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PMID:20637498

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Citation

Cantagrel, V, Lefeber, DJ, Ng, BG, Guan, Z, Silhavy, JL, Bielas, SL, Lehle, L, Hombauer, H, Adamowicz, M, Swiezewska, E, De Brouwer, AP, Blümel, P, Sykut-Cegielska, J, Houliston, S, Swistun, D, Ali, BR, Dobyns, WB, Babovic-Vuksanovic, D, van Bokhoven, H, Wevers, RA, Raetz, CR, Freeze, HH, Morava, E, Al-Gazali, L and Gleeson, JG (2010) SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell 142:203-17

Abstract

N-linked glycosylation is the most frequent modification of secreted and membrane-bound proteins in eukaryotic cells, disruption of which is the basis of the congenital disorders of glycosylation (CDGs). We describe a new type of CDG caused by mutations in the steroid 5alpha-reductase type 3 (SRD5A3) gene. Patients have mental retardation and ophthalmologic and cerebellar defects. We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation.

Links

PubMed PMC2940322 Online version:10.1016/j.cell.2010.06.001

Keywords

3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/metabolism; Abnormalities, Multiple/metabolism; Animals; Butadienes/metabolism; Consanguinity; Dolichol/metabolism; Embryo, Mammalian/metabolism; Genome-Wide Association Study; Glycosylation; Hemiterpenes/metabolism; Humans; Intellectual Disability/metabolism; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mice; Mutation; Pentanes/metabolism; Saccharomyces cerevisiae/genetics; Saccharomyces cerevisiae/metabolism; Saccharomyces cerevisiae Proteins/genetics; Saccharomyces cerevisiae Proteins/metabolism; Unfolded Protein Response

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

YEAST:DFG10

involved_in

GO:0019348: dolichol metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

YEAST:DFG10

involved_in

GO:0016095: polyprenol catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

YEAST:DFG10

involved_in

GO:0006488: dolichol-linked oligosaccharide biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

YEAST:DFG10

involved_in

GO:0019408: dolichol biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

YEAST:DFG10

enables

GO:0003865: 3-oxo-5-alpha-steroid 4-dehydrogenase activity

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q9H8P0

F

Seeded From UniProt

complete

HUMAN:PORED

located_in

GO:0005783: endoplasmic reticulum

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PORED

involved_in

GO:0019348: dolichol metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PORED

involved_in

GO:0016095: polyprenol catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PORED

involved_in

GO:0006488: dolichol-linked oligosaccharide biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PORED

part_of

GO:0005783: endoplasmic reticulum

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PORED

involved_in

GO:0006488: dolichol-linked oligosaccharide biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PORED

involved_in

GO:0016095: polyprenol catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PORED

enables

GO:0016628: oxidoreductase activity, acting on the CH-CH group of donors, NAD or NADP as acceptor

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PORED

involved_in

GO:0019348: dolichol metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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