2. Academic Validation
  3. Chemoinformatic-Guided Engineering of Polyketide Synthases

Chemoinformatic-Guided Engineering of Polyketide Synthases

  • J Am Chem Soc. 2020 Jun 3;142(22):9896-9901. doi: 10.1021/jacs.0c02549.
Amin Zargar 1 2 3,  Ravi Lal 1 2,  Luis Valencia 1 2,  Jessica Wang 1 2,  Tyler William H Backman 1 2,  Pablo Cruz-Morales 1 2,  Ankita Kothari 2,  Miranda Werts 1 2,  Andrew R Wong 1 2,  Constance B Bailey 1 2 3,  Arthur Loubat 1 2,  Yuzhong Liu 1 2,  Yan Chen 1 2,  Samantha Chang 1 2,  Veronica T Benites 1 2 4,  Amanda C Hernández 1 2,  Jesus F Barajas 1 2 4,  Mitchell G Thompson 1 2,  Carolina Barcelos 1 2,  Rasha Anayah 1 2,  Hector Garcia Martin 1 2 4 5,  Aindrila Mukhopadhyay 1 2,  Christopher J Petzold 1 2 4,  Edward E K Baidoo 1 2 4,  Leonard Katz 1 3,  Jay D Keasling 1 2 3 6 7 8 9
Affiliations

Affiliations

  • 1 Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.
  • 2 Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States.
  • 3 QB3 Institute, University of California-Berkeley, 5885 Hollis Street, Fourth Floor, Emeryville, California 94608, United States.
  • 4 Department of Energy, Agile BioFoundry, Emeryville, California 94608, United States.
  • 5 BCAM, Basque Center for Applied Mathematics, 48009 Bilbao, Spain.
  • 6 Department of Chemical & Biomolecular Engineering, University of California, Berkeley, California 94720, United States.
  • 7 Department of Bioengineering, University of California, Berkeley, California 94720, United States.
  • 8 Novo Nordisk Foundation Center for Biosustainability, Technical University Denmark, DK2970 Horsholm, Denmark.
  • 9 Synthetic Biochemistry Center, Institute for Synthetic Biology, Shenzhen Institutes for Advanced Technologies, 518055 Shenzhen, China.
PMID: 32412752 DOI: 10.1021/jacs.0c02549
Abstract

Polyketide synthase (PKS) engineering is an attractive method to generate new molecules such as commodity, fine and specialty chemicals. A significant challenge is re-engineering a partially reductive PKS module to produce a saturated β-carbon through a reductive loop (RL) exchange. In this work, we sought to establish that chemoinformatics, a field traditionally used in drug discovery, offers a viable strategy for RL exchanges. We first introduced a set of donor RLs of diverse genetic origin and chemical substrates into the first extension module of the lipomycin PKS (LipPKS1). Product titers of these engineered unimodular PKSs correlated with chemical structure similarity between the substrate of the donor RLs and recipient LipPKS1, reaching a titer of 165 mg/L of short-chain fatty acids produced by the host Streptomyces albus J1074. Expanding this method to larger intermediates that require bimodular communication, we introduced RLs of divergent chemosimilarity into LipPKS2 and determined triketide lactone production. Collectively, we observed a statistically significant correlation between atom pair chemosimilarity and production, establishing a new chemoinformatic method that may aid in the engineering of PKSs to produce desired, unnatural products.

Figures
Products