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A "biphasic glycosyltransferase high-throughput screen" identifies novel anthraquinone glycosides in the diversification of phenolic natural products.
Mohideen, F Ifthiha; Kwan, David H.
Affiliation
  • Mohideen FI; Department of Biology, Centre for Applied Synthetic Biology, and Centre for Structural and Functional Genomics, Concordia University, Montreal, Quebec, Canada.
  • Kwan DH; Department of Biology, Centre for Applied Synthetic Biology, and Centre for Structural and Functional Genomics, Concordia University, Montreal, Quebec, Canada; Department of Chemistry and Biochemistry, Concordia University, Montreal, Quebec, Canada; PROTEO, Quebec Network for Research on Protein Function, Quebec City, Quebec, Canada. Electronic address: david.kwan@concordia.ca.
J Biol Chem ; 299(3): 102931, 2023 03.
Article in En | MEDLINE | ID: mdl-36682498
ABSTRACT
The sugar moieties of many glycosylated small molecule natural products are essential for their biological activity. Glycosyltransferases (GTs) are enzymes responsible for installing these sugar moieties on a variety of biomolecules. Many GTs active on natural products are inherently substrate promiscuous and thus serve as useful tools in manipulating natural product glycosylation to generate new combinations of sugar units (glycones) and scaffold molecules (aglycones) in a process called glycodiversification. It is important to have an effective screening tool to detect the activity of promiscuous enzymes and their resulting glycoside products. Toward this aim, we developed a strategy for screening natural product GTs in a high-throughput fashion enabled by rapid isolation and detection of chromophoric or fluorescent glycosylated natural products. This involves a solvent extraction step to isolate the resulting polar glycoside product from the unreacted aglycone acceptor substrate and the detection of the formed glycoside by the innate absorbance or fluorescence of the aglycone moiety. Using our approach, we screened a collection of natural product GTs against a panel of precursors to therapeutically important molecules. Three GTs showed previously unreported promiscuity toward anthraquinones resulting in novel ε-rhodomycinone glycosides. Considering the pharmaceutical value of clinically used anthraquinone glycosides that are biosynthesized from an ε-rhodomycinone precursor, and the significance that the sugar moiety has on the biological activity of these drugs, our results are of particular importance toward the glycodiversification of therapeutics in this class. The GTs identified and the novel compounds they produce show promise toward new biocatalytic tools and therapeutics.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Biological Products / Glycosyltransferases / Drug Discovery / Glycosides Language: En Journal: J Biol Chem Year: 2023 Document type: Article Affiliation country: Canada

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Biological Products / Glycosyltransferases / Drug Discovery / Glycosides Language: En Journal: J Biol Chem Year: 2023 Document type: Article Affiliation country: Canada