Efficient Synthesis of Glucovanillin and Elucidation of Its Molecular Mechanisms in Ameliorating T2DM via Core Target...

This study focuses on the synthesis of glucovanillin mediated by UGT109A1 and its mechanism against Type 2 Diabetes Mellitus (T2DM). Recombinant UGT109A1 successfully synthesized glucovanillin from vanillin using UDP-Glc as the sugar donor. Through network pharmacology, 140 potential targets were identified. Seven key targets were further screened using LASSO and SVM-RFE algorithms. Among these, SLC5A1 and ADK showed strong diagnostic potential, with AUC values ranging from 0.85 to 0.89. Immune infiltration analysis linked these core targets to M2 macrophages. Single-cell transcriptomics revealed that ADK is widely expressed but enriched in B cells, while TLR9 is confined to plasmacytoid dendritic cells (pDCs). Cell-to-cell communication analysis identified a pDC-to-B cell signaling axis. In vitro assays demonstrated that glucovanillin exhibits concentration-dependent inhibitory activity against α-glucosidase with moderate potency, with an IC₅₀ of 413.84 ± 12.80 μM. Molecular docking, 200 ns molecular dynamics simulations (MD), and MM/PBSA calculations showed that glucovanillin binds more strongly to α-glucosidase (-7.4 kcal/mol) than vanillin (-5.4 kcal/mol). Therefore, the glycosylation mediated by UGT109A1 enhanced the bioactivity and targeting specificity of vanillin. In summary, glucovanillin exerts anti-T2DM effects through a dual mechanism involving α-glucosidase inhibition and regulation of key targets, making it a promising lead compound for T2DM treatment.