Chemoinformatic-Guided Engineering of Polyketide Synthases.

Autor:	Zargar A; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States.; QB3 Institute, University of California-Berkeley, 5885 Hollis Street, Fourth Floor, Emeryville, California 94608, United States., Lal R; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Valencia L; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Wang J; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Backman TWH; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Cruz-Morales P; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Kothari A; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Werts M; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Wong AR; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Bailey CB; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States.; QB3 Institute, University of California-Berkeley, 5885 Hollis Street, Fourth Floor, Emeryville, California 94608, United States., Loubat A; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Liu Y; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Chen Y; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Chang S; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Benites VT; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States.; Department of Energy, Agile BioFoundry, Emeryville, California 94608, United States., Hernández AC; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Barajas JF; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States.; Department of Energy, Agile BioFoundry, Emeryville, California 94608, United States., Thompson MG; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Barcelos C; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Anayah R; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Martin HG; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States.; Department of Energy, Agile BioFoundry, Emeryville, California 94608, United States.; BCAM, Basque Center for Applied Mathematics, 48009 Bilbao, Spain., Mukhopadhyay A; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States., Petzold CJ; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States.; Department of Energy, Agile BioFoundry, Emeryville, California 94608, United States., Baidoo EEK; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States.; Department of Energy, Agile BioFoundry, Emeryville, California 94608, United States., Katz L; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; QB3 Institute, University of California-Berkeley, 5885 Hollis Street, Fourth Floor, Emeryville, California 94608, United States., Keasling JD; Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94710, United States.; QB3 Institute, University of California-Berkeley, 5885 Hollis Street, Fourth Floor, Emeryville, California 94608, United States.; Department of Chemical & Biomolecular Engineering, University of California, Berkeley, California 94720, United States.; Department of Bioengineering, University of California, Berkeley, California 94720, United States.; Novo Nordisk Foundation Center for Biosustainability, Technical University Denmark, DK2970 Horsholm, Denmark.; Synthetic Biochemistry Center, Institute for Synthetic Biology, Shenzhen Institutes for Advanced Technologies, 518055 Shenzhen, China.
Jazyk:	angličtina
Zdroj:	Journal of the American Chemical Society [J Am Chem Soc] 2020 Jun 03; Vol. 142 (22), pp. 9896-9901. Date of Electronic Publication: 2020 May 18.
DOI:	10.1021/jacs.0c02549
Abstrakt:	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.
Databáze:	MEDLINE
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