Biosynthesis of a Tricyclo[6.2.2.02,7]dodecane System by a Berberine Bridge Enzyme-Like Aldolase

Hang Li, Jinyu Hu, Haochen Wei, Peter S. Solomon, Keith A. Stubbs, Yit Heng Chooi

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Abstract

The aldol reaction is one of the most fundamental stereocontrolled carbon–carbon bond-forming reactions and is mainly catalyzed by aldolases in nature. Despite the fact that the aldol reaction has been widely proposed to be involved in fungal secondary metabolite biosynthesis, a dedicated aldolase that catalyzes stereoselective aldol reactions has only rarely been reported in fungi. Herein, we activated a cryptic polyketide biosynthetic gene cluster that was upregulated in the fungal wheat pathogen Parastagonospora nodorum during plant infection; this resulted in the production of the phytotoxic stemphyloxin II (1). Through heterologous reconstruction of the biosynthetic pathway and in vitro assay by using cell-free lysate from Aspergillus nidulans, we demonstrated that a berberine bridge enzyme (BBE)-like protein SthB catalyzes an intramolecular aldol reaction to establish the bridged tricyclo[6.2.2.02,7]dodecane skeleton in the post-assembly tailoring step. The characterization of SthB as an aldolase enriches the catalytic toolbox of classic reactions and the functional diversities of the BBE superfamily of enzymes.

Original languageEnglish
JournalChemistry - A European Journal
DOIs
Publication statusE-pub ahead of print - 25 Sep 2019

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