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PreprintCited by 15Microbial Natural Products and BiosynthesisBiochemical and Structural CharacterizationChemical Synthesis and Analysis

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Docking Domain Engineering in a Modular Polyketide Synthase and its Impact on Structure and Function

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Buyachuihan, Lynn, Zhao, Yue, Schelhas, Christian, Grininger, Martin·2023·ACS Chemical Biology
DOI 10.1101/2023.02.03.526980

Preprint — published as 10.1021/acschembio.3c00074 · Paper page

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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
ORCID
Venue
ACS Chemical Biology
Publisher
openRxiv
Published
2023-02-04
Volume
18
Issue
7
Pages
1500-1509
ISSN
1554-8929 (ISSN-L)
DOI
10.1101/2023.02.03.526980
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
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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