Regioselective Glycosylation of Demethylbellidifolin by Glycosyltransferase AbCGT Yields Potent Anti-Renal Fibrosis Compound

TL;DR

Scientists used an enzyme to create a new compound that may help treat kidney fibrosis by improving the properties of a natural substance.

Contribution

A novel glycosyltransferase-based system was developed to produce a potent anti-renal fibrosis compound through regioselective glycosylation.

Findings

The compound 1,3,5,8-tetrahydroxyxanthone 5-O-β-D-glucopyranoside showed significant anti-renal fibrotic activity.

A UDP-glucose recycling system improved the production of the target glycoside.

A F138A mutant of AbCGT increased glycosylation yield by 2.3-fold.

Abstract

Glycosylation serves as an effective strategy to enhance the solubility, bioavailability, and pharmacological activity of polyhydroxyphenols. In this study, we explored the glycosylation of natural and natural-inspired phenolic compounds using the glycosyltransferase AbCGT and evaluated the anti-renal fibrotic potential of the resulting glycosides. Among them, 1,3,5,8-tetrahydroxyxanthone 5-O-β-D-glucopyranoside (2-1a), synthesized via the regioselective 5-O-glycosylation of demethylbellidifolin, demonstrated significant anti-renal fibrotic activity. In contrast, its homologous glycosyltransferase, UGT73AE1, predominantly glycosylated demethylbellidifolin at the 3-OH position. Molecular docking studies revealed the structural basis for this regioselectivity difference. To enhance the production of 2-1a, we established a UDP-glucose (UDPG) recycling system by coupling AbCGT with Glycine max sucrose synthase (GmSuSy) and subsequently optimized the reaction conditions. Furthermore, targeted mutagenesis of AbCGT informed by molecular docking analysis identified a F138A mutant that enhanced glycosylation yield by 2.3-fold. This work develops a novel glycosyltransferase-based catalytic system and identifies a new compound with potential anti-renal fibrotic activity.

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