Previously, alpha-
mannosidases were classified as
enzymes that process newly formed N-
glycans or degrade mature
glycoproteins. In this review, we suggest that two endoplasmic reticulum (ER) alpha-
mannosidases, previously assigned processing roles, have important catabolic activities. Based on new evidence, we propose that the ER/cytosolic
mannosidase is involved in the degradation of
dolichol intermediates that are not needed for protein glycosylation, whereas the soluble form of
Man9-mannosidase is responsible for the degradation of
glycans on defective or malfolded
proteins that are specifically retained and broken down in the ER. The degradation of
oligosaccharides derived from
dolichol intermediates by ER/cytosolic
mannosidase now explains why cats and cattle with
alpha-mannosidosis store and excrete some unexpected
oligosaccharides containing only one GlcNAc residue. Similarly, the action of ER/cytosolic
mannosidase, followed by the action of the recently described human lysosomal alpha(1 --> 6)-
mannosidase, together explain why
alpha-mannosidosis patients store and excrete large amounts of
oligosaccharides that resemble biosynthetic intermediates, rather than partially degraded
glycans. The relative contributions of the lysosomal and extra-lysosomal catabolic pathways can be derived by comparing the ratio of
trisaccharide Man beta (1 --> 4)GlcNAc beta (1 --> 4)GlcNAc to
disaccharide Man beta (1 --> 4)GlcNAc accumulated in tissues from goats with
beta-mannosidosis. A similar determination in human
beta-mannosidosis patients is not possible because the same intermediate, Man beta (1 --> 4)-GlcNAc is a product of both pathways. Based on inhibitor studies with pyranose and furanose analogues, alpha-
mannosidases may be divided into two groups. Those in Class 1 are (1 --> 2)-specific
enzymes like Golgi
mannosidase I, whereas those in Class 2, like
lysosomal alpha-mannosidase, can hydrolyse (1 --> 2), (1 --> 3) and (1 --> 6) linkages. A similar classification has recently been derived by others from protein sequence homologies. Based on this new classification of the alpha-
mannosidases, it is possible to speculate about their probable evolution from two primordial genes. The first would have been a Class 1 ER
enzyme involved in the degradation of
glycans on incompletely assembled or malfolded
glycoproteins. The second would have been a Class 2 lysosomal
enzyme responsible for turnover. Later, other alpha-
mannosidases, with new processing or catabolic functions, would have developed from these, by loss or gain of critical insertion or retention sequences, to yield the full
complement of alpha-
mannosidases known today.