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Expanding Extender Substrate Selection for Unnatural Polyketide Biosynthesis by Acyltransferase Domain Exchange within a Modular Polyketide Synthase
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- Englund, Elias (författare)
- KTH,Science for Life Laboratory, SciLifeLab,Joint BioEnergy Inst, Emeryville, CA 94608 USA.
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- Schmidt, Matthias (författare)
- Joint 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.
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- Nava, Alberto A. (författare)
- 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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- (creator_code:org_t)
- American Chemical Society (ACS), 2023
- 2023
- Engelska.
- Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 145:16, s. 8822-8832
- Tidskriftsartikel (refereegranskat)
Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
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