The maturation of N-
glycans to complex type structures on cellular and secreted
proteins is essential for the roles that these structures play in cell adhesion and recognition events in metazoan organisms. Critical steps in the biosynthetic pathway leading from high
mannose to complex structures include the trimming of
mannose residues by processing
mannosidases in the endoplasmic reticulum (ER) and Golgi complex. These exo-
mannosidases comprise two separate families of
enzymes that are distinguished by enzymatic characteristics and sequence similarity. Members of the Class 2
mannosidase family (glycosylhydrolase family 38) include
enzymes involved in trimming reactions in N-
glycan maturation in the Golgi complex (Golgi
mannosidase II) as well as catabolic
enzymes in lysosomes and cytosol. Studies on the
biological roles of complex type N-
glycans have employed a variety of strategies including the treatment of cells with
glycosidase inhibitors, characterization of human patients with enzymatic defects in processing
enzymes, and generation of mouse models for the
enzyme deficiency by selective gene disruption approaches. Corresponding studies on Golgi
mannosidase II have employed
swainsonine, an
alkaloid natural plant product that causes "locoism", a phenocopy of the
lysosomal storage disease,
alpha-mannosidosis, as a result of the additional targeting of the broad-specificity lysosomal
mannosidase by this compound. The human deficiency in Golgi
mannosidase II is characterized by
congenital dyserythropoietic anemia with
splenomegaly and various additional abnormalities and complications. Mouse models for Golgi
mannosidase II deficiency recapitulate many of the pathological features of the human disease and confirm that the unexpectedly mild effects of the
enzyme deficiency result from a tissue-specific and
glycoprotein substrate-specific alternate pathway for synthesis of complex N-
glycans. In addition, the mutant mice develop symptoms of a systemic autoimmune disorder as a consequence of the altered glycosylation. This review will discuss the biochemical features of Golgi
mannosidase II and the consequences of its deficiency in mammalian systems as a model for the effects of alterations in vertebrate N-
glycan maturation during development.