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Expanding Extender ...
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Englund, EliasKTH,Science for Life Laboratory, SciLifeLab,Joint BioEnergy Inst, Emeryville, CA 94608 USA.
(author)
Expanding Extender Substrate Selection for Unnatural Polyketide Biosynthesis by Acyltransferase Domain Exchange within a Modular Polyketide Synthase
- Article/chapterEnglish2023
Publisher, publication year, extent ...
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American Chemical Society (ACS),2023
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Numbers
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LIBRIS-ID:oai:DiVA.org:kth-326911
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https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-326911URI
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https://doi.org/10.1021/jacs.2c11027DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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QC 20230515
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Modular polyketide synthases (PKSs) are poly-merases that employ alpha-carboxyacyl-CoAs as extender substrates. This enzyme family contains several catalytic modules, where each module is responsible for a single round of polyketide chain extension. Although PKS modules typically use malonyl-CoA or methylmalonyl-CoA for chain elongation, many other malonyl-CoA analogues are used to diversify polyketide structures in nature. Previously, we developed a method to alter an extension substrate of a given module by exchanging an acyltransferase (AT) domain while maintaining protein folding. Here, we report in vitro polyketide biosynthesis by 13 PKSs (the wild-type PKS and 12 AT-exchanged PKSs with unusual ATs) and 14 extender substrates. Our similar to 200 in vitro reactions resulted in 13 structurally different polyketides, including several polyketides that have not been reported. In some cases, AT-exchanged PKSs produced target polyketides by >100-fold compared to the wild-type PKS. These data also indicate that most unusual AT domains do not incorporate malonyl-CoA and methylmalonyl-CoA but incorporate various rare extender substrates that are equal to in size or slightly larger than natural substrates. We developed a computational workflow to predict the approximate AT substrate range based on active site volumes to support the selection of ATs. These results greatly enhance our understanding of rare AT domains and demonstrate the benefit of using the proposed PKS engineering strategy to produce novel chemicals in vitro.
Subject headings and genre
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Schmidt, MatthiasJoint BioEnergy Inst, Emeryville, CA 94608 USA.;Lawrence Berkeley Natl Lab, Biol Syst & Engn Div, Berkeley, CA 94720 USA.;Rhein Westfal TH Aachen, Inst Appl Microbiol, Aachen Biol & Biotechnol, D-52074 Aachen, Germany.
(author)
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Nava, Alberto A.Lawrence Berkeley Natl Lab, Biol Syst & Engn Div, Berkeley, CA 94720 USA.;Univ Calif Berkeley, Dept Chem & Biomol Engn, Berkeley, CA 94720 USA.
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Lechner, AnnaUniv Calif Berkeley, Dept Chem & Biomol Engn, Berkeley, CA 94720 USA.;Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA.
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Deng, KaiJoint BioEnergy Inst, Emeryville, CA 94608 USA.;Sandia Natl Labs, Dept Biomat & Biomfg, Livermore, CA 94550 USA.
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Jocic, ReneeJoint BioEnergy Inst, Emeryville, CA 94608 USA.;Lawrence Berkeley Natl Lab, Biol Syst & Engn Div, Berkeley, CA 94720 USA.
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Lin, YingxinUniv Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
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Roberts, JacobLawrence Berkeley Natl Lab, Biol Syst & Engn Div, Berkeley, CA 94720 USA.;Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA.
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Benites, Veronica T.Joint BioEnergy Inst, Emeryville, CA 94608 USA.
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Kakumanu, RamuJoint BioEnergy Inst, Emeryville, CA 94608 USA.;Lawrence Berkeley Natl Lab, Biol Syst & Engn Div, Berkeley, CA 94720 USA.
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Gin, Jennifer W.Joint BioEnergy Inst, Emeryville, CA 94608 USA.;Lawrence Berkeley Natl Lab, Biol Syst & Engn Div, Berkeley, CA 94720 USA.
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Chen, YanJoint BioEnergy Inst, Emeryville, CA 94608 USA.;Lawrence Berkeley Natl Lab, Biol Syst & Engn Div, Berkeley, CA 94720 USA.
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Liu, YuzhongUniv Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA.
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Petzold, Christopher J.Joint BioEnergy Inst, Emeryville, CA 94608 USA.;Lawrence Berkeley Natl Lab, Biol Syst & Engn Div, Berkeley, CA 94720 USA.
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Baidoo, Edward E. K.Joint BioEnergy Inst, Emeryville, CA 94608 USA.;Lawrence Berkeley Natl Lab, Biol Syst & Engn Div, Berkeley, CA 94720 USA.
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Northen, Trent R.Joint BioEnergy Inst, Emeryville, CA 94608 USA.;Lawrence Berkeley Natl Lab, Environm Genom & Syst Biol Div, Berkeley, CA 94720 USA.
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Adams, Paul D.Joint BioEnergy Inst, Emeryville, CA 94608 USA.;Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA.;Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA.
(author)
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Katz, LeonardJoint BioEnergy Inst, Emeryville, CA 94608 USA.;Univ Calif Berkeley, Inst QB3, Berkeley, CA 94720 USA.
(author)
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Yuzawa, SatoshiJoint BioEnergy Inst, Emeryville, CA 94608 USA.;Lawrence Berkeley Natl Lab, Biol Syst & Engn Div, Berkeley, CA 94720 USA.;Keio Univ, Inst Adv Biosci, Tsuruoka, Yamagata 9970017, Japan.;Keio Univ, Grad Sch Media & Governance, Syst Biol Program, Fujisawa, Kanagawa 2520882, Japan.
(author)
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Keasling, Jay D.Joint BioEnergy Inst, Emeryville, CA 94608 USA.;Lawrence Berkeley Natl Lab, Biol Syst & Engn Div, Berkeley, CA 94720 USA.;Univ Calif Berkeley, Dept Chem & Biomol Engn, Berkeley, CA 94720 USA.;Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA.;Sandia Natl Labs, Dept Biomat & Biomfg, Livermore, CA 94550 USA.;Tech Univ Denmark, Novo Nord Fdn Ctr Biosustainabil, DK-2800 Kongens Lyngby, Denmark.;Shenzhen Inst Adv Technol, Ctr Synthet Biochem, Shenzhen 518055, Guangdong, Peoples R China.
(author)
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KTHScience for Life Laboratory, SciLifeLab
(creator_code:org_t)
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In:Journal of the American Chemical Society: American Chemical Society (ACS)145:16, s. 8822-88320002-78631520-5126
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Englund, Elias
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Schmidt, Matthia ...
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Nava, Alberto A.
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Lechner, Anna
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Deng, Kai
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Jocic, Renee
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Lin, Yingxin
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Roberts, Jacob
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Benites, Veronic ...
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Kakumanu, Ramu
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Gin, Jennifer W.
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Chen, Yan
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Liu, Yuzhong
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Petzold, Christo ...
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Baidoo, Edward E ...
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Northen, Trent R ...
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Adams, Paul D.
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Katz, Leonard
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Yuzawa, Satoshi
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Keasling, Jay D.
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Royal Institute of Technology