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Enzyme Nomenclature
Information on EC 2.7.8.17 - UDP-N-acetylglucosamine-lysosomal-enzyme N-acetylglucosaminephosphotransferase
for references in articles please use BRENDA:EC2.7.8.17
Word Map on EC 2.7.8.17
- 2.7.8.17
- mucolipidosis
- mannose
- 6-phosphate
- i-cell
- glcnac-phosphotransferase
-
missorting
- mliii
- stuttering
- polydystrophy
-
gamma-subunits
-
phosphomannosyl
-
pseudo-hurler
-
nagpa
-
man-6-p
-
enzyme-targeting
- alpha-methylmannoside
- uteroferrin
- n-acetylglucosamine-1-phosphate
-
alpha2beta2gamma2
- medicine
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The enzyme appears in viruses and cellular organisms
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EC NUMBER 
COMMENTARY 
2.7.8.17
-
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RECOMMENDED NAME
GeneOntology No.
UDP-N-acetylglucosamine-lysosomal-enzyme N-acetylglucosaminephosphotransferase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose = UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose = UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
-
-
-
-
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose = UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
the alpa/beta subunits of GlcNAc-1-phosphotransferase recognize and bind the conformation-dependent protein determinant of acid hydrolases as well as critical lysines. The subunits then mediate the catalytic function of the transferase. Interaction of the alpa/beta subunits with the protein determinant of acid hydrolases stimulates the catalytic function of the transferase. The gamma subunit enhances the rate of GlcNAc-P transfer to the oligosaccharides of acid hydrolase acceptors. The requirement for the gamma subunit to achieve optimal levels of phosphorylation varies greatly among the different acid hydrolases, and in some instances the gamma subunit is dispensable
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
substituted phospho group transfer
-
-
-
-
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SYSTEMATIC NAME
IUBMB Comments
UDP-N-acetyl-D-glucosamine:lysosomal-enzyme N-acetylglucosaminephosphotransferase
Some other glycoproteins with high-mannose can act as acceptors, but much more slowly than lysosomal enzymes.
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CAS REGISTRY NUMBER
COMMENTARY
84012-69-1
-
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
alpha/beta-, and gamma-subunit encoding genes
Q3T906 AND Q9UJJ9
UniProt
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
additional information
malfunction
-
deletion of the Alg14 N-terminal region causes a severe growth defect at high temperature. Malfunction can be partially complemented by overexpression of Alg7
malfunction
-
extracts of two mutant cell lines transfer UDP-N-acetyl-D-glucosamine from N-acetyl-D-glucosamine to mannose residues at less than 5% the wild type value. In addition, the lysosomal hydrolases of these mutant clones fail to bind to a cation-independent mannose 6-phosphate receptor affinity column
malfunction
-
30% of the acid hydrolases of gamma gene knockout mice brain are phosphorylated at levels equivalent to that in wild-type brain, although 25% are poorly phosphorylated compared to wild-type. The rest of the acid hydrolases of the gamma-deficient sample are phosphorylated at an intermediate level. This shows that some acid hydrolases are highly dependent on the presence of the gamma subunit to acquire the Man-6-P, although others are well phosphorylated by the alpha/beta subunits alone
malfunction
-
mucolipidosis II (MLII) and III alpha/beta are autosomal-recessive diseases of childhood caused by mutations in GNPTAB encoding the alpha/beta-subunit precursor protein of the GlcNAc-1-phosphotransferase complex. Biological significance of eight selected disease-causing GNPTAB mutations found in MLII and MLIII alpha/beta patients in Brazil, overview. The frameshift E757KfsX1 and the non-sense R587X mutations result in a severe clinical phenotype in homozygosity. In addition to the loss of combinatorial cytosolic targeting motifs, luminal missense mutations located in the stealth region 2 of the alpha-subunit impair the transport of the alpha/beta-subunit precursor to the Golgi apparatus
malfunction
the lysosomal storage disorder ML III gamma is caused by defects in the gamma subunit of UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. In patients with this disorder, most of the newly synthesized lysosomal enzymes are secreted rather than being sorted to lysosomes, resulting in increased levels of these enzymes in the plasma. Several missense mutations in GNPTG, the gene encoding the gamma subunit, are reported in mucolipidosis III gamma patients. gamma-Subunit deficient HeLa cells have greatly reduced levels of many lysosomal acid hydrolases compared with the parental HeLa cells and display a lysosomal storage phenotype
malfunction
-
some mutations in the Stealth domain harboring the catalytic site greatly impaires the activity of the enzyme without affecting its Golgi localization and proteolytic processing. Missense mutations in conserved cysteine residues in the Notch repeat 1 domain do not affect the catalytic activity but impair mannose phosphorylation of certain lysosomal hydrolases
malfunction
-
some mutations in the Stealth domain harboring the catalytic site greatly impaires the activity of the enzyme without affecting its Golgi localization and proteolytic processing. Missense mutations in conserved cysteine residues in the Notch repeat 1 domain do not affect the catalytic activity but impair mannose phosphorylation of certain lysosomal hydrolases
malfunction
mucolipidoses II and III (ML II and MLIII) are lysosomal disorders in which the mannose 6-phosphate recognition marker is absent from lysosomal hydrolases and other glycoproteins due to mutations in GNPTAB, which encodes two of three subunits of the heterohexameric enzyme, N-acetylglucosamine-1-phosphotransferase. Both disorders are caused by the same gene, but ML II represents the more severe phenotype. Bone manifestations of ML II include hip dysplasia, scoliosis, rickets and osteogenesis imperfecta, phhentype overview. A recombinant adeno-associated viral vector (AAV2/8-GNPTAB) confers high and prolonged gene expression of GNPTAB and thereby influence the pathology in the cartilage and bone tissue of a GNPTAB knock out (KO) mouse model. AAV8-mediated expression of N-acetylglucosamine-1-phosphate transferase attenuates bone loss in a mouse model of mucolipidosis II with significant increases in bone mineral density and content
malfunction
-
recombinant GlcNAc-1-phosphotransferase containing a missense mutation in the DMAP interaction domain (Lys732Asn) identified in a patient with mucolipidosis II exhibits full activity toward the simple sugar alpha-methyl D-mannoside but impaired phosphorylation activity toward acid hydrolases, recombinant expression of the K732N mutant in a zebrafish model of mucolipidosis II fails to correct the phenotypic abnormalities
malfunction
-
loss of function results in impaired lysosomal targeting of these acid hydrolases and decreased lysosomal degradation. Two mucolipidosis III patient missense mutations, Lys4Gln and Ser15Tyr, in the N-terminal cytoplasmic tail of the alpha-subunit of phosphotransferase impair retention of the catalytically active enzyme in the Golgi complex. This results in mistargeting of the mutant enzymes to lysosomes, where they are degraded, or to the cell surface and release into the medium. The mislocalization of the active enzymes is the basis for mucolipidosis III alphabeta in a subset of patients
physiological function
-
the enzyme modifies lysosomal hydrolases with mannose 6-phosphate targeting signals. The proteolytic cleavage of alpha/beta-subunit precursor protein is a prerequisite for the catalytic activity of the GlcNAc-1-phosphotransferase and therefore plays an important role in the biogenesis of lysosomes
physiological function
the enzyme tags lysosomal enzymes with the mannose 6-phosphate lysosomal targeting signal. The gamma-subunit is required for efficient phosphorylation of a subset of the lysosomal enzymes
physiological function
-
the enzyme UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase is involved in lysosomal enzyme recognition. UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase tags newly synthesized lysosomal enzymes with mannose 6-phosphate recognition markers, which are required for their targeting to the endolysosomal system
physiological function
-
the enzyme UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase is involved in lysosomal enzyme recognition. UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase tags newly synthesized lysosomal enzymes with mannose 6-phosphate recognition markers, which are required for their targeting to the endolysosomal system
physiological function
-
the enzyme mediates the initial step in the addition of the mannose 6-phosphate targeting signal on newly synthesized lysosomal enzymes, which serves to direct the lysosomal enzymes to lysosomes. GlcNAc-1-phosphotransferase is able to distinguish the about 60 lysosomal enzymes from the numerous nonlysosomal glycoproteins with identical Asn-linked glycans, that lack a common structural motif. The two Notch repeat modules and the DNA methyltransferase-associated protein interaction domain of the alpha-subunit are key components of this recognition process. Different combinations of these domains are involved in binding to individual lysosomal enzymes. In the majority of instances the mannose 6-phosphate receptor homology domain of the gamma-subunit is required for optimal phosphorylation, the gamma-binding site is located on the alpha-subunit, the gamma-subunit binds to amino acids 535-694 of the alpha-subunit
physiological function
-
UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase mediates the initial step in the formation of the mannose 6-phosphate recognition signal on lysosomal acid hydrolases. The DMAP interaction domain of the alpha subunit functions in the selective recognition of acid hydrolase substrates
physiological function
-
the Golgi-localized enzyme mediates the first step in the synthesis of the mannose 6-phosphate recognition marker on lysosomal acid hydrolases
additional information
-
identification of domains of the enzyme involved in catalytic function, overview
additional information
-
identification of domains of the enzyme involved in catalytic function, overview
additional information
-
the lysosomal integral membrane protein type 2 (LIMP-2/SCARB2) is a mannose 6-phosphate-independent trafficking receptor for beta-glucocerebrosidase and no substrate of the enzyme, M6P-independent lysosomal sorting of LIMP-2, overview
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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
UDP-N-acetyl-D-glucosamine + alpha-methyl D-mannoside
UMP + 6-(N-acetyl-D-glucosaminyl-phospho)-alpha-methyl D-mannoside
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + alpha-methyl-D-mannoside
UMP + 6-(N-acetyl-D-glucosaminyl-phospho)-alpha-methyl D-mannoside
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + alpha-N-acetylglucosaminidase
UMP + ?
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + cathepsin A
UMP + ?
-
capthepsin A and cathepsin D have one closely related phosphotransferase recognition site represented by a structurally and topologically conserved beta-hairpin loop
-
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-cathepsin Z D-mannose
UMP + lysosomal-cathepsin Z N-acetyl-D-glucosaminyl-phospho-D-mannose
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
UDP-N-acetyl-D-glucosamine + methyl alpha-D-mannopyranoside
UMP + methyl (6-O-alpha-N-acetyl-D-glucosaminylphospho)-alpha-D-mannopyranoside
UDP-N-acetyl-D-glucosamine + methyl-alpha-D-mannoside
UMP + N-acetyl-D-glucosamine-phospho-(methyl-alpha-D-mannoside)
UDP-N-acetyl-D-glucosamine + beta-hexosaminidase
UMP + ?
-
the alpha-chain of beta-hexosaminidase is a poorer acceptor than the beta-chain, and the beta chain in the B isoenzyme is a better acceptor than the beta-chain in the A isoenzyme
-
-
?
UDP-N-acetyl-D-glucosamine + cathepsin D
UMP + ?
-
substitution of two lysines (E203K/E267K) of the substrate cathepsin D stimulates mannose phosphorylation 116fold. Subtitution of additional residues in the beta loop particularly lysines, increase phosphorylation 4fold further
-
-
?
UDP-N-acetyl-D-glucosamine + cathepsin D
UMP + ?
-
capthepsin A and cathepsin D have one closely related phosphotransferase recognition site represented by a structurally and topologically conserved beta-hairpin loop
-
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
Q3T906 AND Q9UJJ9
-
-
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
Q3T906 AND Q9UJJ9
-
localization of tagged protein products in the Golgi of wild-type and mutant enzymes expressing HeLa cells, overview
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
-
initial enzyme in biosynthesis of mannose 6-phosphate
-
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
-
substrates are lysosomal acid hydrolases
-
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
-
the specificity of the reaction is determined by the ability of the alpha/beta subunits to recognize a conformation-dependent protein determinant present on the acid hydrolases, the DNA methyltransferase-associated protein (DMAP) interaction domain of the alpha subunit functions in this recognition process. Recombinant GST-DMAP domain pulls down several acid hydrolases, but not nonlysosomal glycoproteins
-
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
Q69ZN6 AND Q6S5C2
-
-
-
?
UDP-N-acetyl-D-glucosamine + methyl alpha-D-mannopyranoside
UMP + methyl (6-O-alpha-N-acetyl-D-glucosaminylphospho)-alpha-D-mannopyranoside
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + methyl alpha-D-mannopyranoside
UMP + methyl (6-O-alpha-N-acetyl-D-glucosaminylphospho)-alpha-D-mannopyranoside
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + methyl-alpha-D-mannoside
UMP + N-acetyl-D-glucosamine-phospho-(methyl-alpha-D-mannoside)
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + methyl-alpha-D-mannoside
UMP + N-acetyl-D-glucosamine-phospho-(methyl-alpha-D-mannoside)
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + methyl-alpha-D-mannoside
UMP + N-acetyl-D-glucosamine-phospho-(methyl-alpha-D-mannoside)
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + methyl-alpha-D-mannoside
UMP + N-acetyl-D-glucosamine-phospho-(methyl-alpha-D-mannoside)
-
-
-
-
-
UDP-N-acetyl-D-glucosamine + methyl-alpha-D-mannoside
UMP + N-acetyl-D-glucosamine-phospho-(methyl-alpha-D-mannoside)
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + methyl-alpha-D-mannoside
UMP + N-acetyl-D-glucosamine-phospho-(methyl-alpha-D-mannoside)
-
-
-
-
?
additional information
?
-
-
the enzyme catalyzes the initial step in the synthesis of the mannose 6-phosphate determinant required for efficient intracellular targeting of newly synthesized lysosomal hydrolase to the lysosome
-
-
-
additional information
?
-
-
the enzyme is specific for lysosomally destined acceptor glycoproteins
-
-
-
additional information
?
-
enzyme catalyzes modification of lysosomal enzymes with mannose 6-phosphate. This modification is catalyzed by UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. The modified lysosomal enzymes are then targeted to the lysosome
-
-
-
additional information
?
-
-
the lysosomal integral membrane protein type 2 (LIMP-2/SCARB2) is a mannose 6-phosphate-independent trafficking receptor for beta-glucocerebrosidase and no substrate of the enzyme, M6P-independent lysosomal sorting of LIMP-2, overview. beta-Glucocerebrosidase is also no substrate for the enzyme
-
-
-
additional information
?
-
-
the critical step in lysosomal targeting of soluble lysosomal enzymes is the recognition by an UDP-N-acetylglucosamine:lysosomal enzyme-N-acetylglucosamine-1-phosphotransferase
-
-
-
additional information
?
-
-
UDPglucose is also a substrate with a catalytic efficiency about 12fold worse than UDP-GlcNAc. The enzyme phosphorylates lysosomal enzymes in an in vitro assay at least 100fold more efficiently than either other glycoproteins with similar carbohydrate chains or free oligosaccharides
-
-
-
additional information
?
-
-
the recognition and catalytic site of the phosphotransferase are located on different subunits
-
-
-
additional information
?
-
-
phosphorylated recognition markers in lysosomal enzymes appear to be synthesized by transfer of alpha-N-acetylglucosamine 1-phosphate groups to C6 hydroxyl of mannose residues in glycosylated enzyme precursors and a subsequent hydrolysis from the diester groups of the N-acetylglucosamine residue
-
-
-
UDP-N-acetyl-D-glucosamine + arylsulfatase A
additional information
-
-
binding of arylsulfatase A to the phosphotransferase is not restricted to a limited surface area but involves the simultaneous recognition of large parts of arylsulfatase A
-
-
?
UDP-N-acetyl-D-glucosamine + arylsulfatase A
additional information
-
-
mature arylsulfatase A from human urine
formation of GlcNAc(alpha1)phospho(6)mannose diesters in high mannose oligosaccharides in arylsulfatase A
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
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
UDP-N-acetyl-D-glucosamine + lysosomal-cathepsin Z D-mannose
UMP + lysosomal-cathepsin Z N-acetyl-D-glucosaminyl-phospho-D-mannose
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
Q3T906 AND Q9UJJ9
-
localization of tagged protein products in the Golgi of wild-type and mutant enzymes expressing HeLa cells, overview
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
-
initial enzyme in biosynthesis of mannose 6-phosphate
-
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
-
substrates are lysosomal acid hydrolases
-
-
?
UDP-N-acetyl-D-glucosamine + lysosomal-enzyme D-mannose
UMP + lysosomal-enzyme N-acetyl-D-glucosaminyl-phospho-D-mannose
Q69ZN6 AND Q6S5C2
-
-
-
?
additional information
?
-
-
the enzyme catalyzes the initial step in the synthesis of the mannose 6-phosphate determinant required for efficient intracellular targeting of newly synthesized lysosomal hydrolase to the lysosome
-
-
-
additional information
?
-
Q3T906
enzyme catalyzes modification of lysosomal enzymes with mannose 6-phosphate. This modification is catalyzed by UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. The modified lysosomal enzymes are then targeted to the lysosome
-
-
-
additional information
?
-
-
the lysosomal integral membrane protein type 2 (LIMP-2/SCARB2) is a mannose 6-phosphate-independent trafficking receptor for beta-glucocerebrosidase and no substrate of the enzyme, M6P-independent lysosomal sorting of LIMP-2, overview. beta-Glucocerebrosidase is also no substrate for the enzyme
-
-
-
additional information
?
-
-
the critical step in lysosomal targeting of soluble lysosomal enzymes is the recognition by an UDP-N-acetylglucosamine:lysosomal enzyme-N-acetylglucosamine-1-phosphotransferase
-
-
-
additional information
?
-
-
phosphorylated recognition markers in lysosomal enzymes appear to be synthesized by transfer of alpha-N-acetylglucosamine 1-phosphate groups to C6 hydroxyl of mannose residues in glycosylated enzyme precursors and a subsequent hydrolysis from the diester groups of the N-acetylglucosamine residue
-
-
-
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
Mn2+
Mg2+
-
the divalent cation requirement is satisfied by Mn2+ better than by Mg2+
Mn2+
-
the divalent cation requirement is satisfied by Mn2+ better than by Mg2+
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
cathepsin D
-
deglycosylated cathepsin D inhibits the activity of both forms of GlcNAc-1-phosphotransferase toward cathepsin D
-
additional information
-
selective inhibition of cathepsin D phosphorylation by rabbit anti-bovine GlcNAc phosphotransferase
-
additional information
-
most potent inhibition of phosphorylation by homologous peptides derived from the regions located on cathepsin molecules opposite to oligosaccharide chains which are phosphorylated by phosphotransferase
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.11
pro-tripeptidyl peptidase
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase; pH 7.4, 37°C, alpha2beta2 GlcNAc-1-phosphotransferase
-
1
soybean agglutinin
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase; pH 7.4, 37°C, alpha2beta2 GlcNAc-1-phosphotransferase
-
0.025
cathepsin D
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase; pH 7.4, 37°C, alpha2beta2 GlcNAc-1-phosphotransferase
-
3.3
Man9GlcNAc1 oligosaccharide
-
pH 7.4, 37°C, alpha2beta2 GlcNAc-1-phosphotransferase
5.7
Man9GlcNAc1 oligosaccharide
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase
33
methyl alpha-D-mannopyranoside
-
pH 7.4, 37°C, alpha2beta2 GlcNAc-1-phosphotransferase
48
methyl alpha-D-mannopyranoside
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase
0.033
uteroferrin
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase
-
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.11
cathepsin D
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase
-
0.75
Man9GlcNAc1 oligosaccharide
-
pH 7.4, 37°C, alpha2beta2 GlcNAc-1-phosphotransferase
1.55
Man9GlcNAc1 oligosaccharide
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase
0.5
methyl alpha-D-mannopyranoside
-
pH 7.4, 37°C, alpha2beta2 GlcNAc-1-phosphotransferase
0.75
methyl alpha-D-mannopyranoside
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase
0.008
pro-tripeptidyl peptidase
-
pH 7.4, 37°C, alpha2beta2 GlcNAc-1-phosphotransferase
-
0.038
pro-tripeptidyl peptidase
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase
-
0.0041
soybean agglutinin
-
pH 7.4, 37°C, alpha2beta2 GlcNAc-1-phosphotransferase
-
0.005
soybean agglutinin
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase
-
0.033
uteroferrin
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase
-
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0166
methyl alpha-D-mannopyranoside
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase; pH 7.4, 37°C, alpha2beta2 GlcNAc-1-phosphotransferase
0.09
RNase B
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase; pH 7.4, 37°C, alpha2beta2 GlcNAc-1-phosphotransferase
-
0.005
soybean agglutinin
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase; pH 7.4, 37°C, alpha2beta2 GlcNAc-1-phosphotransferase
-
4.45
cathepsin D
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase
-
0.23
Man9GlcNAc1 oligosaccharide
-
pH 7.4, 37°C, alpha2beta2 GlcNAc-1-phosphotransferase
0.266
Man9GlcNAc1 oligosaccharide
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase
0.075
pro-tripeptidyl peptidase
-
pH 7.4, 37°C, alpha2beta2 GlcNAc-1-phosphotransferase
-
0.36
pro-tripeptidyl peptidase
-
pH 7.4, 37°C, alpha2beta2gamma2 GlcNAc-1-phosphotransferase
-
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
5.5 - 8.5
-
pH 5.5: about 50% of maximal activity, pH 8.5: about 75% of maximal activity
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
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TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
20 - 40
-
20°C: about 50% of maximal activity, 40°C: about 25% of maximal activity
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
-
PT alpha/beta-subunit precursor protein is exported into the Golgi apparatus whereas coexpressed separate alpha- and beta-subunits fail to reach the cis-Golgi compartment. Endoplasmic reticulum exit of the PT alpha/beta-subunit precursor protein is dependent on Sar-1 protein
-
N-terminal region of Alg14 is respnsible for its localization to the endoplasmic reticulum membrane
-
uncleaved and cleaved forms of the PT alpha/beta-subunit precursor are localized in the Golgi apparatus
-
proteolytic S1P-mediated activation of the alpha/beta-subunit precursor of GlcNAc-1-phosphotransferase into mature subunits occurs in the cis-Golgi apparatus
-
single residues in the cytoplasmic tail of a Golgi-resident protein are important for localization to this compartment
localization of gamma-chain of UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase
-
the alpha/beta-subunit precursor is a type III membrane protein of 1256 amino acids with two transmembrane domains. Its exit from the endoplasmic reticulum requires a combinatorial sorting motif located in the N- and C-terminal cytoplasmic tails. The luminal alpha-subunit exhibits a conserved modular structure
additional information
-
subcellular localization study of wild-type and mutant enzymes, as well as isolated alpha- and beta-subunits, phenotypes, overview. Amino acid residues at positions I346, W357, S399 and I403 in the stealth domain 2 play an important role for the export of the alpha/beta-subunit precursor from the endoplasmic reticulum
-
additional information
-
the mature Golgi-localized phosphotransferase and a small portion of the alphabeta precursor reach the medial/trans cisternae, where they then undergo retrograde transport to maintain their concentration in the cis-Golgi
-
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PDB
SCOP
CATH
ORGANISM
UNIPROT
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
51000
-
2 * 166000 + 2 * 51000 + 2 * 56000, a 540000 Da enzyme complex is composed of disulfide-linked homodimers of 166000 and 51000 Da subunits and two identical, noncovalently associated 56000 Da subunits, SDS-PAGE
56000
-
2 * 166000 + 2 * 51000 + 2 * 56000, a 540000 Da enzyme complex is composed of disulfide-linked homodimers of 166000 and 51000 Da subunits and two identical, noncovalently associated 56000 Da subunits, SDS-PAGE
166000
-
2 * 166000 + 2 * 51000 + 2 * 56000, a 540000 Da enzyme complex is composed of disulfide-linked homodimers of 166000 and 51000 Da subunits and two identical, noncovalently associated 56000 Da subunits, SDS-PAGE
190000
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SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
-
x * 190000, inactive mutant alphabeta precursor, SDS-PAGE, x * 45000, K4Q mutant beta subunit, SDS-PAGE, x * 41000, S15Y mutant beta subunit, SDS-PAGE
heterodimer
hexamer
additional information
heterodimer
-
alphabeta, 1 * 145000, alpha-subunit + 1 * 45000, beta-subunit, about, SDS-PAGE
hexamer
-
2 * 166000 + 2 * 51000 + 2 * 56000, a 540000 Da enzyme complex is composed of disulfide-linked homodimers of 166000 and 51000 Da subunits and two identical, noncovalently associated 56000 Da subunits, SDS-PAGE
additional information
-
multisubunit enzyme with an alpha2beta2gamma2 arrangement
additional information
-
dimerization is important for the enzyme to assemble in high molecular mass GlcNAc-1-phosphotransferase 1 subunits
additional information
-
domain organization of the full-length wild-type and mutant apha/beta-subunit precursor protein of the GlcNAc-1-phosphotransferase, overview
additional information
-
the gamma-subunit contains two recognizable domains as follows: a Man-6-P receptor homology (MRH) domain and a DMAP interaction domain. The MRH domain contains residues critical for mannose binding, but it lacks those needed for phosphate binding. The gamma-subunit binds to the spacer region (residues 535-694) of the alpha-subunit. The two Notch repeat modules and the DNA methyltransferase-associated protein interaction domain of the alpha-subunit are key components of the substrate recognition process
additional information
-
the recognition and catalytic site of the phosphotransferase are located on different subunits
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
proteolytic modification
glycoprotein
-
enzyme contains N-glycosylation sites at position 88 and 115. N-glycosylation is important for intracellular trafficking of the gamma subunit
glycoprotein
-
an N-linked oligosaccharide, hydrolysis by peptide-N-glycosidase F (PNGase F)
glycoprotein
the gamma subunit of GlcNAc-1-phosphotransferase is a soluble glycoprotein
glycoprotein
-
the wild-type inactive alphabeta precursor protein contains a very low amount of complex-type glycans, all of the N-linked glycans are of the high mannose-type, which is consistent with its endoplasmic reticulum localization. The mutant K4Q alphabeta phosphotransferase contains increased complex-type N-linked glycans
proteolytic modification
-
upon arrival in the Golgi apparatus, the newly synthesized alpha/beta subunit precursor is catalytically activated by site-1 protease (S1P). A stretch of amino acids in the N-terminus of the beta-subunit is essential for precise S1P-mediated cleavage and activity of theGlcNAc-1-phosphotransferase. The proteolytic cleavage of the alpha/beta-subunit precursor protein is a prerequisite for the catalytic activity of the GlcNAc-1-phosphotransferase and therefore plays an important role in the biogenesis of lysosomes. Proteolytic S1P-mediated activation of the alpha/beta-subunit precursor of GlcNAc-1-phosphotransferase into mature subunits occurs in the cis-Golgi apparatus
proteolytic modification
-
proteolytic cleavage of the alpha/beta enzyme precursor
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
treatment with papain or phospholipase C from Bacillus cereus inactivates the enzyme in a time- and dose-dependent manner
-
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
partial
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
alpha2beta2gamma2 and alpha2beta2 GlcNAc-1-phosphotransferase are stably expressed in CHO-K1 cells (transmembrane segments are missing)
-
cloning of a single cDNA and gene that encodes a precursor of the alpha- and beta-subunits of human GlcNAc-phosphotransferase (gene symbol, GNPTAB). Transfection of the alpha/beta-subunits precursor cDNA with or without cotransfection of the regulatory gamma-subunitc DNA results in an increase in GlcNAc-phosphotransferase activity on low molecular weight substrate. This demonstrates that the alpha/beta-subunits precursor cDNA encodes the catalytic domain of the enzyme
-
gene GNPTAB encodes the alpha- and beta-subunits of GlcNAc-1-phosphotransferase, low efficiency of GNPTAB mRNA expression due to its large size
-
gene GNPTAB encodes the alpha/beta-subunit of GlcNAc-1-phosphotransferase, recombinant expression of C-terminally V5/His-tagged wild-type and mutant enzymes in HEK293 cells
-
gene GNPTAB, the alphabeta precursors of wild-type, and mutant K4Q or S15Y enzymes with a C-terminal V5-tag are expressed in HEK-293 cells
-
gene GNPTG encoding the gamma-subunit of the enzyme, transient expression of wild-type and mutant gamma-subunits in HeLa cells
gene GNTPAB encoding the alpha/beta-subunits, quantitative real-time PCR expression analysis, recombinant expression of nucleotides 8-3715
genes GNPTABG encode the alpha2beta2gamma2 enzyme, generation of generate alpha/beta and gamma bicistronic constructs, recombinant expression of HA-tagged wild-type and GNPTAB-/- and GNPTG-/- mutant enzymes in HeLa cells, recombinant expression of domain deletion mutants in HEK-293 cells
-
overexpression of gamma-chain of UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase in NIH-3T3 cells induces accumulation of macromolecules, formation of large cytoplasmic vacuoles and decrease of lysosomal enzymes in cells. Transient ectopic expression of the gamma subunit in endoplasmic reticulum induces lowered lysosomal enzyme activity in cells
plasmids encoding WT and K732N alpha/beta cDNA with C-terminal V5/His tags are generated and transfected into HEK-293 cells and monitoring of the proteolytic cleavage of the alpha/beta precursor by the appearance of the mature V5-tagged beta-subunit. Recombinant expression of wild-type and mutant GST-DMAP domain
-
recombinant expression of C-terminally myc-tagged wild-type and mutant enzymes in HEK-293 cells
-
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C447Y
-
site-directed mutagenesis, the mutation does not affect the catalytic activity of the GlcNAc-1-phosphotransferase. Enzyme-deficient embryos rescued with C447Y mRNA only corrects 84% of mutational features, and embryos rescued with the mutant mRNA appear visually different, i.e. shorter, from embryos rescued with wild-type mRNA
C473S
-
site-directed mutagenesis, the mutation does not affect the catalytic activity of the GlcNAc-1-phosphotransferase. Enzyme-deficient embryos rescued with C473S mRNA only corrects 80% of mutational features, and embryos rescued with the mutant mRNA appear visually different, i.e. shorter, from embryos rescued with wild-type mRNA
A592T
-
site-directed mutagenesis, mutation involved in enzyme dysfunction, that has no effect on the mutant enzyme
A955V/K928R
-
site-directed mutagenesis, mutation involved in enzyme dysfunction
C142Y
naturally occuring mutation of the gamma-subunit that causes misfolding of the gamma-subunit, the misfolded protein is retained in the endoplasmic reticulum, where it forms aggregates, and fails to rescue the lysososmal targeting of lysosomal acid glycosidases
C157S/C245S
-
mutant can be detected as 36 kDa monomeric form but not as a dimer
C245S
-
mutant can be detected as 36 kDa monomeric form but not as a dimer. Mutant is localised in the Golgi apparatus, indicating that dimerization is not essential for endoplasmic reticulum exit of the gamma-subunit. Monomeric C245S mutant does not assemble with endogenous GlcNAc-1-phosphotransferase 1 subunits
C442Y
-
site-directed mutagenesis, mutation involved in enzyme dysfunction, the Notch 1 mutant is efficiently delivered to the Golgi complex and the alphabeta precursor undergoes proteolytic cleavage
C461G
-
site-directed mutagenesis, mutation involved in enzyme dysfunction, the Notch 1 mutant is efficiently delivered to the Golgi complex and the alphabeta precursor undergoes proteolytic cleavage
C468S
-
site-directed mutagenesis, mutation involved in enzyme dysfunction, the Notch 1 mutant is efficiently delivered to the Golgi complex and the alphabeta precursor undergoes proteolytic cleavage
C505Y
C84S/C157S/C245S
-
mutant can be detected as 36 kDa monomeric form but not as a dimer
D407A
-
site-directed mutagenesis, mutation involved in enzyme dysfunction, the mutant in the Stealth domain trafficks to the Golgi
D407A/A663G
-
site-directed mutagenesis, mutation involved in enzyme dysfunction
G106S
naturally occuring mutation of the gamma-subunit that causes misfolding of the gamma-subunit, the misfolded protein is retained in the endoplasmic reticulum, where it forms aggregates, and fails to rescue the lysososmal targeting of lysosomal acid glycosidases
G126S
naturally occuring mutation of the gamma-subunit that causes misfolding of the gamma-subunit, the misfolded protein is retained in the endoplasmic reticulum, where it forms aggregates, and fails to rescue the lysososmal targeting of lysosomal acid glycosidases
G575R
-
naturally occuring missense mutation identified in Brazilian mucolipidosis MLII/MLIII alpha/beta patients. The mutant shows 3% of wild-type activity
I348L
-
site-directed mutagenesis, mutation involved in enzyme dysfunction, the mutant behaves similar to the wild-type enzyme
I403T
K1236A/R1237A/K1238A
-
mutant containing a mutation of C-terminal endoplasmic reticulum export motif mainly co-localizes with the cis-Golgi marker protein but fails to co-distribute with the endoplasmic reticulum protein marker
K1236M
K4Q
K732N
L1001P
-
site-directed mutagenesis, mutation involved in enzyme dysfunction, the mutant partially exits from the endoplasmic reticulum and is almost inactive
L5A/L6A
-
replacement of the N-terminal dileucine motif with alanine residues results in a significant reduction of the PT alpha/beta-subunit precursor protein cleavage. Densitometric evaluation of intensities of immunoreactive bands show that the formation of the beta-subunit is reduced by 46% compared with the wild-type construct. Mutant mainly co-localizes with the cis-Golgi marker protein but fails to co-distribute with the endoplasmic reticulum protein marker
L5A/L6A/R1253A/I1254A/R1255A
-
double mutant containing a mutation of N-terminal and C-terminal endoplasmic reticulum export motif shows a strong inhibitory effect on cleavage of the PT alpha/beta-subunit precursor protein. Mutation leads to retention in the endoplasmic reticulum
L5A/L6A/R1253L/I1254L/R1255X
-
the transfer of the dileucine motif to the C-terminal domain replacing the dibasic-based motif 1253RIR1255 in combination with the substitution of the N-terminal dileucine motif, blocks the endoplasmic exit and the subsequent proteolytic cleavage to mature PT beta-subunit
L5R/L6R/R1253A/I1254A/R1255A
-
substitution of the N-terminal L-Leu/L-Leu motif by dibasic-based motifs RIR or RR in combination with alanine substitution of the C-terminal motif prevents the alpha/beta-subunit precursor protein from reaching the Golgi apparatus for cleavage
L785W
-
site-directed mutagenesis, mutation involved in enzyme dysfunction, the DMAP interaction domain mutation has full activity toward alpha-MM but impaired ability to phosphorylate lysosomal acid hydrolases
N115Q
-
electrophoretic migration similar to wild-type at 34 kDa, mutant sensitive to PNGase F treatment
N88Q
-
electrophoretic migration similar to wild-type at 34 kDa, mutant sensitive to PNGase F treatment
N88Q/N115Q
-
electrophoretic migration at 31 kDa, double mutant insensitive to PNGase F treatment, non-glycosylated polypeptide. Non-glycosylated gamma-subunits do not colocalize with the Golgi apparatus marker GM130
R1242A/R1243A/R1244A
-
by mutation of the arginine motif in beta subunit it is shown that this signal is not a functional endoplasmic reticulum retention signal
R1244A/R1245A/R1246A
-
mutant containing a mutation of C-terminal endoplasmic reticulum export motif mainly co-localizes with the cis-Golgi marker protein but fails to co-distribute with the endoplasmic reticulum protein marker
R1253A/I1254A/R1255A
-
mutant containing a mutation of C-terminal endoplasmic reticulum export motif mainly co-localizes with the cis-Golgi marker protein but fails to co-distribute with the endoplasmic reticulum protein marker
R334L
-
site-directed mutagenesis, mutation involved in enzyme dysfunction, the mutant fails to exit from the endoplasmic reticulum and is inactive
R334Q
-
site-directed mutagenesis, mutation involved in enzyme dysfunction, the mutant fails to exit from the endoplasmic reticulum and is inactive
R587P
-
site-directed mutagenesis, mutation involved in enzyme dysfunction, the R587P mutant shifts from a predominant endoplasmic reticulum localization to a predominant Golgi localization
R925A
-
mutation results in an uncleavable PT alpha/beta-subunit precursor protein. Mutant co-localizes mainly with the cis-Golgi marker protein, no detection in endoplasmic reticulum
R986C
-
site-directed mutagenesis, mutation involved in enzyme dysfunction, the mutant in the Stealth domain trafficks to the Golgi
S15Y
-
naturally occurring mutation in the N-terminal cytoplasmic tail of the alpha-subunit leading to a mislocated enzyme, mistargeting of the mutant enzymes to lysosomes, where they are degraded, or to the cell surface and release into the medium, but the mutant enzyme shows 41% of wild-type activity. Half-life of the mutant is decreased compared to the wild-type enzyme
S399F
T1223del
-
naturally occurig heterozygous mutation identified in Brazilian mucolipidosis MLII/MLIII alpha/beta patients. The mutant T1223del is correctly transported and proteolytically cleaved into mature alpha- and beta-subunits exhibiting 85% of GlcNAc-1-phosphotransferase activity of the wild-type enzyme
T286M
naturally occuring mutation of the gamma-subunit that does not alter the gamma-subunit function, the mutant variant enters the Golgi like the wild-type enzyme
T644M
-
naturally occuring heterozygous mutation identified in Brazilian mucolipidosis MLII/MLIII alpha/beta patients. The mutant T644M is correctly transported and proteolytically cleaved into mature alpha- and beta-subunits exhibiting 50% of GlcNAc-1-phosphotransferase activity of the wild-type enzyme
V182D/Q205P
-
site-directed mutagenesis, mutation involved in enzyme dysfunction
W81L
-
site-directed mutagenesis, mutation involved in enzyme dysfunction, that has no effect on the mutant enzyme
DELTA1-47
-
N-terminal region (residues 1-47) of Saccharomyces cerevisiae Alg14 localizes its green fluorescent protein fusion to the endoplasmic reticulum membrane. Coimmunoprecipitation demonstrates that the N-terminal region of Alg14 is required for direct interaction with Alg7
G163A/G165A
-
mutant fails to rescue a loss of Alg14 function. Mutant is inactivated by loss of conserved G-loop
V131A/I135A/V139A/V143A/V146A/F150A
-
a mutant in which six hydrophobic residues are replaced with L-Ala is able to rescue the loss of Alg14 function, indicating that the mutated hydrophobic residues do not have a deleterious effect on Alg14 activity. Growth of these cells is extremely slow at 30°C
V131I/I135L/V139I/V143I/V146I/F150L
-
a mutant in which six hydrophobic residues are replaced with L-Ala is able to rescue the loss of Alg14 function
additional information
C505Y
-
naturally occuring missense mutation identified in Brazilian mucolipidosis MLII/MLIII alpha/beta patients. The mutant shows 7% of wild-type activity
I403T
-
naturally occuring missense mutation identified in Brazilian mucolipidosis MLII/MLIII alpha/beta patients, lack of processing of the mutant alpha/beta-subunit precursor I403T
I403T
-
site-directed mutagenesis, mutation involved in enzyme dysfunction, the mutant partially exits from the endoplasmic reticulum and is almost inactive
K1236M
-
proteolytic cleavage of mutant is not affected. Mutant is localised mainly in the Golgi apparatus
K4Q
-
patient mutation K4Q impairs the endoplasmic reticulum export of the PT alpha/beta-subunit precursor protein. Mutant shows reduced levels of the PT beta-subunit. Mutant is localised in the Golgi apparatus and in the endoplasmic reticulum
K4Q
-
naturally occurring mutation in the N-terminal cytoplasmic tail of the alpha-subunit leading to a mislocated enzyme, mistargeting of the mutant enzymes to lysosomes, where they are degraded, or to the cell surface and release into the medium, the mutant enzymes shows 32% of wild-type activity. The mutant K4Q alphabeta phosphotransferase contains increased complex-type N-linked glycans. Half-life of the mutant is decreased compared to the wild-type enzyme
K732N
-
site-directed mutagenesis, mutation involved in enzyme dysfunction, the DMAP interaction domain mutation has full activity toward alpha-MM but impaired ability to phosphorylate lysosomal acid hydrolases
K732N
-
naturally occurring mutation in the DMAP interaction domain of the alpha-subunit identified in a patient with mucolipidosis II, the mutant exhibits full activity toward the simple sugar alpha-methyl D-mannoside but impaired phosphorylation activity toward acid hydrolases. The K732N mutation does not impair the transport of the alpha/beta precursor from the endoplasmic reticulum to the Golgi, nor the proteolytic cleavage that generates the alpha and beta subunits. Recombinant expression of the K732N mutant in a zebrafish model of mucolipidosis II fails to correct the phenotypic abnormalities
S399F
-
site-directed mutagenesis, mutation involved in enzyme dysfunction, the mutant partially exits from the endoplasmic reticulum and is almost inactive
S399F
-
a naturally occurring mucolipidosis III, MLIII, alphabeta mutant, the mutant enzyme remains in the endoplasmic reticulum and is not translocated to the Golgi due to reduced proteolytic cleavage of the precursor
additional information
-
generation of GNPTAB-deficient zebrafish, comprehensive analysis of the remaining missense mutations in GNPTAB reported in human mucolipidosis II and III alphabeta-patients using cell- and zebrafish-based approaches
additional information
-
the frameshift E757KfsX1 and the non-sense R587X mutations result in the retention of enzymatically inactive truncated precursor proteins in the endoplasmic reticulum due to loss of cytosolic endoplasmic reticulum exit motifs consistent with a severe clinical phenotype in homozygosity. Subcellular localization study of wild-type and mutant enzymes, as well as isolated alpha- and beta-subunits, overview
additional information
-
generation of GNPTAB-deficient zebrafish, comprehensive analysis of the remaining missense mutations in GNPTAB reported in human mucolipidosis II and III alphabeta-patients using cell- and zebrafish-based approaches; mutations in the GNPTAB gene give rise to the severe lysosomal storage disorder mucolipidosis II (I-cell disease) and the attenuated mucolipidosis III alphabeta (pseudo-Hurler polydystrophy). Subcellular localization ofalphabeta-phosphotransferase Stealth domain is altered compared to wild-type in HeLa cells
additional information
-
construction of GNPTAB-/- and GNPTG-/- mutant enzymes, all three alleles of GNPTAB are disrupted with one allele having a 17-bp deletion, c.216_232del, whereas the other two alleles have a 1-bp deletion c.221delC. The gamma-subunit-deficient DELTAN1-DMAP mutant has catalytic activity but is unable to phosphorylate lysosomal enzymes. Deletion of Notch 2 strongly inhibits phosphorylation of all the glycosidases, whereas deletion of Notch 1 is less detrimental, with levels of phosphorylation ranging from 100% down to 60% of wild-type activity. The effect of deleting the DMAP interaction domain is also variable, ranging from a 10% decrease in phosphorylation relative to wild-type to a 64% decrease in alpha-Man phosphorylation. Deletion of the S2 domain, which results in the loss of binding of the gamma-subunit, strongly inhibits phosphorylation of all the glycosidases
additional information
Q69ZN6 AND Q6S5C2
generation of GlcNAc-1-phosphotransferase-defective mice and enzyme-defective mouse embryonic fibroblasts
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
AAV-mediated expression of gene GNPTAB in mucolipidosis II, ML II, mice can attenuate bone loss via inhibition of IL-6 production
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