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Information on EC 2.4.1.260 - dolichyl-P-Man:Man7GlcNAc2-PP-dolichol alpha-1,6-mannosyltransferase and Organism(s) Homo sapiens and UniProt Accession Q9BV10

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IUBMB Comments
The formation of N-glycosidic linkages of glycoproteins involves the ordered assembly of the common Glc3Man9GlcNAc2 core-oligosaccharide on the lipid carrier dolichyl diphosphate. Early mannosylation steps occur on the cytoplasmic side of the endoplasmic reticulum with GDP-Man as donor, the final reactions from Man5GlcNAc2-PP-Dol to Man9Glc-NAc2-PP-Dol on the lumenal side use dolichyl beta-D-mannosyl phosphate.
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Homo sapiens
UNIPROT: Q9BV10
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The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
Synonyms
alg12, alg12 mannosyltransferase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ALG12 alpha1,6mannosyltransferase
-
ALG12 mannosyltransferase
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dolichyl-P-Man:Man7GlcNAc2-PP-dolichyl alpha6-mannosyltransferase
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dolichyl-P-mannose:Man7GlcNAc2-PP-dolichyl mannosyltransferase
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SYSTEMATIC NAME
IUBMB Comments
dolichyl beta-D-mannosyl phosphate:D-Man-alpha-(1->2)-D-Man-alpha-(1->2)-D-Man-alpha-(1->3)-[D-Man-alpha-(1->2)-D-Man-alpha-(1->3)-D-Man-alpha-(1->6)]-D-Man-beta-(1->4)-D-GlcNAc-beta-(1->4)-D-GlcNAc-diphosphodolichol alpha-1,6-mannosyltransferase
The formation of N-glycosidic linkages of glycoproteins involves the ordered assembly of the common Glc3Man9GlcNAc2 core-oligosaccharide on the lipid carrier dolichyl diphosphate. Early mannosylation steps occur on the cytoplasmic side of the endoplasmic reticulum with GDP-Man as donor, the final reactions from Man5GlcNAc2-PP-Dol to Man9Glc-NAc2-PP-Dol on the lumenal side use dolichyl beta-D-mannosyl phosphate.
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
SwissProt
Manually annotated by BRENDA team
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
primary fibroblasts obtained from skin biopsies
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
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generation of a HepG2 cell model of Alg12-congenital disorders of glycosylation by down-regulating dolichyl-P-mannose Man7GlcNAc2-PP-dolichol mannosyltransferase (Alg12), in order to provoke the accumulation of Man7GlcNAc2-PP-dolichol. The accumulation of Man7GlcNAc2-PP-dolichol in ALG12-downregulated cells coincides with the inhibition in cell growth noted between 4 and 8 days posttransfection. In down-regulated cells, brefeldin A provokes Golgi apparatus-endomannosidase trimming of Glc3Man9GlcNAc2-PP dolichol to yield a Man8GlcNAc2-PP-dolichol structure that does not give rise to cytoplasmic Man8GlcNAc2-P. Brefeldin A also strikingly increases oligosaccharyl phosphates derived from mature diphosphodolichol within the endomembrane system without affecting levels of Man7GlcNAc2-PP-dolichol or cytoplasmic Man7GlcNAc2-P
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
ALG12_HUMAN
488
11
54655
Swiss-Prot
Secretory Pathway (Reliability: 1)
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
F142V
the F142V replacement in hALG12p is the cause of inefficient addition of the eighth mannose residue onto Man7GlcNAc2-PP-dolichol during glycoprotein biosynthesis in a patient with type I congenital disorders of glycosylation. The patient is homozygous for the point mutation that causes an amino acid substitution in a conserved region of dolichyl-P-Man:Man7GlcNAc2-PP-dolichyl alpha6-mannosyltransferase. Skin biopsy fibroblasts from a CDG I patient have a reduced capacity to add the eighth mannose residue onto the lipid-linked oligosaccharide precursor. The fibroblasts of the patient are capable of the direct transfer of Man7GlcNAc2 from dolichol onto protein and that this N-linked structure can be glucosylated by UDP-glucose:glycoprotein glucosyltransferase in the endoplasmic reticulum
R146Q
congenital disorder of glycosylation type lg is identified in a child presenting with psychomotor retardation, hypotonia, growth retardation, dysmorphic features and anorexia. In the patient’s fibroblasts, the biosynthetic intermediate GlcNAc2Man7 oligosaccharide is detected both on the lipid carrier dolichyl pyrophosphate and on newly synthesized glycoproteins, pointing to a defect in the dolichyl pyrophosphate–GlcNAc2Man7-dependent ALG12 alpha1,6 mannosyltransferase. Analysis of the ALG12 cDNA in the CDG patient revealed compound heterozygosity for two point mutations that result in the amino acid substitutions T67M and R146Q, respectively. The impact of these mutations on ALG12 protein function is investigated in the Saccharomyces cerevisiae alg12 glycosylation mutant by showing that the yeast ALG12 gene bearing the homologous mutations T61M and R161Q and the human mutant ALG12 cDNA alleles fail to normalize the growth defect phenotype of the alg12 yeast model, whereas expression of the normal ALG12 cDNA complements the yeast mutation. The ALG12 mannosyltransferase defect defines a type of congenital disorder of glycosylation, designated CDG-Ig
T67M
congenital disorder of glycosylation type lg is identified in a child presenting with psychomotor retardation, hypotonia, growth retardation, dysmorphic features and anorexia. In the patient’s fibroblasts, the biosynthetic intermediate GlcNAc2Man7 oligosaccharide is detected both on the lipid carrier dolichyl pyrophosphate and on newly synthesized glycoproteins, pointing to a defect in the dolichyl pyrophosphate–GlcNAc2Man7-dependent ALG12 alpha1,6 mannosyltransferase. Analysis of the ALG12 cDNA in the CDG patient revealed compound heterozygosity for two point mutations that result in the amino acid substitutions T67M and R146Q, respectively. The impact of these mutations on ALG12 protein function is investigated in the Saccharomyces cerevisiae alg12 glycosylation mutant by showing that the yeast ALG12 gene bearing the homologous mutations T61M and R161Q and the human mutant ALG12 cDNA alleles fail to normalize the growth defect phenotype of the alg12 yeast model, whereas expression of the normal ALG12 cDNA complements the yeast mutation. The ALG12 mannosyltransferase defect defines a type of congenital disorder of glycosylation, designated CDG-Ig
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of the human ALG12 cDNA under the control of the GPD promoter in Dalg12wbp1–2 yeasts. Growth of Dalg12wbp1–2 yeasts is restored by expression of this cDNA, thus establishing the function of the corresponding protein. The two mutant ALG12 alleles found in the congenital disorder of glycosylation patient, namely ALG12[T67M] and ALG12[R146Q], do very weakly restore growth to the levels reached with the normal human ALG12 cDNA
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
a patient with heterozygous variants in the ALG12 gene, c.367 G>A (G123R) and c.1439 T>C (L480P), shows serum transferrin with underoccupancy of N-glycosylation sites. Total serum proteins and IgG N-glycans show accumulating amounts of definite high-mannose and hybrid structures. ALG12-congenital disorder of glycosylation displays CDG-I and II defects and it is associated with distinct, abnormal glycosylation of total serum and IgG N-glycans
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Chantret, I.; Dupre, T.; Delenda, C.; Bucher, S.; Dancourt, J.; Barnier, A.; Charollais, A.; Heron, D.; Bader-Meunier, B.; Danos, O.; Seta, N.; Durand, G.; Oriol, R.; Codogno, P.; Moore, S.E.H.
Congenital disorders of glycosylation type Ig is defined by a deficiency in dolichyl-P-mannose:Man7GlcNAc2-PP-dolichyl mannosyltransferase
J. Biol. Chem.
277
25815-25822
2002
Homo sapiens (Q9BV10), Homo sapiens
Manually annotated by BRENDA team
Grubenmann, C.E.; Frank, C.G.; Kjaergaard, S.; Berger, E.G.; Aebi, M.; Hennet, T.
ALG12 mannosyltransferase defect in congenital disorder of glycosylation type Ig
Hum. Mol. Genet.
11
2331-2339
2002
Homo sapiens (Q9BV10), Homo sapiens
Manually annotated by BRENDA team
Massarweh, A.; Bosco, M.E.; Iatmanen-Harbi, S.; Tessier, C.; Amana, L.; Busca, P.; Chantret, I.; Gravier-Pelletier, C.; Moore, S.E.
Brefeldin A promotes the appearance of oligosaccharyl phosphates (OSP) derived from Glc3Man9GlcNAc2-PP-dolichol within the endomembrane system of HepG2 cells
J. Lipid Res.
57
1477-1491
2016
Homo sapiens
Manually annotated by BRENDA team
Sturiale, L.; Bianca, S.; Garozzo, D.; Terracciano, A.; Agolini, E.; Messina, A.; Palmigiano, A.; Esposito, F.; Barone, C.; Novelli, A.; Fiumara, A.; Jaeken, J.; Barone, R.
ALG12-CDG novel glycophenotype insights endorse the molecular defect
Glycoconj. J.
36
461-472
2019
Homo sapiens (Q9BV10), Homo sapiens
Manually annotated by BRENDA team