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Information on EC 2.4.1.261 - dolichyl-P-Man:Man8GlcNAc2-PP-dolichol alpha-1,2-mannosyltransferase and Organism(s) Homo sapiens and UniProt Accession Q9H6U8
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2.4.1.261 dolichyl-P-Man:Man8GlcNAc2-PP-dolichol alpha-1,2-mannosyltransferaseIUBMB 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. ALG9 mannosyltransferase catalyses the addition of two different alpha-1,2-mannose residues: the addition of alpha-1,2-mannose to Man6GlcNAc2-PP-Dol (EC 2.4.1.259) and the addition of alpha-1,2-mannose to Man8GlcNAc2-PP-Dol (EC 2.4.1.261).
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The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
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Synonyms
ALG9, ALG9 alpha1,2 mannosyltransferase, ALG9 mannosyltransferase, dolichylphosphomannose-dependent ALG9 mannosyltransferase, EBS3, EC 2.4.1.130, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
PATHWAY SOURCE
PATHWAYS
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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-alpha-(1->6)]-D-Man-beta-(1->4)-D-GlcNAc-beta-(1->4)-D-GlcNAc-diphosphodolichol alpha-1,2-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. ALG9 mannosyltransferase catalyses the addition of two different alpha-1,2-mannose residues: the addition of alpha-1,2-mannose to Man6GlcNAc2-PP-Dol (EC 2.4.1.259) and the addition of alpha-1,2-mannose to Man8GlcNAc2-PP-Dol (EC 2.4.1.261).
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
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-alpha-(1->6)]-D-Man-beta-(1->4)-D-GlcNAc-beta-(1->4)-D-GlcNAc-diphosphodolichol
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->2)-D-Man-alpha-(1->6)]-D-Man-alpha-(1->6)]-D-Man-beta-(1->4)-D-GlcNAc-beta-(1->4)-D-GlcNAc-diphosphodolichol + dolichyl phosphate
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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
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-alpha-(1->6)]-D-Man-beta-(1->4)-D-GlcNAc-beta-(1->4)-D-GlcNAc-diphosphodolichol
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->2)-D-Man-alpha-(1->6)]-D-Man-alpha-(1->6)]-D-Man-beta-(1->4)-D-GlcNAc-beta-(1->4)-D-GlcNAc-diphosphodolichol + dolichyl phosphate
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
inactivation of Alg9 results in impaired maturation and defective glycosylation of polycystin-1
malfunction
an ALG9-defective (congenital disorders of glycosylation type IL) patient who is homozygous for the p.Y286C (c.860A>G) mutation. This patient presents with psychomotor retardation, axial hypotonia, epilepsy, failure to thrive, inverted nipples, hepatomegaly, and pericardial effusion. Due to the ALG9 deficiency, the cells of this patient accumulated the lipid-linked oligosaccharides Man6GlcNAc2-PP-dolichol and Man8GlcNAc2-PP-dolichol. Lipid-linked Man6GlcNAc2 and Man8GlcNAc2 are transferred onto proteins with the same efficiency. In addition, glycoproteins bearing these Man6GlcNAc2 and Man8GlcNAc2 structures efficiently enter in the glucosylation/deglucosylation cycle of the quality control system to assist in protein folding. In comparison with control cells, patients cells degrade misfolded glycoproteins at an increasing rate. The Man8GlcNAc2 isomer C on the patients glycoproteins is found to promote the degradation of misfolded glycoproteins
malfunction
congenital disorders of glycosylation, a deficiency of the ALG9 alpha1,2 mannosyltransferase enzyme, causes an accumulation of lipid-linked-GlcNAc2Man6 and -GlcNAc2Man8 structures, which is paralleled by the transfer of incomplete oligosaccharide precursors to protein. A homozygous point-mutation E523K is detected in the ALG9 gene. The ALG9 defect found in the patient with congenital disorders of glycosylation, who presents with developmental delay, hypotonia, seizures, and hepatomegaly, shows that efficient lipid-linked oligosaccharide synthesis is required for proper human development and physiology
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). ALG9_HUMAN
611
8
69863
Swiss-Prot
Mitochondrion (Reliability: 4)
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E523K
the ALG9 defect defines a form of congenital disorders of glycosylation named CDG-IL. The patient with this ALG9 defect, who presents with developmental delay, hypotonia, seizures, and hepatomegaly
Y286C
patient, who is homozygous for the ALG9 mutation p.Y286C, deleterious effect Y286C on the ALG9 function. Compared the complementation efficiency of the wild-type and mutant ALG9 cDNA in yeast cells deficient for alg9. In an assay, the growth efficiency of the transformed yeast double mutant alg9 wbp1-2 is tested. Deficiency in lipid-linked oligosaccharide biosynthesis (alg9) in combination with reduced oligosaccharyltransferase activity (wbp1-2) results in a temperature-sensitive phenotype at 30°C. At this restrictive temperature, both the normal and mutant ALG9 cDNAs are able to restore growth. The HsALG9 transformants perform similar to the yeast alg9. The complementation with the mutant construct (HsALG9 (Y286C)) is less efficient, resulting is a reduced growth restoration. This difference becomes more prominent when the transformants are grown at 32°C. The hypoglycosylation of the alg9 yeast strain is reflected in the presence of CPY glycoforms lacking one or two N-linked oligosacharides. The human ALG9 cDNA complements the yeast mutation partially, as shown by the improved glycosylation of CPY. The complementation efficiency of the HsALG9 (Y286C) is less efficient and almost comparable to the empty vector
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
homozygous splice variant NM_024740.2: c.1173+2T4A in the ALG9 gene causes rare lethal autosomal recessive Gillessen-Kaesbach-Nishimura skeletal dysplasia. Skipping of exon 10 leads to shorter RNA and results in an increase in monoglycosylated transferrin
medicine
ALG9 homozygous splice variant NM_024740.2: c.1173+2T4A causes skipping of exon 10, leading to shorter RNA and resulting in an increase in monoglycosylated transferrin. Patients show a lethal skeletal dysplasia with visceral malformations as the most severe phenotype, i.e. Gillessen-Kaesbach-Nishimura skeletal dysplasia
medicine
in a patient with homozygous mutation in ALG9, c.860A > G, i.e. Y287C, prenatally, dysmorphic features, numerous renal cysts and minor cardiac malformations were detected. Postnatally, dysmorphic features include shallow orbits, micrognathia, hypoplastic nipples, talipes equinovarus, lipodystrophy and cutis marmorata
medicine
inactivation of Alg9 results in impaired maturation and defective glycosylation of polycystin-1. Seven of eight (88%) cases selected have at least four kidney cysts, compared with none in matched controls
medicine
patients with ALG9-congenital disorder of glycosylation present with drug-resistant infantile epilepsy, hypotonia, dysmorphic features, failure to thrive, global developmental disability, and skeletal dysplasia. One patient presented with nonimmune hydrops fetalis, showing global atrophy with delayed myelination caused by homozygous mutation c.1075G>A, i.e. E359K
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Frank, C.G.; Grubenmann, C.E.; Eyaid, W.; Berger, E.G.; Aebi, M.; Hennet, T.
Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL
Am. J. Hum. Genet.
75
146-150
2004
Homo sapiens (Q9H6U8)
Weinstein, M.; Schollen, E.; Matthijs, G.; Neupert, C.; Hennet, T.; Grubenmann, C.E.; Frank, C.G.; Aebi, M.; Clarke, J.T.; Griffiths, A.; Seargeant, L.; Poplawski N.
CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features
Am. J. Med. Genet. A
136
194-197
2005
Homo sapiens (Q9H6U8)
Vleugels, W.; Keldermans, L.; Jaeken, J.; Butters, T.D.; Michalski, J.C.; Matthijs, G.; Foulquier, F.
Quality control of glycoproteins bearing truncated glycans in an ALG9-defective (CDG-IL) patient
Glycobiology
19
910-917
2009
Homo sapiens (Q9H6U8)
Tham, E.; Eklund, E.A.; Hammarsjoe, A.; Bengtson, P.; Geiberger, S.; Lagerstedt-Robinson, K.; Malmgren, H.; Nilsson, D.; Grigelionis, G.; Conner, P.; Lindgren, P.; Lindstrand, A.; Wedell, A.; Albage, M.; Zielinska, K.; Nordgren, A.; Papadogiannakis, N.; Nishimura, G.; Grigelioniene, G.
A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9
Eur. J. Hum. Genet.
24
198-207
2016
Homo sapiens (Q9H6U8)
Tham, E.; Eklund, E.; Hammarsjoe, A.; Bengtson, P.; Geiberger, S.; Lagerstedt-Robinson, K.; Malmgren, H.; Nilsson, D.; Grigelionis, G.; Conner, P.; Lindgren, P.; Lindstrand, A.; Wedell, A.; Albage, M.; Zielinska, K.; Nordgren, A.; Papadogiannakis, N.; Nishimura, G.; Grigelioniene, G.
A novel phenotype in N-glycosylation disorders Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9
Eur. J. Hum. Genet.
24
198-207
2016
Homo sapiens (Q9H6U8)
Besse, W.; Chang, A.; Luo, J.; Triffo, W.; Moore, B.; Gulati, A.; Hartzel, D.; Mane, S.; Torres, V.; Somlo, S.; Mirshahi, T.
ALg9 mutation carriers develop kidney and liver cysts
J. Am. Soc. Nephrol.
30
2091-2102
2019
Homo sapiens (Q9H6U8)
AlSubhi, S.; AlHashem, A.; AlAzami, A.; Tlili, K.; AlShahwan, S.; Lefeber, D.; Alkuraya, F.; Tabarki, B.
Further delineation of the ALG9-CDG phenotype
JIMD Rep.
27
107-112
2016
Homo sapiens (Q9H6U8)
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