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.