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Expanding catalytic versatility of modular polyketide synthases for alcohol biosynthesis
Open accessPublished version of a preprint
Abstract
Modular polyketide synthases biosynthesize structurally diverse natural products by a set of catalytic domains that operate in an assembly line fashion. Although extensive research has focused on the rational reprogramming of modular polyketide synthases, little has been attempted to introduce noncanonical catalytic reactions on the assembly line. Here, we demonstrate the insertion of a thioester reductase domain, which can generate a terminal alcohol group instead of the canonical carboxylic acid, onto the assembly line polyketide synthases. We show that the didomain insertion of the acyl carrier protein and thioester reductase pair is generally effective for engineering of various polyketide synthase pathways. As a proof of concept, stereoselective and stereodivergent bioproduction of non-natural diols, namely, 1,3-butanediols and 2-methyl-1,3-butanediols, is achieved by harnessing the modularity of polyketide synthases. Our study expands the catalytic versatility of modular polyketide synthases and paves the way toward biosynthesis of designer alcohols.
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Metadata
- Authors
- Yao, S., Xie, S., Liu, R.-Z., Huang, Z., & Zhang, L.
- Affiliations
- Westlake University (CN)
- Corresponding author
- Zhang, Lihan
- Venue
- Nature Chemical Biology
- Published
- 2025-04-18
- Volume
- 21
- Issue
- 9
- Pages
- 1368-1375
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W4409565523
- Cited by
- 14
- References
- 71
- Citations by year
- 2026: 9 · 2025: 5
- FWCI
- 7.95
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by
- www.springernature.com/gp/researchers/text-and-data-mining (tdm)
- www.springernature.com/gp/researchers/text-and-data-mining (vor)
- Locations
- Nature Chemical Biology (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (22177092)
- Science and Technology Department of Zhejiang Province (2023SDXHDX0007)
- Topics
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Microbial Natural Products and Biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme Catalysis and Immobilization
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Keywords
- modular polyketide synthases, 1,3-butanediol, stereodivergent synthesis, acyl carrier protein
- MeSH terms
- Alcohols, Catalysis, Catalytic Domain, Polyketide Synthases, Biocatalysis
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