Functions (from Uniprot)

Catalyzes the first committed step in the biosynthesis of complex N-glycans. It controls conversion of high mannose to complex N-glycans; the final hydrolytic step in the N-glycan maturation pathway.

Catalytic activity (from Uniprot)

Hydrolysis of the terminal (1->3)- and (1->6)-linked alpha-D-mannose residues in the mannosyl-oligosaccharide Man₅(GlcNAc)₃.

Disease relevance of MAN2A1

• Incomplete synthesis of N-glycans in congenital dyserythropoietic anemia type II caused by a defect in the gene encoding alpha-mannosidase II [1].
• In Vero monkey cells and HEp-2 human epidermoid carcinoma cells infected with herpes simplex virus 1 the proteins beta-COP, galactosyltransferase, and alpha-mannosidase II associated with the Golgi apparatus appear to be associated with numerous smaller structures dispersed throughout the cytoplasm [2].
• In this report, the enzyme activities and the expression levels of mRNAs of N-acetylglucosaminyltransferases (GnT)-I to -V, beta-1,4-galactosyltransferase, and alpha-mannosidase II in normal human placentae and three human choriocarcinoma cell lines were investigated [3].
• Swainsonine produces minimal toxicity when administered i.v. to cancer patients at dosages that inhibit both Golgi alpha-mannosidase II and lysosomal alpha-mannosidases [4].
• The indolizidine alkaloid swainsonine, a potent inhibitor of Golgi alpha-mannosidase II, has been shown to reduce tumor cell metastasis, enhance cellular immune responses, and reduce solid tumor growth in mice [5].

High impact information on MAN2A1

• Alpha-mannosidase-II (alphaM-II) catalyzes the first committed step in the biosynthesis of complex asparagine-linked (N-linked) oligosaccharides (N-glycans) [6].
• After 1 h at 37 degrees C, VT1B accumulated in a juxtanuclear structure that colocalized with several Golgi markers, including alpha-mannosidase II, beta-COP, and NBD-ceramide [7].
• Isolation, characterization, and expression of cDNAs encoding murine alpha-mannosidase II, a Golgi enzyme that controls conversion of high mannose to complex N-glycans [8].
• Transient expression of the alpha-mannosidase II cDNA in COS cells resulted in 8-12-fold overexpression of enzyme activity, and the appearance of cross-reactive material in a perinuclear membrane array consistent with a Golgi localization [8].
• We have isolated overlapping clones from a murine cDNA library encoding the full length alpha-mannosidase II open reading frame and most of the 5' and 3' untranslated region [8].

Chemical compound and disease context of MAN2A1

• A 48 h pretreatment of two malignant and invasive human melanoma cell lines with either swainsonine (an inhibitor of Golgi alpha-mannosidase II) or deoxymannojirimycin (a Golgi alpha-mannosidase I inhibitor) resulted in a dose-dependent decrease in the cells' ability to invade a reconstituted basement membrane in vitro [9].

Biological context of MAN2A1

• Partial human alpha-mannosidase II cDNA clones were also isolated and the gene was localized to human chromosome 5 [8].
• Many proteins synthesized through the secretory pathway receive posttranslational modifications, including N-glycosylation. alpha-Mannosidase II (MII) is a key enzyme converting precursor high-mannose-type N-glycans to matured complex-type structures [10].
• Novel purification of the catalytic domain of Golgi alpha-mannosidase II. Characterization and comparison with the intact enzyme [11].
• This results in reduced levels and/or altered Golgi localization of alpha-mannosidase II and beta-1,4 galactosyltransferase I, which links it to the glycosylation deficiency [12].
• Previously, we cloned and characterized an insect (Sf9) cell cDNA encoding a class II alpha-mannosidase with amino acid sequence and biochemical similarities to mammalian Golgi alpha-mannosidase II [13].

Anatomical context of MAN2A1

• Rat liver alpha-mannosidase II, a hydrolase involved in the processing of asparagine-linked oligosaccharides, is an integral membrane glycoprotein facing the lumen of Golgi membranes [11].
• This staining pattern was similar to that of alpha-mannosidase II which is a known resident enzyme of the Golgi complex [14].
• Morphological observations further revealed that alpha-mannosidase II (a cis/medial-Golgi marker), but not TGN38 (a trans-Golgi network marker), rapidly redistributes to the ER in the presence of NDGA, resulting in the disappearance of the characteristic Golgi structure [15].
• CS-HA1 mutants colocalized with ER markers, e.g., calreticulin, and partially overlapped with Golgi complex markers, e.g., alpha-mannosidase II, in HeLa cells and myotubes [16].
• Analysis of these induced storage products by h.p.l.c. showed that both compounds also inhibited Golgi alpha-mannosidase II and that 6-deoxy-6-fluoro-DIM was also a good inhibitor of the endoplasmic reticulum alpha-mannosidase and specific lysosomal alpha (1-6)-mannosidase [17].

Associations of MAN2A1 with chemical compounds

• Golgi alpha-mannosidase II (GlcNAc transferase I-dependent alpha 1,3[alpha 1,6] mannosidase, EC 3.2.1.114) catalyzes the final hydrolytic step in the N-glycan maturation pathway acting as the committed step in the conversion of high mannose to complex type structures [8].
• (a) The catalytic activity of the intact and cleaved forms of alpha-mannosidase II were indistinguishable in Km, Vmax, inhibition by the alkaloid, swainsonine, and in their activity toward the natural substrate GlcNAc-Man5GlcNAc [11].
• The GalNAc bearing hybrid structures, either with or without sulfate, cannot be processed to mono- or disulfated complex oligosaccharides due to the inability of either alpha-mannosidase II or GlcNAc-transferase II to act on GalNAc containing oligosaccharides [18].
• When N-acetyl-beta-glucosaminidase or alpha-mannosidase II was inhibited by specific inhibitors, the amount of terminal N-acetylglucosamine in hemagglutinin from Sf9 cells was significantly enhanced [19].
• Thus novel glycosylation pathways have been uncovered in two such knockouts, namely alpha-mannosidase II null mice and UDP-N-acetylglucosamine: alpha 6-D-mannoside beta 1,2-N-acetylglucosaminyltransferase II null mice [20].

Co-localisations of MAN2A1

• When coexpressed with alpha-mannosidase II, alpha-mannosidase IIx colocalizes with alpha-mannosidase II in COS cells [21].

Other interactions of MAN2A1

• Previously, we isolated a cDNA encoding a protein homologous to alpha-mannosidase II and designated it alpha-mannosidase IIx [21].
• The PEC(Z)/PBs were next transfected with the alpha 1,2 mannosidase Ib (Man Ib), N-acetylglucosaminyltransferase I (GnT-I) or alpha-mannosidase II (Man II) gene in order to reduce the levels of high mannose type of N-glycan [22].
• The amino acid sequence of several peptide regions, including a calcium-binding consensus sequence, bears striking similarities to an ER alpha-1,2-mannosidase from yeast, whereas, by contrast, no sequence similarity was detectable with rat liver ER alpha-mannosidase and Golgi alpha-mannosidase II [23].
• Biochemical data support the hypothesis that this disease is due to a deficiency of N-acetylglucosaminyltransferase II (GnT II) or alpha-Mannosidase II (alpha-Man II), which represent the key to glycosylation [24].
• Most recently a HEMPAS case has been identified as being defective in the gene encoding Golgi alpha-mannosidase II by using cDNA probe of alpha-mannosidase II [25].

Analytical, diagnostic and therapeutic context of MAN2A1

• Molecular cloning and expression of cDNAs encoding human alpha-mannosidase II and a previously unrecognized alpha-mannosidase IIx isozyme [26].
• Immunofluorescence analysis showed a distinct perinuclear pattern of XT-I-GFP and XT-II-GFP similar to that of alpha-mannosidase II, which is a known enzyme of the Golgi cisternae [27].
• In patients receiving swainsonine (50-550 micrograms/kg per day) continuously for 5 days by intravenous infusion, serum concentrations of the drug reached 3-11.8 mg/L, 100 to 400 times greater than the 50% inhibitory concentration for Golgi alpha-mannosidase II and lysosomal alpha-mannosidases [28].
• Degenerate primers against conserved regions in known class II alpha-mannosidase protein sequences were used to generate an alpha-mannosidase II-specific PCR product from Sf9 cell DNA [29].
• Southern blotting indicated that alpha-mannosidase II is a single copy gene in Sf9 cells [29].

References