MAMMALIAN ALPHA-MANNOSIDASES-MULTIPLE FORMS BUT A COMMON PURPOSE

Previously, alpha-mannosidases were classified as enzymes that process newly formed N-glycans or degrade mature glycoproteins. In this revie w we suggest that two endoplasmic reticulum (ER) alpha-mannosidases, p reviously assigned processing roles, have important catabolic activiti es. Based on new evidence, we propose that the ER/cytosolic mannosidas e is involved in the degradation of dolichol intermediates that are no t needed for protein glycosylation, whereas the soluble form of Man(9) -mannosidase is responsible for the degradation of glycans on defectiv e or malfolded proteins that are specifically retained and broken dean in the ER. The degradation of oligosaccharides derived from dolichol intermediates by ER/cytosolic mannosidase now explains why cats and ca ttle with alpha-mannosidosis store and excrete some unexpected oligosa ccharides containing only one GlcNAc residue. Similarly, the action of ER/cytosolic mannosidase, followed by the action of the recently desc ribed human lysosomal alpha(1-->6)-mannosidase, together explain why a lpha-mannosidosis patients store and excrete large amounts of oligosac charides that resemble biosynthetic intermediates, rather than partial ly degraded glycans. The relative contributions of the lysosomal and e xtra-lysosomal catabolic pathways can be derived by comparing the rati o of trisaccharide Man beta(1-->4)GlcNAc beta(1-->4)GlcNAc to disaccha ride Man beta(1-->4)GlcNAc accumulated in tissues from goats with beta -mannosidosis. A similar determination in human beta-mannosidosis pati ents is not possible because the same intermediate, Man beta(1-->4)Glc NAc is a product of both pathways. Based on inhibitor studies with pyr anose and furanose analogues, alpha-mannosidases may be divided into t wo groups. Those in Class 1 are (1-->2)-specific enzymes like Golgi ma nnosidase I, whereas those in Class 2, like lysosomal alpha-mannosidas e, can hydrolyse (1-->2), (1-->3) and (1-->6) linkages. A similar clas sification has recently been derived by others from protein sequence h omologies. Based on this new classification of the alpha-mannosidases, it is possible to speculate about their probable evolution from two p rimordial genes. The first would have been a Class 1 ER enzyme involve d 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 pr ocessing or catabolic functions, would have developed from these, by l oss or gain of critical insertion or retention sequences, to yield the full complement of alpha-mannosidases known today.