Biosynthesis of AS2077715 and Funiculosin: Pathway Reconstitution and Identification of Enzymes that Form the All-cis Cyclopentanetetraol Moiety

Abstract

The complete biosynthetic pathways of the potent antifungals AS2077715 (1) and funiculosin (2) are reconstituted and characterized. A five-enzyme cascade, including a multifunctional flavin-dependent monooxygenease and a repurposed Omethyltransferase, is involved to perform the dearomatization, stereoselective ring contraction, and redox transformations to morph a hydroxyphenyl-containing precursor into the unusual all-cis cyclopentanetetraol moiety.

Sorbremnoids A and B: NLRP3 Inflammasome Inhibitors Discovered from Spatially Restricted Crosstalk of Biosynthetic Pathways

“…Enzymatic ring contraction in conjugated benzene systems is rare, exemplified by the ferredoxin-like protein AlpJ in kinamycin biosynthesis (Streptomyces ambofaciens) (Figure S65A) and the collaboration between a flavin-dependent monooxygenase (FMO) with a repurposed O -methyltransferase (OMT) in AS2077715 biosynthesis (Talaromyces coalescens) (Figure S65B). The annotation of BGC pci56 revealed five unique genes compared to its highly homologous agnPKS . These five genes encode two FMOs (Pci56F and Pci56J), a MT (Pc56D), a TF (Pc56H), and an MFS (Pc56G) (Figure S66).…”

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“…Biosynthetic studies have revealed the enzymes involved in the formation of the cyclopentanetetraol moiety of AS2077715 23 , a fungal natural product from Capnodium species 339855. 21 A series of flavin-dependent monooxygenases and an O -methyltransferase convert a hydroxyphenyl motif to the all- cis cyclopentanetetraol via dearomatisation, ring contraction and redox reactions.…”