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Information on EC 3.2.1.114 - mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase and Organism(s) Drosophila melanogaster and UniProt Accession Q24451
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3.2.1.114 mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidaseIUBMB Comments
The enzyme, found in plants and animals, participates in the processing of N-glycans in the Golgi apparatus. It removes two mannosyl residues, one linked by alpha1,3 linkage, and the other linked by alpha1,6 linkage, both of which are removed by the same catalytic site. The enzyme is sensitive to swainsonine.
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Word Map
- 3.2.1.114
- swainsonine
-
n-linked
- n-glycans
- brefeldin
- castanospermine
-
endoglycosidase
-
asparagine-linked
-
high-mannose
-
hybrid-type
-
complex-type
- alpha-mannosidases
-
locoweed
-
indolizidine
- 1-deoxymannojirimycin
-
locoism
- kifunensine
- giantin
- medicine
-
swainsonine-treated
- man5glcnac
-
intra-golgi
- 1-deoxynojirimycin
- oxytropis
-
high-mannose-type
- beta-cop
- mannostatins
- glcnacman5glcnac2
- biotechnology
- drug development
- pharmacology
The taxonomic range for the selected organisms is: Drosophila melanogaster
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Synonyms
mannosidase ii, jack bean alpha-mannosidase, man2a1, alpha-mannosidase iix, dgmii, manii, alpha-mii, drosophila gmii, alpha-d-mannosidase ii, afams1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Golgi alpha-mannosidase II
-
alpha-D-mannosidase II
-
-
-
-
alpha-mannosidase II
alpha-mannosidase III
-
-
-
-
alpha1-3,6-mannosidase
-
-
-
-
exo-1,3-1,6-alpha-mannosidase
-
-
-
-
GlcNAc transferase I-dependent alpha1,3[alpha1,6]mannosidase
-
-
-
-
Golgi alpha-mannosidase II
Man II
-
-
-
-
MAN IIx
-
-
-
-
ManIII
-
-
-
-
mannosidase II
-
-
-
-
mannosidase, exo-1,3-1,6-alpha-
-
-
-
-
mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase
-
-
-
-
additional information
alpha-mannosidase II
-
-
-
-
Golgi alpha-mannosidase II
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Man5GlcNAc3-[protein] + 2 H2O = Man3GlcNAc3-[protein] + 2 alpha-D-mannopyranose
catalytic mechanism
-
Man5GlcNAc3-[protein] + 2 H2O = Man3GlcNAc3-[protein] + 2 alpha-D-mannopyranose
catalytic mechanism
Man5GlcNAc3-[protein] + 2 H2O = Man3GlcNAc3-[protein] + 2 alpha-D-mannopyranose
the conformational change of the bound mannoside to a high-energy B2,5 conformation is facilitated by steric hindrance from, and the formation of strong hydrogen bonds to, resiude D204
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of O-glycosyl bond
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
(1->3)-(1->6)-mannosyl-oligosaccharide alpha-D-mannohydrolase (configuration-retaining)
The enzyme, found in plants and animals, participates in the processing of N-glycans in the Golgi apparatus. It removes two mannosyl residues, one linked by alpha1,3 linkage, and the other linked by alpha1,6 linkage, both of which are removed by the same catalytic site. The enzyme is sensitive to swainsonine.
CAS REGISTRY NUMBER
COMMENTARY
349553-33-9
alpha-mannosidase III
82047-77-6
alpha-mannosidase II
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2,4-dinitrophenyl alpha-D-mannoside + H2O
2,4-dinitrophenol + alpha-D-mannose
-
-
?
2,4-dinitrophenyl-alpha-D-mannopyranoside + H2O
2,4-dinitrophenol + D-mannose
-
-
-
?
2,5-dinitrophenyl-alpha-D-mannopyranoside + H2O
2,5-dinitrophenol + alpha-D-mannose
pH 5.6, room temperature
-
-
?
2,5-dinitrophenyl-alpha-D-mannopyranoside + H2O
2,5-dinitrophenol + D-mannose
-
-
-
?
2-(acetylamino)-2-deoxy-beta-D-glucopyranosyl-(1->2)-alpha-D-mannopyranosyl-(1->3)-[alpha-D-mannopyranosyl-(1->3)-alpha-D-mannopyranosyl-(1->6)]-beta-D-mannopyranosyl-(1->4)-2-(acetylamino)-2-deoxy-alpha-D-glucopyranose + H2O
2-(acetylamino)-2-deoxy-beta-D-glucopyranosyl-(1->2)-alpha-D-mannopyranosyl-(1->3)-[alpha-D-mannopyranosyl-(1->6)]-beta-D-mannopyranosyl-(1->4)-2-(acetylamino)-2-deoxy-alpha-D-glucopyranose + D-mannose
-
-
-
ir
2-(acetylamino)-2-deoxy-beta-D-glucopyranosyl-(1->2)-alpha-D-mannopyranosyl-(1->3)-[alpha-D-mannopyranosyl-(1->3)-[alpha-D-mannopyranosyl-(1->6)]-alpha-D-mannopyranosyl-(1->6)]-beta-D-mannopyranosyl-(1->4)-2-(acetylamino)-2-deoxy-alpha-D-glucopyranose + H2O
2-(acetylamino)-2-deoxy-beta-D-glucopyranosyl-(1->2)-alpha-D-mannopyranosyl-(1->3)-[alpha-D-mannopyranosyl-(1->3)-alpha-D-mannopyranosyl-(1->6)]-beta-D-mannopyranosyl-(1->4)-2-(acetylamino)-2-deoxy-alpha-D-glucopyranose + D-mannose
-
-
-
ir
2-deoxy-2-fluoro-alpha-D-mannosyl fluoride
?
wild-type and D341N mutant GMII, acts as very slow substrate of the mutant enzyme with a rate-limiting deglycosylation step
-
-
?
4-nitrophenyl alpha-D-mannoside + H2O
4-nitrophenol + alpha-D-mannose
-
-
-
?
5-fluoro-beta-L-gulosyl fluoride + H2O
?
acts as slow substrate with a rate-limiting deglycosylation step, wild-type and D341N mutant GMII
-
-
?
4-methylumbelliferyl alpha-D-mannoside + H2O
4-methylumbelliferol + alpha-D-mannose
-
-
-
-
?
4-methylumbelliferyl alpha-D-mannoside + H2O
4-methylumbelliferone + alpha-D-mannose
-
-
-
?
4-nitrophenyl alpha-D-mannoside + H2O
4-nitrophenol + alpha-D-mannose
-
-
-
-
?
4-nitrophenyl-alpha-D-mannopyranoside + H2O
4-nitrophenol + alpha-D-mannose
30 min, 20°C
-
-
?
Manalpha(1-6)[Manalpha(1-3)]Manalpha(1-6)[GlcNAcbeta(1-2)Manalpha(1-3)]Manbeta(1-4)GlcNAcbeta(1-4)GlcNAc + 2 H2O
Manalpha(1-6)[GlcNAcbeta(1-2)Manalpha(1-3)]Manbeta(1-4)GlcNAcbeta(1-4)GlcNAc + 2 alpha-D-mannose
-
N-glycosylation pathway
-
?
additional information
?
-
enzyme/active site structure and substrate binding, catalytic mechanism
-
-
?
additional information
?
-
asparagine-linked glycoprotein biosynthesis
-
-
?
additional information
?
-
-
about 80-fold preference of isoform GMII for the cleavage of substrates containing a nonreducing beta-(1,2)-linked GlcNAc group
-
-
?
additional information
?
-
about 80-fold preference of isoform GMII for the cleavage of substrates containing a nonreducing beta-(1,2)-linked GlcNAc group
-
-
?
additional information
?
-
GMII is involved in the creation of glycoproteins that contain complex carbohydrates. It is responsible for the formation of the core trimannose structure to which all complex carbohydrates are appended. It catalyses the hydrolysis of an alpha(1,6)- and an alpha(1,3)-linked mannose from GlcNAc-Man5-GlcNAc2 to form GlcNAc-Man3-GlcNAc2-Asn-X
-
-
?
additional information
?
-
the cleavage mechanism involves formation of a covalent glycosyl-enzyme intermediate and results in net retention of configuration
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
Manalpha(1-6)[Manalpha(1-3)]Manalpha(1-6)[GlcNAcbeta(1-2)Manalpha(1-3)]Manbeta(1-4)GlcNAcbeta(1-4)GlcNAc + 2 H2O
Manalpha(1-6)[GlcNAcbeta(1-2)Manalpha(1-3)]Manbeta(1-4)GlcNAcbeta(1-4)GlcNAc + 2 alpha-D-mannose
-
N-glycosylation pathway
-
?
additional information
?
-
asparagine-linked glycoprotein biosynthesis
-
-
?
additional information
?
-
GMII is involved in the creation of glycoproteins that contain complex carbohydrates. It is responsible for the formation of the core trimannose structure to which all complex carbohydrates are appended. It catalyses the hydrolysis of an alpha(1,6)- and an alpha(1,3)-linked mannose from GlcNAc-Man5-GlcNAc2 to form GlcNAc-Man3-GlcNAc2-Asn-X
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Zn2+
Zn2+
Zn2+
di-epi-swainsonine has only a single hydroxyl group at C-8 interacting with the zinc ion of the enzyme
Zn2+
is involved in the catalytic activity of the enzyme and in the strong binding of inhibitors
Zn2+
-
GMII contains a Zn atom which forms contacts with substrate analogues, stabilizes catalytic intermediates, and other inhibitors observed in the active site
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(1R,2S,8aS)-1,2-dihydroxyoctahydrothieno[1,2-a]thiopyranium chloride
good inhibitor, lacks a hydroxyl group at C-5, more than 140fold better inhibitor of GMII than di-epi-swainsonine
(1S,2R,5R,8R,8aR)-5-[2-(4-tert-butylphenyl)ethyl]octahydroindolizine-1,2,8-triol
-
(1S,2R,5S,8R,8aR)-5-[2-(4-tert-butylphenyl)ethyl]octahydroindolizine-1,2,8-triol
-
(1S,2R,6R,7R,8S,8aS)-octahydroindolizine-1,2,6,7,8-pentol
most active
(2R,3R,4S)-2-([[(1S)-2-hydroxy-1-phenylethyl]amino]methyl)pyrrolidine-3,4-diol
-
(2R,3R,4S,5R)-2-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)-5-methylpyrrolidine-3,4-diol
-
(2R,3R,4S,5S)-6-amino-2-(hydroxymethyl)-2,3,4,5-tetrahydropyridine-3,4,5-triol
-
(2R,3S,4R)-2-[(1R)-1-hydroxyethyl]pyrrolidine-3,4-diol
most active
(2R,3S,4S)-1-[(2S,3S)-2,4-dihydroxy-3-(sulfooxy)butyl]-3,4-dihydroxy-2-(hydroxymethyl)tetrahydrothiophenium
-
(3R,4R,5R)-3,4-dihydroxy-5-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)-1-methylpyrrolidin-2-one
-
(3R,4R,5R)-3,4-dihydroxy-5-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)pyrrolidin-2-one
-
(3S,4S,5R,6R,E)-3,4,5-trihydroxy-6-(hydroxymethyl)piperidin-2-one O-4-chlorophenylcarbamoyl oxime
-
(5R,6R,7S,8R)-5-methyl-1,5,6,7,8,8a-hexahydrotetrazolo[1,5-a]pyridine-6,7,8-triol
-
(5R,6R,7S,8S)-5-(hydroxymethyl)-1,5,6,7,8,8a-hexahydroimidazo[1,2-a]pyridine-6,7,8-triol
-
1-(4-methylphenyl)-2-[(1S,2R,5R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizin-5-yl]ethanone
-
1-(4-tert-butylphenyl)-2-[(1S,2R,5R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizin-5-yl]ethanone
-
1-(4-tert-butylphenyl)-2-[(1S,2R,5S,8R,8aR)-1,2,8-trihydroxyoctahydroindolizin-5-yl]ethanone
-
1-phenyl-2-[(1S,2R,5R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizin-5-yl]ethanone
-
2-deoxy-2-fluoro-alpha-D-mannosyl fluoride
reversible, D341N mutant GMII
5-fluoro-beta-L-gulosyl fluoride
reversible, wild-type and D341N mutant GMII, inhibits only at low assay temperatures, acts as slow substrate at 37°C
N-[(R)-amino(phenyl)methyl]-5-thio-alpha-D-mannopyranosylamine
-
[[(3S,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)piperidin-2-ylidene]amino] N-(4-chlorophenyl)carbamate
-
(2S,3R,4S)-2-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)pyrrolidine-3,4-diol
-
(3R,4R,5S)-3,4-dihydroxy-5-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)-1-methylpyrrolidin-2-one
competitive inhibitor
(3R,4R,5S)-3,4-dihydroxy-5-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)pyrrolidin-2-one
competitve inhibitor
1-deoxymannojirimycin
-
more inhibitory than kifunensine, mode of binding
N-benzyl mannostatin A
-
structural basis of the inhibition of Golgi alpha-mannosidase II and the role of the thiomethyl moiety in ligand-protein interactions, overview
(2R,3R,4S)-2-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)pyrrolidine-3,4-diol
-
(2R,3R,4S)-2-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)pyrrolidine-3,4-diol
-
1-deoxyaminocyclopentitetrol
-
structural basis of the inhibition of Golgi alpha-mannosidase II and the role of the thiomethyl moiety in ligand-protein interactions, overview
Mannostatin A
-
structural basis of the inhibition of Golgi alpha-mannosidase II and the role of the thiomethyl moiety in ligand-protein interactions, overview
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
25
2-deoxy-2-fluoro-alpha-D-mannosyl fluoride
pH 5.6, 37°C, above, wild-type GMII
0.2
5-fluoro-beta-L-gulosyl fluoride
pH 5.6, 37°C, wild-type GMII
0.05
2,4-dinitrophenyl alpha-D-mannoside
pH 5.6, 37°C, D341N mutant GMII
5.5
2,4-dinitrophenyl alpha-D-mannoside
pH 5.6, 37°C, wild-type GMII
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0051
5-fluoro-beta-L-gulosyl fluoride
pH 5.6, 37°C, wild-type GMII
0.048
2,4-dinitrophenyl alpha-D-mannoside
pH 5.6, 37°C, D341N mutant GMII
8.6
2,4-dinitrophenyl alpha-D-mannoside
pH 5.6, 37°C, wild-type GMII
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000076
(1R,2R,3R,4S,5R)-4-amino-5-methoxycyclopentane-1,2,3-triol
-
0.00002
(1S,2R,8R,8aR)-octahydroindolizine-1,2,8-triol
20C, pH 6.8
0.067
(2R,3R,4S)-2-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)pyrrolidine-3,4-diol
20C, pH 6.8
0.001
(3R,4R,5R)-3,4-dihydroxy-5-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)-1-methylpyrrolidin-2-one
20C, pH 6.8
0.022
(3R,4R,5R)-3,4-dihydroxy-5-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)pyrrolidin-2-one
20C, pH 6.8
0.52
(3S,4S,5R,6R,E)-3,4,5-trihydroxy-6-(hydroxymethyl)piperidin-2-one O-4-chlorophenylcarbamoyl oxime
-
0.0027
1-(4-methylphenyl)-2-[(1S,2R,5R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizin-5-yl]ethanone
pH 5.75, 25°C
0.0027
1-(4-tert-butylphenyl)-2-[(1S,2R,5R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizin-5-yl]ethanone
pH 5.75, 25°C
0.0028
1-phenyl-2-[(1S,2R,5R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizin-5-yl]ethanone
pH 5.75, 25°C
7.5
2-deoxy-2-fluoro-alpha-D-mannosyl fluoride
pH 5.6, 37°C, D341N mutant GMII
0.6
5-fluoro-beta-L-gulosyl fluoride
pH 5.6, 37°C, D341N mutant GMII
0.52
[[(3S,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)piperidin-2-ylidene]amino] N-(4-chlorophenyl)carbamate
pH 5.6
0.000076
(1R,2R,3R,4S,5R)-4-amino-5-methoxycyclopentane-1,2,3-triol
-
0.067
(2S,3R,4S)-2-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)pyrrolidine-3,4-diol
-
0.001
(3R,4R,5S)-3,4-dihydroxy-5-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)-1-methylpyrrolidin-2-one
-
0.022
(3R,4R,5S)-3,4-dihydroxy-5-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)pyrrolidin-2-one
-
additional information
additional information
although too weak for full Ki analyses with the amounts of material available, all analogues with salacinol-like stereochemistry at positions 2 and 3 proved to be weak inhibitors of the enzyme with IC50 values of approximately 7.5 mM
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00025
(1S,2R,5R,8R,8aR)-5-[2-(4-tert-butylphenyl)ethyl]octahydroindolizine-1,2,8-triol
Drosophila melanogaster
pH 5.75, 25°C
0.000044
(1S,2R,5S,8R,8aR)-5-[2-(4-tert-butylphenyl)ethyl]octahydroindolizine-1,2,8-triol
Drosophila melanogaster
pH 5.75, 25°C
0.8
(2R,3R,4S)-2-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)pyrrolidine-3,4-diol
Drosophila melanogaster
-
0.72
(2R,3R,4S)-2-([[(1S)-2-hydroxy-1-phenylethyl]amino]methyl)pyrrolidine-3,4-diol
Drosophila melanogaster
-
1
(2R,3R,4S,5R)-2-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)-5-methylpyrrolidine-3,4-diol
Drosophila melanogaster
-
0.000029
1-(4-methylphenyl)-2-[(1S,2R,5R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizin-5-yl]ethanone
Drosophila melanogaster
pH 5.75, 25°C
0.000029
1-(4-tert-butylphenyl)-2-[(1S,2R,5R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizin-5-yl]ethanone
Drosophila melanogaster
pH 5.75, 25°C
0.00025
1-(4-tert-butylphenyl)-2-[(1S,2R,5S,8R,8aR)-1,2,8-trihydroxyoctahydroindolizin-5-yl]ethanone
Drosophila melanogaster
pH 5.75, 25°C
0.00003
1-phenyl-2-[(1S,2R,5R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizin-5-yl]ethanone
Drosophila melanogaster
pH 5.75, 25°C
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
5.75
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
SwissProt
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
type II transmembrane protein with short cytoplasmic tail, single transmembrane domain and large hydrophilic C-terminal domain
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). MAN2_DROME
1108
1
126721
Swiss-Prot
Secretory Pathway (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
by hanging-drop vapor diffusion method, GMII in complex with inhibitors di-epi-swainsonine and 8-epi-lentiginosine, both adopt a 3C6/E7 conformation, water molecule substructure in the active site plays a significant role in dictating inhibitory activity
enzyme with bound unhibitors, X-ray diffraction structure determination and analysis
GMII complexed with inhibitors (2R,3R,4S)-2-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)pyrrolidine-3,4-diol, (2R,3R,4S)-2-([[(1S)-2-hydroxy-1-phenylethyl]amino]methyl)pyrrolidine-3,4-diol, and (2R,3R,4S,5R)-2-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)-5-methylpyrrolidine-3,4-diol, to 1.30-1.45 A resolution
in complex with inhibitor mannostatin A and its derivatives. The interaction with the backbone carbonyl of residue R876 is crucial to the high potency of the inhibitor and enhanced by the hydrophobic interaction between the thiomethyl group and an aromatic pocket vivinal to the cleavage site
in complex with inhibitors (3R,4R,5R)-3,4-dihydroxy-5-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)pyrrolidin-2-one and (3R,4R,5R)-3,4-dihydroxy-5-([[(1R)-2-hydroxy-1-phenylethyl]amino]methyl)-1-methylpyrrolidin-2-one, to 1.08 A and 1.74 A resolution, respectively
in complex with inhibitors mannoimidazole, glucoimidazole, N-octyl-6-epi-valienamine, gluco-hydroxyiminolactam, and [[(3S,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)piperidin-2-ylidene]amino] N-(4-chlorophenyl)carbamate
in complex with natural substrate GlcNAcMan5GlcNAc2 and with oligosaccharide Man5. The natural substrate binds in a large groove on the surface of the enzyme. This groove contains the site of the nucleophile D204, acid/base catalyst D341, and zinc ion. substrate binding does not induce any noticeable conformational change. the larger active site cleft contains three sugar-binding subsites
mutants D204A and D341N in complex with 2,4-dinitrophenyl-alpha-D-mannopyranoside and in complex with oligosaccharides containing an alpha-(1,6)-or alpha-(1,3)-linked 1-thio-alpha-mannoside
crystal structure of enzyme with bound inhibitors kifunensine, swainsonine and 1-deoxymannojirimycin
-
enzyme in complex with inhibitors mannostatin A, N-benzyl mannostatin A, and 1-deoxyaminocyclopentitetrol, crystal growth overnight of enzyme solved in phosphate buffered reservoir solution, crystals are soaked for 3-6 h in 10 mM ligand solution, co-crystallization in Tris buffer without phosphate washing, X-ray diffraction structure determination and analysis, molecular modelling and structure simulation, overview
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D204A
almost complete loss of activity. Residue D204 is involved in the conformational change of the bound mannoside to a high-energy B2,5 conformation. In the mutant, mannose adopts the low-energy 4C1 conformation
D341N
D204A
mutant of Drosophila melanogaster, residual mannosidase activity
D341N
mutant with removed acid/base catalyst, 2fold lower Km and 200fold kcat values compared with the wild-type enzyme
D341N
almost complete loss of activity. Substrate mannose is found in a distorted high energy B2,5 conformation, which is necessary for it to fit in the confined space of the binding pocket
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
GmII is cloned, sequenced and localized to a single site, 85D14-18, on the right arm of chromosome 3
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
the enzyme Golgi alpha-mannosidase II is a promising target for intervention in the glycosylation process
medicine
promising target for drug development in anti-tumor therapies, ability of seven available docking programs to predict the binding mode and binding affinity of alpha-mannosidase II inhibitors
drug development
-
development of specific inhibitors of GMII that can lead to novel anti-metastatic or anti-inflammatory compounds
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Shah, N.; Kuntz, D.A.; Rose, D.R.
Comparison of kifunensine and 1-deoxymannojirimycin binding to class I and II alpha-mannosidases demonstrates different saccharide distortions in inverting and retaining catalytic mechanisms
Biochemistry
42
13812-13816
2003
Drosophila melanogaster
Foster, J.M.; Yudkin, B.; Lockyer, A.E.; Roberts, D.B.
Cloning and sequence analysis of GmII, a Drosophila melanogaster homologue of the cDNA encoding murine Golgi alpha-mannosidase II
Gene
154
183-186
1995
Drosophila melanogaster (Q24451), Drosophila melanogaster, Mus musculus
Numao, S.; Kuntz, D.A.; Withers, S.G.; Rose, D.R.
Insights into the mechanism of Drosophila melanogaster Golgi alpha-mannosidase II through the structural analysis of covalent reaction intermediates
J. Biol. Chem.
278
48074-48083
2003
Drosophila melanogaster (Q24451)
Moremen, K.W.
Golgi alpha-mannosidase II deficiency in vertebrate systems: implications for asparagine-linked oligosaccharide processing in mammals
Biochim. Biophys. Acta
1573
225-235
2002
Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus
Kawatkar, S.P.; Kuntz, D.A.; Woods, R.J.; Rose, D.R.; Boons, G.J.
Structural basis of the inhibition of Golgi alpha-mannosidase II by mannostatin A and the role of the thiomethyl moiety in ligand-protein interactions
J. Am. Chem. Soc.
128
8310-8319
2006
Drosophila melanogaster
Kuntz, D.A.; Ghavami, A.; Johnston, B.D.; Pinto, B.M.; Rose, D.R.
Crystallographic analysis of the interactions of Drosophila melanogaster Golgi alpha-mannosidase II with the naturally occurring glycomimetic salacinol and its analogues
Tetrahedron Asymmetry
16
25-32
2005
Drosophila melanogaster (Q24451)
-
Kuntz, D.A.; Liu, H.; Bols, M.; Rose, D.R.
The role of the active site Zn in the catalytic mechanism of the GH38 Golgi alpha -mannosidase II: implications from noeuromycin inhibition
Biocatal. Biotransform.
24
55-61
2006
Drosophila melanogaster
-
Englebienne, P.; Fiaux, H.; Kuntz, D.A.; Corbeil, C.R.; Gerber-Lemaire, S.; Rose, D.R.; Moitessier, N.
Evaluation of docking programs for predicting binding of Golgi alpha-mannosidase II inhibitors: a comparison with crystallography
Proteins
69
160-176
2007
Drosophila melanogaster (Q24451)
Kumar, N.S.; Kuntz, D.A.; Wen, X.; Pinto, B.M.; Rose, D.R.
Binding of sulfonium-ion analogues of di-epi-swainsonine and 8-epi-lentiginosine to Drosophila Golgi alpha-mannosidase II: The role of water in inhibitor binding
Proteins
71
1484-1496
2008
Drosophila melanogaster (Q24451)
Kuntz, D.A.; Tarling, C.A.; Withers, S.G.; Rose, D.R.
Structural analysis of Golgi alpha-mannosidase II inhibitors identified from a focused glycosidase inhibitor screen
Biochemistry
47
10058-10068
2008
Drosophila melanogaster (Q24451)
Fiaux, H.; Kuntz, D.A.; Hoffman, D.; Janzer, R.C.; Gerber-Lemaire, S.; Rose, D.R.; Juillerat-Jeanneret, L.
Functionalized pyrrolidine inhibitors of human type II alpha-mannosidases as anti-cancer agents: optimizing the fit to the active site
Bioorg. Med. Chem.
16
7337-7346
2008
Canavalia ensiformis, Drosophila melanogaster, Drosophila melanogaster (Q24451), Homo sapiens
Kuntz, D.A.; Zhong, W.; Guo, J.; Rose, D.R.; Boons, G.J.
The molecular basis of inhibition of Golgi alpha-mannosidase II by mannostatin A
ChemBioChem
10
268-277
2009
Drosophila melanogaster, Drosophila melanogaster (Q24451)
Zhong, W.; Kuntz, D.A.; Ember, B.; Singh, H.; Moremen, K.W.; Rose, D.R.; Boons, G.J.
Probing the substrate specificity of Golgi alpha-mannosidase II by use of synthetic oligosaccharides and a catalytic nucleophile mutant
J. Am. Chem. Soc.
130
8975-8983
2008
Drosophila melanogaster, Drosophila melanogaster (Q24451)
Shah, N.; Kuntz, D.A.; Rose, D.R.
Golgi alpha-mannosidase II cleaves two sugars sequentially in the same catalytic site
Proc. Natl. Acad. Sci. USA
105
9570-9575
2008
Drosophila melanogaster (Q24451), Drosophila melanogaster
Kuntz, D.A.; Nakayama, S.; Shea, K.; Hori, H.; Uto, Y.; Nagasawa, H.; Rose, D.R.
Structural investigation of the binding of 5-substituted swainsonine analogues to Golgi alpha-mannosidase II
ChemBioChem
11
673-680
2010
Drosophila melanogaster (Q24451)
Petersen, L.; Ardevol, A.; Rovira, C.; Reilly, P.J.
Molecular mechanism of the glycosylation step catalyzed by Golgi alpha-mannosidase II: a QM/MM metadynamics investigation
J. Am. Chem. Soc.
132
8291-8300
2010
Drosophila melanogaster (Q24451)
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