Cell-surface terminal galactose residues on N-linked glycans (Terminal Gal)

Cell-surface terminal galactose residues on N-linked glycans are carbohydrate structures located at the non-reducing ends of complex oligosaccharides attached to cell-surface proteins. These residues serve as critical recognition motifs for various endogenous and exogenous agents, most notably acting as the primary receptor for adeno-associated virus serotype 9 (AAV9) (Shen et al., 2011). AAV9 is a prominent vector used in gene therapy, such as onasemnogene abeparvovec, where its binding to terminal galactose facilitates viral entry into target tissues like the central nervous system and heart. In the liver, these residues are recognized by the asialoglycoprotein receptor (ASGPR), which mediates the endocytosis and clearance of desialylated glycoproteins from the blood (Ashwell & Morell, 1974). This hepatic clearance mechanism is frequently exploited for liver-targeted drug delivery using galactose or N-acetylgalactosamine (GalNAc) conjugates. Furthermore, the galactosylation state of the Fc region of therapeutic monoclonal antibodies influences their effector functions, including complement-dependent cytotoxicity (CDC) (Aoyama et al., 2019). Pathological changes in terminal galactosylation, such as the reduction of galactose on IgG, are established biomarkers for autoimmune conditions like rheumatoid arthritis (Parekh et al., 1985). Additionally, certain terminal galactose structures, such as alpha-gal, can trigger severe IgE-mediated hypersensitivity reactions in humans (Commins et al., 2009).

Other names

Terminal galactoseGalactose residuesAsialoglycanDesialylated N-glycanN-linked terminal galactoseGalactose-terminated N-glycan

Terminal galactose residues serve as the primary attachment factor and receptor for adeno-associated virus serotype 9 (AAV9), facilitating viral entry into target cells (Bell et al., 2011). They also act as ligands for the asialoglycoprotein receptor (ASGPR) on hepatocytes, mediating the rapid clearance of desialylated glycoproteins from circulation (Ashwell & Morell, 1974). In the context of therapeutic antibodies, terminal galactosylation of the Fc region modulates effector functions such as complement-dependent cytotoxicity (CDC) by influencing C1q binding (Aoyama et al., 2019).