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Information on EC 2.7.8.15 - UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase and Organism(s) Homo sapiens
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EC Tree
2.7.8.15 UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferaseSpecify your search results
Word Map
- 2.7.8.15
- lysosomal
- mucolipidosis
- tunicamycin
- i-cell
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myasthenic
- gnptg
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tunicamycin-resistant
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udp-n-acetylglucosamine:lysosomal
- glcnac-1-phosphotransferase
- polydystrophy
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dolichol-linked
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nagts
- mliii
- alpha-methylmannoside
- uteroferrin
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pseudo-hurler
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man-6-p
- medicine
- biotechnology
- molecular biology
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Archaea, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Archaea, Bacteria
Reaction Schemes
Synonyms
dpagt1, n-acetylglucosamine-1-phosphotransferase, glcnac-phosphotransferase, n-acetylglucosamine-1-phosphate transferase, glcnac-1-p transferase, gnpta, l-g1pt, dolichyl-phosphate n-acetylglucosaminephosphotransferase, dolichol-p-dependent n-acetylglucosamine-1-p transferase, udp-glcnac:dolichol phosphate glcnac-1-phosphate transferase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
acetylglucosamine-1-phosphotransferase, uridine diphosphoacetylglucosamine-dolichyl phosphate
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chitobiosylpyrophosphoryldolichol synthase
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dolichol phosphate N-acetylglucosamine-1-phosphotransferase
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dolichol-P-dependent N-acetylglucosamine-1-P transferase
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dolichol-P-dependent N-acetylglucosamine-1-phosphate transferase
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DPAGT1
G1PT
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GlcNAc-1-P transferase
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GlcNAc-phosphotransferase
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encoded by genes GNPTAB and GNPTG, deficiency causes mucolipidosis II
GPT
L-G1PT
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N-acetylglucosamine-1-phosphate transferase
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UDP-acetylglucosamine-dolichol phosphate acetylglucosamine phosphotransferase
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UDP-acetylglucosamine-dolichol phosphate acetylglucosamine-1-phosphotransferase
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UDP-GlcNAc:dolichol phosphate N-acetylglucosamine-1 phosphate transferase
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UDP-GlcNAc:dolichyl-P GlcNAc1P transferase
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UDP-GlcNAc:dolichyl-phosphate GlcNAc-1-phosphate transferase
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UDP-N-acetyl-D-glucosamine:dolichol phosphate N-acetyl-D-glucosamine-1-phosphate transferase
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UDP-N-acetylglucosamine-dolichylphosphate N-acetylglucosamine phosphotransferase
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UDPGlcNAc:dolichol phosphate N-acetylglucosamine 1-phosphate transferase
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DPAGT1
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GPT
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
substituted phospho group transfer
substituted phospho group transfer
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
UDP-N-acetyl-D-glucosamine:dolichyl-phosphate N-acetyl-D-glucosaminephosphotransferase
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CAS REGISTRY NUMBER
COMMENTARY
70431-08-2
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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-alpha-D-glucosamine + dolichyl phosphate
UMP + N-acetyl-alpha-D-glucosaminyl-diphosphodolichol
UDP-N-acetyl-D-glucosamine + dolichyl phosphate
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deficiency of UDP-GlcNAc:dolichol phosphate N-acetylglucosamine-1 phosphate transferase (DPAGT1) causes a novel congenital disorder of glycosylation type Ij
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?
additional information
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the uridine moiety of UDP-GlcNAc is coordinated with eight hydrogen bonds between the one backbone amide (Leu46), seven side chains of the amino acids and two water molecules. The uridine moiety of tunicamycin occupies the identical binding sites of UDP-GlcNAc
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UDP-N-acetyl-alpha-D-glucosamine + dolichyl phosphate
UMP + N-acetyl-alpha-D-glucosaminyl-diphosphodolichol
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UDP-N-acetyl-alpha-D-glucosamine + dolichyl phosphate
UMP + N-acetyl-alpha-D-glucosaminyl-diphosphodolichol
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UDP-N-acetyl-alpha-D-glucosamine + dolichyl phosphate
UMP + N-acetyl-alpha-D-glucosaminyl-diphosphodolichol
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?
UDP-N-acetyl-alpha-D-glucosamine + dolichyl phosphate
UMP + N-acetyl-alpha-D-glucosaminyl-diphosphodolichol
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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
UDP-N-acetyl-alpha-D-glucosamine + dolichyl phosphate
UMP + N-acetyl-alpha-D-glucosaminyl-diphosphodolichol
UDP-N-acetyl-D-glucosamine + dolichyl phosphate
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deficiency of UDP-GlcNAc:dolichol phosphate N-acetylglucosamine-1 phosphate transferase (DPAGT1) causes a novel congenital disorder of glycosylation type Ij
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?
UDP-N-acetyl-alpha-D-glucosamine + dolichyl phosphate
UMP + N-acetyl-alpha-D-glucosaminyl-diphosphodolichol
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?
UDP-N-acetyl-alpha-D-glucosamine + dolichyl phosphate
UMP + N-acetyl-alpha-D-glucosaminyl-diphosphodolichol
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?
UDP-N-acetyl-alpha-D-glucosamine + dolichyl phosphate
UMP + N-acetyl-alpha-D-glucosaminyl-diphosphodolichol
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?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
aminouridyl phenoxypiperidinbenzyl butanamide
APPB, APPB shows a strong DPAGT1 inhibitory activity and selectively inhibits growth of the solid tumors at low micromolar concentrations, but does not inhibit growth of a leukemia cell and the healthy cells at these concentrations. Growth inhibition of APPB against the solid cancers is correlated with the expression level of DPAGT1. Docking studies of APPB to DPAGT1, overview
additional information
IC50 of compounds in cytotoxic inhibition of growth of several cancer cell lines, overview. Introduction of pharmacologically benign hydrophobic groups which occupy the proposed Dol-P binding site is essential to exhibit DPAGT1 inhibitory activity. Significant conformational changes are observed in the C-terminal end of TM-9, CL-9 and CL-1 in DPAGT1-ligand bound structures, the other portions of DPAGT1 are subtly changed upon binding
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tunicamycin
enzyme binding structure analysis, interferes with the first committed enzyme of N-glycan biosynthesis, DPAGT1. A Mg2+ ion is not involved in the binding mode. Arg301, Asn185, and Asp252 residues directly form hydrogen bonding with the C4-OH, C2-NH and C3-OH groups of the GalNAc moiety. The fatty acid chain of tunicamycin is occupied in the hydrophobic tunnel
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
french Canadian founder population in Saguenay-Lac-Saint-Jean (Quebec, Canada) with mucolipidosis II carrier rate at 1/39 (highest worldwide)
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
UDP-N-acetylglucosamine-dolichylphosphate N-acetylglucosamine phosphotransferase (GPT) is involved in an initial step in the N-glycosylation pathway
physiological function
malfunction
N-glycan biosynthesis can be inhibited by disruption of the first committed enzyme, DPAGT1
malfunction
pathogenic mutations in DPAGT1 are manifested as two possible phenotypes: congenital disorder of glycosylation DPAGT1-CDG (also known as CDG-Ij), and limb-girdle congenital myasthenic syndrome (CMS) with tubular aggregates, analysis of DPAGT1 transcriptional profiles and GTP levels in patient-derived fibroblast. enzyme mutations affect the splicing process, the stability of GTP, or the ability of this protein to correctly localise in the endoplasmic reticulum membrane
physiological function
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GPT is involved in glycosylation of proteins on asparagine amino acids
physiological function
DPAGT1 is an integral membrane protein localized in the endoplasmic reticulum (ER) that catalyzes the transformation from UDP-GlcNAc to N-acetyl-D-glucosaminyl-diphosphodolichol. Anchored N-acetyl-D-glucosaminyldiphosphodolichol in the ER membrane is modified by sequential glycosyltransferases to form dolichol-linked oligosaccharide precursors that are transferred to selected asparagine residues of polypeptide chains by oligosaccharyltransferase. DPAGT1 catalyzes N-glycosylation of beta-catenin and E-cadherin
physiological function
the endoplasmic reticulum (ER)-resident transmembrane protein catalyses the transfer of N-acetylglucosamine from cytosolic UDP-N-acetylglucosamine to dolichol-phosphate, which is also located in the ER membrane. The result is the formation of dolichol-diphosphate-N-acetylglucosamine, the carrier of the sugars that are finally attached to proteins in glycosylation
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). GPT_HUMAN
408
10
46090
Swiss-Prot
Secretory Pathway (Reliability: 1)
B3KY32_HUMAN
408
10
46118
TrEMBL
Secretory Pathway (Reliability: 1)
A0A804HKZ3_HUMAN
313
9
35389
TrEMBL
Secretory Pathway (Reliability: 1)
A0A1W2PQH0_HUMAN
173
3
19682
TrEMBL
Secretory Pathway (Reliability: 1)
H7C2L6_HUMAN
226
5
24889
TrEMBL
Mitochondrion (Reliability: 5)
A0A024R3H8_HUMAN
408
10
46090
TrEMBL
Secretory Pathway (Reliability: 1)
B2R6Z9_HUMAN
400
9
45098
TrEMBL
Secretory Pathway (Reliability: 1)
A0A1W2PPC6_HUMAN
377
8
42588
TrEMBL
Secretory Pathway (Reliability: 1)
A0A1B0GV58_HUMAN
77
2
8610
TrEMBL
Secretory Pathway (Reliability: 1)
A0A804HL46_HUMAN
276
7
30649
TrEMBL
Secretory Pathway (Reliability: 1)
A0A804HJ11_HUMAN
379
9
42814
TrEMBL
Secretory Pathway (Reliability: 1)
B4DXH3_HUMAN
327
5
37195
TrEMBL
Secretory Pathway (Reliability: 5)
A0A804HI18_HUMAN
242
7
26979
TrEMBL
Secretory Pathway (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
in solution, DPAGT1 exists predominantly as a dimer
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
structures of human GPT in complex with tunicamycin for both the canonical Pro129 variant and a His129 variant, to 3.10 A and 2.95 A resolution, respectively. GPT crystallizes as a homodimer with one tunicamycin molecule bound to the active site of each protomer near the cytosolic side of the ER membrane. Comparison of the GPT-tunicamycin complex to the MraY-tunicamycin complex. GPT and MraY (EC 2.7.8.13) have drastically different dimer organization and differ in the the role of Mg2+ in tunicamycin inhibition, in active site shape and solvent accessibility and in the lipid substrate specificity
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
F110S
naturally occuring mutation in gene DPAGT1, c.329T>C, patient with hypotonia, muscle weakness, hypoacusia, psychomotor retardation, the mutation affects splicing and enzyme protein
L120M
naturally occuring mutation in gene DPAGT1, c.358C>A, patient with hypotonia phenotype, the mutation affects splicing and enzyme protein
L385R
naturally occuring mutation in gene DPAGT1, c.1154T>G, patients with foetal hypokinesia, facial dysmorphism, hypertrichosis, hypotonia, papilar atrophy, bilateral cochlear impairment, the mutation affects splicing and enzyme protein
R301C
naturally occuring mutation in gene DPAGT1, c.901C>T, the mutation affects splicing and enzyme protein
R301H
naturally occuring mutation in gene DPAGT1, c.902G>A, the mutation affects splicing and enzyme protein
V264G
naturally occuring mutation in gene DPAGT1, c.791T>G, the mutation affects splicing and enzyme protein
additional information
additional information
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c.3503_3504delTC: heterozygous, two-nucleotide deletion in exon 19, causes frameshift and premature translational stop (p.L1168QfsX5), detected by PCR in all tested parents of children with mucolipidosis II
additional information
analysis of DPAGT1 transcriptional profiles and GTP levels in patient-derived fibroblasts. The enzyme mutations affect the splicing process, the stability of GTP, or the ability of this protein to correctly localise in the endoplasmic reticulum membrane, role of endoplasmic reticulum stress, detailed overview
additional information
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analysis of DPAGT1 transcriptional profiles and GTP levels in patient-derived fibroblasts. The enzyme mutations affect the splicing process, the stability of GTP, or the ability of this protein to correctly localise in the endoplasmic reticulum membrane, role of endoplasmic reticulum stress, detailed overview
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene GPAGT1, genotyping, quantitative RT-PCR enzyme expression analysis, transient recombinant expression of enzyme mutations in COS-7 cells
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
selective DPAGT1 inhibitors have the promising therapeutic potential for certain solid cancers that require increased branching of N-linked glycans in their growth progressions. Inhibition of DPAGT1 may be the Achilles' heel of the biosynthesis of essential N-glycan in solid tumors
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Wu, X.; Rush, J.S.; Karaoglu, D.; Krasnewich, D.; Lubinsky, M.S.; Waechter, C.J.; Gilmore, R.; Freeze, H.H.
Deficiency of UDP-GlcNAc: dolichol phosphate N-acetylglucosamine-1 phosphate transferase (DPAGT1) causes a novel congenital disorder of glycosylation type Ij
Hum. Mutat.
22
144-150
2003
Homo sapiens
Plante, M.; Claveau, S.; Lepage, P.; Lavoie, E.M.; Brunet, S.; Roquis, D.; Morin, C.; Vezina, H.; Laprise, C.
Mucolipidosis II: a single causal mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTAB) in a French Canadian founder population
Clin. Genet.
73
236-244
2008
Homo sapiens
Bretthauer, R.K.
Structure, expression, and regulation of UDP-GlcNAc: dolichol phosphate GlcNAc-1-phosphate transferase (DPAGT1)
Curr. Drug Targets
10
477-482
2009
Bos taurus, Cricetulus griseus, Homo sapiens, Mus musculus, Rattus norvegicus
Kurosu, M.
Structure-based drug discovery by targeting N-glycan biosynthesis, dolichyl-phosphate N-acetylglucosaminephosphotransferase
Future Med. Chem.
11
927-933
2019
Homo sapiens (Q9H3H5)
Yuste-Checa, P.; Vega, A.I.; Martin-Higueras, C.; Medrano, C.; Gamez, A.; Desviat, L.R.; Ugarte, M.; Perez-Cerda, C.; Perez, B.
DPAGT1-CDG functional analysis of disease-causing pathogenic mutations and role of endoplasmic reticulum stress
PLoS ONE
12
e0179456
2017
Homo sapiens (Q9H3H5), Homo sapiens
EXTERNAL LINKS (specific for EC-Number 2.7.8.15)
Transporter Classification Database (TCDB): 9.B.146.1.5
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