Aglycone-dependent binding of high-mannose-type glycans by UDP-glucose: glycoprotein glucosyltransferase 1: Relationship between hydrophobicity and activity.

The endoplasmic reticulum glycoprotein quality control system regulates glycoprotein fate through glycan-mediated signaling. UDP-glucose: glycoprotein glucosyltransferase 1 (UGGT1) plays a central role in recognizing misfolded glycoproteins and promoting their refolding by reglucosylating their high-mannose-type-glycans. Based on previous studies that investigated UGGT1 function using glycoprotein-mimicking probes, the hydrophobicity of the aglycone may be related to UGGT1 activity. Herein, we report a systematic study on the relationship between UGGT1 activity and the hydrophobicity of aglycones using Man9GlcNAc2-type glycan derivatives with structurally diverse aglycone structures. A positive relationship was observed between the calculated partition coefficient (CLogP) of the aglycones and UGGT1-mediated glucose transfer, and this relationship was maintained across structurally diverse aglycones. Notably, the hydroxy-containing coumarin aglycone examined in this study deviated from this relationship, suggesting that additional interactions, such as hydrogen bonding, may contribute to substrate binding beyond hydrophobic effects. These findings identify aglycone hydrophobicity as an important physicochemical factor associated with UGGT1 activity and provide a practical guideline for the rational design of glycan-based probes.