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

Proceedings of the National Academy of Sciences of the United States of America
Linan XieYuquan Xu

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 gl...Continue Reading

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Citations

Sep 29, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Monika DymarskaEdyta Kostrzewa-Susłow
Mar 17, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Fangmin DouBaoqing Dun
Aug 29, 2020·International Journal of Molecular Sciences·Mateusz ŁużnyTomasz Janeczko
Aug 14, 2019·Applied Microbiology and Biotechnology·Samir Bahadur ThapaJae Kyung Sohng
Jul 26, 2019·Scientific Reports·Ewa KozłowskaTomasz Janeczko
Nov 6, 2020·International Journal of Biological Macromolecules·Bing LiuRui Bao
Feb 11, 2021·Natural Product Research·Tatsuro YoneyamaAkemi Umeyama
Mar 30, 2021·Journal of Agricultural and Food Chemistry·Mateusz ŁużnyTomasz Janeczko
Jul 12, 2019·Journal of Agricultural and Food Chemistry·Linan XieYuquan Xu

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