Assessing and harnessing updated polyketide synthase modules through combinatorial engineering

Katherine A. Ray, Joshua D. Lutgens, Ramesh Bista, Jie Zhang, Ronak R. Desai, Melissa Hirsch, Takeshi Miyazawa, Antonio Cordova and Adrian T. Keatinge-Clay ()
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Katherine A. Ray: The University of Texas at Austin
Joshua D. Lutgens: The University of Texas at Austin
Ramesh Bista: The University of Texas at Austin
Jie Zhang: The University of Texas at Austin
Ronak R. Desai: The University of Texas at Austin
Melissa Hirsch: The University of Texas at Austin
Takeshi Miyazawa: The University of Texas at Austin
Antonio Cordova: The University of Texas at Austin
Adrian T. Keatinge-Clay: The University of Texas at Austin

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract The modular nature of polyketide assembly lines and the significance of their products make them prime targets for combinatorial engineering. The recently updated module boundary has been successful for engineering short synthases, yet larger synthases constructed using the updated boundary have not been investigated. Here we describe our design and implementation of a BioBricks-like platform to rapidly construct 5 triketide, 25 tetraketide, and 125 pentaketide synthases to test every module combination of the pikromycin synthase. Anticipated products are detected from 60% of the triketide synthases, 32% of the tetraketide synthases, and 6.4% of the pentaketide synthases. We determine ketosynthase gatekeeping and module-skipping are the principal impediments to obtaining functional synthases. The platform is also employed to construct active hybrid synthases by incorporating modules from the erythromycin, spinosyn, and rapamycin assembly lines. The relaxed gatekeeping of a ketosynthase in the rapamycin synthase is especially encouraging in the quest to produce designer polyketides.

Date: 2024
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DOI: 10.1038/s41467-024-50844-6

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