Reshaping the 2‐Pyrone Synthase Active Site for Chemoselective Biosynthesis of Polyketides. Issue 5 (20th December 2022)

• Record Type: Journal Article
• Authors: Zhou, Yu; Mirts, Evan N.; Yook, Sangdo; Waugh, Matthew; Martini, Rachel; Jin, Yong‐Su; Lu, Yi
• Is Part Of: Angewandte Chemie international edition. Volume 62:Issue 5(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: biocatalysis -- metabolic engineering -- polyketides -- synthetic biology; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202212440
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : Implementation of novel synthetic pathways into metabolic network is challenging. Empowered by protein engineering and synthetic biology, a whole‐cell transformation process is reported to utilize engineered 2‐pyrone synthase with novel reactivity in metabolic networks to convert carboxylic acids and intracellular malonyl‐CoA directly into the pyrone products with high yields, catalytic efficiency and good selectivity.