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Docking Domain Engineering in a Modular Polyketide Synthase and its Impact on Structure and Function
Open accessPreprint — published as 10.1021/acschembio.3c00074 · Paper page
Abstract
Modular polyketide synthases (PKSs) are attractive targets for the directed, biosynthetic production of platform chemicals and pharmaceuticals by protein engineering. In this study, we analyze docking domains from the 6-deoxyerythronolide B synthase, SYNZIP domains, and the SpyCatcher:SpyTag complex as engineering tools to couple the polypeptides VemG and VemH to functional venemycin synthases. Our data show that the high-affinity interaction or covalent connection of modules, enabled by SYNZIP domains and the SpyCatcher:SpyTag complex, can be advantageous, e.g., in synthesis at low protein concentrations, but their rigidity and steric demand decrease synthesis rates. However, we also show that efficiency can be recovered when inserting a hinge region distant from the rigid interface. This study demonstrates that engineering approaches should take the conformational properties of modular PKSs into account and establishes a three-polypeptide split-venemycin synthase as an exquisite in vitro platform for the analysis and engineering of modular PKSs.
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Metadata
- Authors
- Buyachuihan, L., Zhao, Y., Schelhas, C., & Grininger, M.
- Affiliations
- Goethe University Frankfurt (DE)
- Corresponding author
- Grininger, Martin
- Venue
- ACS Chemical Biology
- Publisher
- openRxiv
- Published
- 2023-02-04
- Volume
- 18
- Issue
- 7
- Pages
- 1500-1509
- ISSN
- 1554-8929 (ISSN-L)
- OpenAlex
- W4383186420
- Cited by
- 15
- References
- 1
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 4 · 2023: 3
- FWCI
- 2.34
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by
- Locations
- ACS Chemical Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (GR3854/6-1)
- Hessisches Ministerium für Wissenschaft und Kunst
- Topics
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Microbial Natural Products and Biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- modular polyketide synthases, docking domains, 6-deoxyerythronolide B synthase, SpyTag/SpyCatcher, protein engineering, hinge region, conformational rigidity
- MeSH terms
- Protein Engineering, Polyketide Synthases
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- Buyachuihan, L., Zhao, Y., Schelhas, C., & Grininger, M. (2023). Docking Domain Engineering in a Modular Polyketide Synthase and its Impact on Structure and Function. ACS Chemical Biology. https://doi.org/10.1101/2023.02.03.526980
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