Mammalian α-mannosidases—multiple forms but a common purpose?

Abstract

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.

Purification and biochemica characterisation of endoplasmic reticulum α 1,2-mannosidase from Sporothrix schenckiil

“…Members of family 38 are less specific than enzymes from family 47, removing α1,2, α1,3 and α1,6-linked mannose units (Daniel et al 1994, Herscovics 1999a. Enzymes from family 47 are α1,2-mannosidases that participate in the trimming of N-glycans and in ER-associated degradation (Herscovics 1999a, b, 2001, Helenius & Aebi 2004.…”

Inhibition of the α-mannosidase Man2c1 gene expression enhances adhesion of Jurkat cells

“…Protein N-glycosylation plays important roles in immunity [1] and a-mannosidase is one type of the key enzymes in N-glycosylation [2][3][4][5]. Although many have been known on the molecular nature and function of these enzymes, the biological significance of a-mannosidases is still not completely understood.…”

“…The protein solution (25 µg in 20 µl) was subjected to 7.5% SDS/PAGE and then transferred onto a nitrocellulose membrane (Schleicher & Schuell). The membrane was blocked with TBS (150 mM NaCl, 20 mM Tris, 0.5% Tween 20) containing 3% BSA and incubated with mAb 6A8 [5], followed by incubation with horseradish peroxidase-conjugated rabbit anti-mouse IgG+IgM (Jackson Immunoresearch Laboratories). After thorough washing with TBS containing 3% BSA and Tween 20, the protein bands on the membranes were visualized by SuperSignal ® West Pico Trial Kit (Pierce).…”

“…a-Mannosidase is one type of the key enzymes in catalyzing N-glycosylation, which catalyzes the hydrolysis of terminal non-reducing a-D-mannose residues in a-d-mannosides and is involved in the trimming reaction during N-glycan maturation [2][3][4]. a-Mannosidase has multiple forms [5]. Based on the biochemical properties, catalytic mechanism and characteristic regions of conserved amino acid sequences, a-mannosidases have been divided into two broad classes, class I and class II [2][3][4][5].…”

“…a-Mannosidase has multiple forms [5]. Based on the biochemical properties, catalytic mechanism and characteristic regions of conserved amino acid sequences, a-mannosidases have been divided into two broad classes, class I and class II [2][3][4][5]. Class I enzyme contains glyco_hydro_47 domain and only cleaves a1,2-mannose residues.…”