Endoplasmic reticulum alpha-glucosidase I

Endoplasmic reticulum (ER) alpha-glucosidase I is an essential enzyme located in the lumen of the endoplasmic reticulum. It catalyzes the initial trimming step by removing the outermost α-1,2-linked glucose residue from Glc₃Man₉GlcNAc₂ oligosaccharides attached to nascent glycoproteins. This action is followed by further glucose removal by ER alpha-glucosidase II. The sequential trimming facilitates binding to chaperones such as calnexin and calreticulin, which are crucial for correct protein folding and quality control within the ER. Properly folded proteins are then transported to the Golgi apparatus for further processing; misfolded proteins may be retained in the ER or targeted for degradation via ER-associated degradation (ERAD). Inhibition of ER alpha-glucosidases disrupts viral envelope glycoprotein maturation, impairing morphogenesis and infectivity of many enveloped viruses including hepatitis C virus (HCV), dengue virus, influenza virus, flaviviruses, and filoviruses. The gene encoding this enzyme is essential: knockout or severe mutation impairs quality control mechanisms within cells leading to accumulation of misfolded proteins and potential cell stress responses or disease phenotypes.

Inhibition of ER alpha-glucosidase I disrupts viral envelope glycoprotein maturation, impairing morphogenesis and infectivity of many enveloped viruses. Selective inhibition can be achieved with specific iminosugars that mimic substrate structure.