Endoplasmic reticulum alpha-glucosidase I and II (ER alpha-glucosidase I/II)

Endoplasmic reticulum (ER) alpha-glucosidases I and II are essential enzymes located in the ER lumen that catalyze the initial steps of N-linked glycan processing (Burns and Touster, 1982). Alpha-glucosidase I (MOGS) removes the terminal alpha-1,2-linked glucose residue, while alpha-glucosidase II (a heterodimer of GANAB and PRKCSH) removes the two subsequent alpha-1,3-linked glucose residues from the Glc3Man9GlcNAc2 precursor (Grinna and Robbins, 1979). This sequential trimming is a prerequisite for glycoproteins to enter the calnexin/calreticulin chaperone cycle, which facilitates proper protein folding and quality control (Dalziel et al., 2014). Many enveloped viruses, such as Dengue, Ebola, and SARS-CoV-2, depend on these host enzymes for the maturation of their surface glycoproteins, making them attractive targets for broad-spectrum antiviral therapy (Kiappes et al., 2018). Inhibition of these enzymes by iminosugars like celgosivir or UV-4 leads to the production of misfolded viral proteins that are subsequently degraded, thereby reducing viral titers (Whitby et al., 2005). Beyond infectious diseases, these enzymes are implicated in cancer progression and genetic disorders like polycystic liver and kidney disease (Porath et al., 2016). However, the clinical utility of ER alpha-glucosidase inhibitors is often hampered by gastrointestinal toxicity resulting from the cross-inhibition of intestinal glucosidases (Reuser and Wisselaar, 1994).

Other names

MOGSGANABPRKCSHMannosyl-oligosaccharide glucosidaseGlucosidase IIGCS1ER alpha-glucosidase IER alpha-glucosidase IIGIIGlucosidase II alpha subunitGlucosidase II beta subunit

ER alpha-glucosidase inhibitors act as structural mimetics of glucose, competitively binding to the active sites of alpha-glucosidase I and II. This prevents the removal of terminal glucose residues from N-linked glycans on nascent proteins, which is a critical step for entry into the calnexin/calreticulin chaperone system. Consequently, glycoproteins fail to fold correctly and are targeted for endoplasmic reticulum-associated degradation (ERAD), a mechanism that is particularly effective against the maturation of viral envelope proteins and certain oncogenic factors (Kiappes et al., 2018; Dalziel et al., 2014).