N-terminal catalytic domain of eukaryotic class II alpha-mannosidases; glycoside hydrolase family 38 (GH38)
The family corresponds to a group of eukaryotic class II alpha-mannosidases (AlphaMII), which contain Golgi alpha-mannosidases II (GMII), the major broad specificity lysosomal alpha-mannosidases (LAM, MAN2B1), the noval core-specific lysosomal alpha 1,6-mannosidases (Epman, MAN2B2), and similar proteins. GMII catalyzes the hydrolysis of the terminal both alpha-1,3-linked and alpha-1,6-linked mannoses from the high-mannose oligosaccharide GlcNAc(Man)5(GlcNAc)2 to yield GlcNAc(Man)3(GlcNAc)2 (GlcNAc, N-acetylglucosmine), which is the committed step of complex N-glycan synthesis. LAM is a broad specificity exoglycosidase hydrolyzing all known alpha 1,2-, alpha 1,3-, and alpha 1,6-mannosidic linkages from numerous high mannose type oligosaccharides. Different from LAM, Epman can efficiently cleave only the alpha 1,6-linked mannose residue from (Man)3GlcNAc, but not (Man)3(GlcNAc)2 or other larger high mannose oligosaccharides, in the core of N-linked glycans. Members in this family are retaining glycosyl hydrolases of family GH38 that employs a two-step mechanism involving the formation of a covalent glycosyl enzyme complex. Two carboxylic acids positioned within the active site act in concert: one as a catalytic nucleophile and the other as a general acid/base catalyst.
Structure:3CZN; Drosophila melanogaster Golgi Alpha-Mannosidase II (D204A nucleophile mutant) binds GnMan5Gn/Zn2+ in the active site, contacts at 4A
Comment:Drosophila melanogaster Golgi Alpha-Mannosidase II (3CZN) contains an active site made up of three sugar-binding subsites (the catalytic, holding, and anchor sites) and a Zn2+ binding site
Jiyao W et al.(2023). "The conserved domain database in 2023.",