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dolichyl beta-D-glucosyl phosphate + alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphospho-Dol25
alpha-D-Glc-(1->3)-alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphospho-Dol25 + dolichyl phosphate
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dolichyl beta-D-glucosyl phosphate + alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphosphodolichol
alpha-D-Glc-(1->3)-alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphosphodolichol + dolichyl phosphate
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Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Analysis of multiple mutations in the hALG6 gene in a patient with congenital disorder of glycosylation Ic.
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Employment of single-strand conformation polymorphism analysis in screening for ?-1,3 glucosyltransferase gene mutation A333V in Croatian population.
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Frequency Determination of ?-1,3 Glucosyltransferase p.Y131H and p.F304S Polymorphisms in the Croatian Population Revealed Five Novel Single Nucleotide Polymorphisms in the hALG6 Gene.
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malfunction
alg6 mutants accumulate lipid-linked Man9GlcNAc2
malfunction
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alg6-1 mutants accumulate Man9GlcNAc2-P-P-dolichol as their largest lipid-linked oligosaccharide in vivo and in vitro. alg6-1 cells are unable to transfer glucose from dolichol phosphoglucose to the unglucosylated lipid-linked oligosaccharide
physiological function
ALG6 deficient MI8-5 cells express 2fold lower levels of oligosaccharyltransferase STT3B than the parental Chinese hamster ovary cells. The combination of reduced expression of STT3B and the lack of the optimal Dol-PP-GlcNAc2Man9Glc3 donor synergize to cause very severe hypoglycosylation of proteins in MI8-5 cells
physiological function
fibroblasts from an ALG6-congenital disorders of glycosylation patient that carries the A333V mutation on the maternal ALG6 allele and the S308R and Y131H mutations on the paternal ALG6 allele assemble Dol-PP-GlcNAc2Man9 as the largest oligosaccharide donor. 3040% of oligosaccharyltransferase STT3A-dependent glycosylation sites and 20% of oligosaccharyltransferase STT3B-dependent sites are skipped in ALG6-congenital disorders of glycosylation fibroblasts
physiological function
three-state mechanism, where Dol-P-Glc binds before the Man9-containing acceptor substrate, because the glucose moiety is at the bottom of the active site cavity. Donor and acceptor substrates bind sequentially and Asp69 acts as a general base that abstracts the proton of the 3-hydroxyl group of the terminal A-branch mannose of the acceptor substrate to activate it for a nucleophilic attack
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A333V
analysis of lipid-linked oligosaccharides in cultured fibroblasts indicates accumulation of Man9GlcNAc2-PP-Dol. Sequence analysis of ALG6 reveals a deletion of exon 3 (c.257 + 5G > A) in combination with a missense mutation (c.998C > T, p.Ala333Val). The patient shows skeletal dysplasia with brachytelephalangy
delI299/F304S
patient with three mutations in the hALG6 gene. The maternal allele has an intronic G -> A mutation resulting in skipping of exon3 (IVS3 + 5G > A). This produces a nonfunctional enzyme as shown by its inability to restore normal glycosylation in a Saccharomyces cerevisiae strain lacking a functional ALG6. The paternal allele has two mutations. One is a deletion of three bases (895897delATA) leading to an in-frame deletion of isoleucine 299 (delI299) located in a transmembrane domain. The second mutation on the same allele 911T > C causes a F304S change. When expressed in the ALG6 deficient yeast strain, this allele restores glycosylation but the mRNA is unstable or inefficiently transcribed, contributing to the impaired glycosylation in the patient
F304S
natural variant, common polymorphism reduces the ability to rescue defective glycosylation of an alg6-deficient strain of S. cerevisiae during rapid growth, may exacerbate the clinical severity of patients with CDG1A
Y131H
frequent natural variant, the cause of congenital disorder of glycosylation-Ic (CDG-Ic). One patient with typical CDG-Ic symptoms and a homozygous p.Tyr131His alteration in ALG6. In contrast to most CDG patients, her LLO and plasma transferrin glycosylation appeared normal. Thus, it is unclear whether Y131H causes CDG-Ic or contributes to the symptoms
D307A
activity is unaffected by the mutation
D69N
strong reduction of activity
D99N
activity is unaffected by the mutation
E306A
activity is unaffected by the mutation
E379A
activity is unaffected by the mutation
H378A
strong reduction of activity
H378D
strong reduction of activity
H378E
strong reduction of activity
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medicine
single nucleotide polymorphisms ALG6 rs10889417 G>A and GALNTL4 rs12270446 G>C independently predict cutaneous melanoma disease-specific survival. The low death-risk-associated rs10889417 A allele is associated with increase in ALG6 mRNA expression levels in cultured skin fibroblasts and whole blood cells and the rs12270446 G allele is associated with decrease in GALNTL4 mRNA expression levels in skin tissues
synthesis
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genetic engineering of N-glycan biosynthesis in Yarrowia lipolytica so that it produces Man(3)GlcNAc(2) structures on its glycoproteins. Disruption of the ALG3 gene, EC 2.4.1.258, results in modification of proteins mainly with Man(5)GlcNAc(2) and GlcMan(5)GlcNAc(2) glycans, and to a lesser extent with Glc(2)Man(5)GlcNAc(2) glycans. To avoid underoccupancy of glycosylation sites, Alg6, EC 2.4.1.267, is concomitantly overexpressed. Overexpression of the heterodimeric Aspergillus niger glucosidase II results in removal the terminal glucose residues. Overexpression of an alpha-1,2-mannosidase leads to Man(3)GlcNAc(2) structures, which are substrates for the synthesis of complex-type glycans. The final Yarrowia lipolytica strain produces proteins glycosylated with the trimannosyl core N-glycan (Man(3)GlcNAc(2)), which is the common core of all complex-type N-glycans
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Drijvers, J.M.; Lefeber, D.J.; de Munnik, S.A.; Pfundt, R.; van de Leeuw, N.; Marcelis, C.; Thiel, C.; Koerner, C.; Wevers, R.A.; Morava, E.
Skeletal dysplasia with brachytelephalangy in a patient with a congenital disorder of glycosylation due to ALG6 gene mutations
Clin. Genet.
77
507-509
2010
Homo sapiens (Q9Y672)
brenda
Reiss, G.; te Heesen, S.; Zimmerman, J.; Robbins, P.W.; Aebi, M.
Isolation of the ALG6 locus of Saccharomyces cerevisiae required for glucosylation in the N-linked glycosylation pathway
Glycobiology
6
493-498
1996
Saccharomyces cerevisiae (Q12001)
brenda
Westphal, V.; Kjaergaard, S.; Schollen, E.; Martens, K.; Grunewald, S.; Schwartz, M.; Matthijs, G.; Freeze, H.H.
A frequent mild mutation in ALG6 may exacerbate the clinical severity of patients with congenital disorder of glycosylation Ia (CDG-Ia) caused by phosphomannomutase deficiency
Hum. Mol. Genet.
11
599-604
2002
Homo sapiens (Q9Y672)
brenda
Westphal, V.; Xiao, M.; Kwok, P.Y.; Freeze, H.H.
Identification of a frequent variant in ALG6, the cause of congenital disorder of glycosylation-Ic
Hum. Mutat.
22
420-421
2003
Homo sapiens (Q9Y672)
brenda
Runge, K.W.; Huffaker, T.C.; Robbins, P.W.
Two yeast mutations in glucosylation steps of the asparagine glycosylation pathway
J. Biol. Chem.
259
412-417
1983
Saccharomyces cerevisiae
brenda
Westphal, V.; Schottstdt, C.; Marquardt, T.; Freeze, H.H.
Analysis of multiple mutations in the hALG6 gene in a patient with congenital disorder of glycosylation Ic
Mol. Genet. Metab.
70
219-223
2000
Homo sapiens (Q9Y672)
brenda
De Pourcq, K.; Tiels, P.; Van Hecke, A.; Geysens, S.; Vervecken, W.; Callewaert, N.
Engineering Yarrowia lipolytica to produce glycoproteins homogeneously modified with the universal Man3GlcNAc2 N-glycan core
PLoS ONE
7
e39976
2012
Yarrowia lipolytica
brenda
Shrimal, S.; Gilmore, R.
Reduced expression of the oligosaccharyltransferase exacerbates protein hypoglycosylation in cells lacking the fully assembled oligosaccharide donor
Glycobiology
25
774-783
2015
Cricetulus griseus (G3GZD6), Homo sapiens (Q9Y672)
brenda
Zhou, B.; Zhao, Y.; Liu, H.; Luo, S.; Amos, C.; Lee, J.; Li, X.; Nan, H.; Wei, Q.
Novel genetic variants of ALG6 and GALNTL4 of the glycosylation pathway predict cutaneous melanoma-specific survival
Cancers (Basel)
12
288
2020
Homo sapiens (Q9Y672)
brenda
Bloch, J.S.; Pesciullesi, G.; Boilevin, J.; Nosol, K.; Irobalieva, R.N.; Darbre, T.; Aebi, M.; Kossiakoff, A.A.; Reymond, J.L.; Locher, K.P.
Structure and mechanism of the ER-based glucosyltransferase ALG6
Nature
579
443-447
2020
Saccharomyces cerevisiae (Q12001)
brenda