian Gao and Meagan Burnet and Gyorgy Babnigg and Philip Laible and Christine Singer and William Michener and Davinia Salvachua and {Garcia Martin}, Hector and Robert Haushalter and Jay Keasling",

year = "2025",

doi = "10.1038/s41929-025-01325-6",

language = "American English",

volume = "8",

pages = "389--402",

journal = "Nature Catalysis",

issn = "2520-1158",

publisher = "Nature Publishing Group",

number = "4",

}

Lee, N, Schmidt, M, Li, C, Filbin, C, Klass, S, Yaguchi, A, Fear, AL, Backman, T, Abel, B, Kim, Y-M, Kim, W, Johnson, C, Chen, Y, Gin, J, Petzold, C, Baidoo, E, Gao, Y, Burnet, M, Babnigg, G, Laible, P, Singer, C , Michener, W , Salvachua, D, Garcia Martin, H, Haushalter, R & Keasling, J 2025, 'Retrobiosynthesis of Unnatural Lactams via Reprogrammed Polyketide Synthase', Nature Catalysis, vol. 8, no. 4, pp. 389-402. https://doi.org/10.1038/s41929-025-01325-6

TY - JOUR

T1 - Retrobiosynthesis of Unnatural Lactams via Reprogrammed Polyketide Synthase

AU - Lee, Namil

AU - Schmidt, Matthias

AU - Li, Chenyi

AU - Filbin, Connor

AU - Klass, Sarah

AU - Yaguchi, Allison

AU - Fear, Anna Lisa

AU - Backman, Tyler

AU - Abel, Brooks

AU - Kim, Young-Mo

AU - Kim, Woojoo

AU - Johnson, Christopher

AU - Chen, Yan

AU - Gin, Jennifer

AU - Petzold, Christopher

AU - Baidoo, Edward

AU - Gao, Yuqian

AU - Burnet, Meagan

AU - Babnigg, Gyorgy

AU - Laible, Philip

AU - Singer, Christine

AU - Michener, William

AU - Salvachua, Davinia

AU - Garcia Martin, Hector

AU - Haushalter, Robert

AU - Keasling, Jay

PY - 2025

Y1 - 2025

N2 - 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 ..delta..-valerolactam (VL) and three enantiopure ..alpha..-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 ..alpha..-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.

AB - 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 ..delta..-valerolactam (VL) and three enantiopure ..alpha..-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 ..alpha..-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.

KW - biomolecule

KW - lactam

KW - nylon-6 replacement

KW - polyketide synthase

KW - Pseudomonas putida

U2 - 10.1038/s41929-025-01325-6

DO - 10.1038/s41929-025-01325-6

M3 - Article

SN - 2520-1158

VL - 8

SP - 389

EP - 402

JO - Nature Catalysis

JF - Nature Catalysis

IS - 4

ER -

Retrobiosynthesis of Unnatural Lactams via Reprogrammed Polyketide Synthase

Abstract

NREL Publication Number

Keywords

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