Structure, mechanism and inhibition of Golgi α-mannosidase II

The mature N-glycan on human glycoproteins is built up by the activity and regulation of enzymes in the endoplasmic reticulum and Golgi apparatus. A key enzyme in the maturation of N-glycans is the first glycoside hydrolase in the Golgi pathway, alpha-mannosidase II (GMII). This enzyme has the unusual ability to cleave two different glycosidic linkages in it catalytic center. As such, it removes two terminal mannoses following the activity of N-acetyl-glucosaminyl transferase I, and is a critical step in the formation of mature glycans. Structural analyses of the Drosophila homologue of GMII have led to insights into its unusual mechanism and substrate specificity. In addition, the results build the foundation for the development of specific clinically relevant inhibitors.