Methylglucosylation of aromatic amino and phenolic moieties of drug-like biosynthons by combinatorial biosynthesis

Linan Xie, Liwen Zhang, Chen Wang, Xiaojing Wang, Ya ming Xu, Hefen Yu, Ping Wu, Shenglan Li, Lida Han, Leslie Gunatilaka, Xiaoyi Wei, Min Lin, Istvan Molnar, Yuquan Xu

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Glycosylation is a prominent strategy to optimize the pharmacokinetic and pharmacodynamic properties of drug-like small-molecule scaffolds by modulating their solubility, stability, bioavailability, and bioactivity. Glycosyltransferases applicable for “sugarcoating” various small-molecule acceptors have been isolated and characterized from plants and bacteria, but remained cryptic from filamentous fungi until recently, despite the frequent use of some fungi for whole-cell biocatalytic glycosylations. Here, we use bioinformatic and genomic tools combined with heterologous expression to identify a glycosyltransferase–methyltransferase (GT–MT) gene pair that encodes a methylglucosylation functional module in the ascomycetous fungus Beauveria bassiana. The GT is the founding member of a family nonorthologous to characterized fungal enzymes. Using combinatorial biosynthetic and biocatalytic platforms, we reveal that this GT is a promiscuous enzyme that efficiently modifies a broad range of drug-like substrates, including polyketides, anthraquinones, flavonoids, and naphthalenes. It yields both O- and N-glucosides with remarkable regio- and stereospecificity, a spectrum not demonstrated for other characterized fungal enzymes. These glucosides are faithfully processed by the dedicated MT to afford 4-O-methyl-glucosides. The resulting “unnatural products” show increased solubility, while representative polyketide methylglucosides also display increased stability against glycoside hydrolysis. Upon methylglucosi-dation, specific polyketides were found to attain cancer cell line-specific antiproliferative or matrix attachment inhibitory activities. These findings will guide genome mining for fungal GTs with novel substrate and product specificities, and empower the efficient combinatorial biosynthesis of a broad range of natural and unnatural glycosides in total biosynthetic or biocatalytic formats.

Original languageEnglish (US)
Pages (from-to)E4980-E4989
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number22
DOIs
StatePublished - May 29 2018

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Keywords

  • Combinatorial biosynthesis
  • Fungi
  • Glycosyltransferase
  • O-methyltransferase
  • Polyketide

ASJC Scopus subject areas

  • General

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