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Biosensor Guided Polyketide Synthases Engineering for Optimization of Domain Exchange Boundaries
KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH). Joint BioEnergy Institute, Emeryville, CA, USA.
Joint BioEnergy Institute, Emeryville, CA, USA; Institute of Applied Microbiology, Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany; Biological Systems and Engineering Division, Lawrence Berkeley National laboratory, Berkeley, CA, USA.
Joint BioEnergy Institute, Emeryville, CA, USA; Department of Chemical & Biomolecular Engineering, University of California, Berkeley, Berkeley, CA, USA.
Joint BioEnergy Institute, Emeryville, CA, USA; Biological Systems and Engineering Division, Lawrence Berkeley National laboratory, Berkeley, CA, USA; Department of Chemical & Biomolecular Engineering, University of California, Berkeley, Berkeley, CA, USA.
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2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 4871Article in journal (Refereed) Published
Abstract [en]

Type I modular polyketide synthases (PKSs) are multi-domain enzymes functioning like assembly lines. Many engineering attempts have been made for the last three decades to replace, delete and insert new functional domains into PKSs to produce novel molecules. However, inserting heterologous domains often destabilize PKSs, causing loss of activity and protein misfolding. To address this challenge, here we develop a fluorescence-based solubility biosensor that can quickly identify engineered PKSs variants with minimal structural disruptions. Using this biosensor, we screen a library of acyltransferase (AT)-exchanged PKS hybrids with randomly assigned domain boundaries, and we identify variants that maintain wild type production levels. We then probe each position in the AT linker region to determine how domain boundaries influence structural integrity and identify a set of optimized domain boundaries. Overall, we have successfully developed an experimentally validated, high-throughput method for making hybrid PKSs that produce novel molecules.

Place, publisher, year, edition, pages
Springer Nature , 2023. Vol. 14, no 1, article id 4871
National Category
Biochemistry and Molecular Biology
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URN: urn:nbn:se:kth:diva-334951DOI: 10.1038/s41467-023-40464-xISI: 001049310000019PubMedID: 37573440Scopus ID: 2-s2.0-85168221320OAI: oai:DiVA.org:kth-334951DiVA, id: diva2:1792663
Note

QC 20230830

Available from: 2023-08-30 Created: 2023-08-30 Last updated: 2023-09-21Bibliographically approved

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Englund, Elias

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