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Comprehensive in Vitro Analysis of Acyltransferase Domain Exchanges in Modular Polyketide Synthases and Its Application for Short-Chain Ketone Production

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† ⊥ ○ QB3 Institute, Department of Bioengineering, Department of Chemical and Biomolecular Engineering, University of California, Berkeley, California 94720, United States
Joint BioEnergy Institute, Emeryville, California 94608, United States
§ Sandia National Laboratories, Livermore, California 94551, United States
Environmental Genomics and Systems Biology Division, #Molecular Biophysics and Integrated Bioimaging Division, and Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
Synthetic Biology Research Center, Emeryville, California 94608, United States
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kogle Allé, DK2970-Hørsholm, Denmark
Cite this: ACS Synth. Biol. 2017, 6, 1, 139–147
Publication Date (Web):August 22, 2016
https://doi.org/10.1021/acssynbio.6b00176
Copyright © 2016 American Chemical Society

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    Abstract

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    Type I modular polyketide synthases (PKSs) are polymerases that utilize acyl-CoAs as substrates. Each polyketide elongation reaction is catalyzed by a set of protein domains called a module. Each module usually contains an acyltransferase (AT) domain, which determines the specific acyl-CoA incorporated into each condensation reaction. Although a successful exchange of individual AT domains can lead to the biosynthesis of a large variety of novel compounds, hybrid PKS modules often show significantly decreased activities. Using monomodular PKSs as models, we have systematically analyzed the segments of AT domains and associated linkers in AT exchanges in vitro and have identified the boundaries within a module that can be used to exchange AT domains while maintaining protein stability and enzyme activity. Importantly, the optimized domain boundary is highly conserved, which facilitates AT domain replacements in most type I PKS modules. To further demonstrate the utility of the optimized AT domain boundary, we have constructed hybrid PKSs to produce industrially important short-chain ketones. Our in vitro and in vivo analysis demonstrated production of predicted ketones without significant loss of activities of the hybrid enzymes. These results greatly enhance the mechanistic understanding of PKS modules and prove the benefit of using engineered PKSs as a synthetic biology tool for chemical production.

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