Reshaping the 2‐Pyrone Synthase Active Site for Chemoselective Biosynthesis of Polyketides

Zhou, Yu; Mirts, Evan N.; Yook, Sangdo; Waugh, Matthew; Martini, Rachel; Jin, Yong‐Su; Lu, Yi

doi:10.1002/ange.202212440

Title: Reshaping the 2‐Pyrone Synthase Active Site for Chemoselective Biosynthesis of Polyketides

Journal Article · Tue Dec 20 00:00:00 UTC 2022 · Angewandte Chemie

DOI: https://doi.org/10.1002/ange.202212440 · OSTI ID:1905903

^[1]; Mirts, Evan N. ^[2]; Yook, Sangdo ^[3]; Waugh, Matthew ^[2]; Martini, Rachel ^[4];

^[3];

^[1]

DOE Center for Advanced Bioenergy and Bioproducts Innovation University of Illinois at Urbana-Champaign 1206 W Gregory Dr Urbana IL 61801 USA, Department of Chemistry The University of Texas at Austin 105 E 24th St Austin TX 78712 USA
DOE Center for Advanced Bioenergy and Bioproducts Innovation University of Illinois at Urbana-Champaign 1206 W Gregory Dr Urbana IL 61801 USA
DOE Center for Advanced Bioenergy and Bioproducts Innovation University of Illinois at Urbana-Champaign 1206 W Gregory Dr Urbana IL 61801 USA, Department of Food Science and Human Nutrition University of Illinois at Urbana-Champaign 905 S. Goodwin Avenue Urbana IL 61801 USA, Carl R. Woese Institute for Genomic Biology University of Illinois at Urbana-Champaign 1206 W Gregory Dr Urbana IL 61801 USA
Department of Biochemistry University of Illinois at Urbana-Champaign 600 South Mathews Avenue Urbana IL 61801 USA

Abstract Engineering enzymes with novel reactivity and applying them in metabolic pathways to produce valuable products are quite challenging due to the intrinsic complexity of metabolic networks and the need for high in vivo catalytic efficiency. Triacetic acid lactone (TAL), naturally generated by 2‐pyrone synthase (2PS), is a platform molecule that can be produced via microbial fermentation and further converted into value‐added products. However, these conversions require extra synthetic steps under harsh conditions. We herein report a biocatalytic system for direct generation of TAL derivatives under mild conditions with controlled chemoselectivity by rationally engineering the 2PS active site and then rewiring the biocatalytic pathway in the metabolic network of E. coli to produce high‐value products, such as kavalactone precursors, with yields up to 17 mg/L culture. Computer modeling indicates sterics and hydrogen‐bond interactions play key roles in tuning the selectivity, efficiency and yield.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: SC0018420

OSTI ID:: 1905903

Journal Information:: Angewandte Chemie, Journal Name: Angewandte Chemie Journal Issue: 5 Vol. 135; ISSN 0044-8249

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: Germany

Language:: English

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