SRD5A3 Is Required for Converting Polyprenol to Dolichol and Is Mutated in a Congenital Glycosylation Disorder

被引：223

作者：

Cantagrel, Vincent ^{[3
]}

Lefeber, Dirk J. ^{[4
,5
]}

Ng, Bobby G. ^{[9
]}

Guan, Ziqiang ^{[10
]}

Silhavy, Jennifer L. ^{[3
]}

Bielas, Stephanie L. ^{[3
]}

Lehle, Ludwig ^{[11
]}

Hombauer, Hans ^{[12
,13
]}

Adamowicz, Maciej ^{[14
]}

Swiezewska, Ewa ^{[16
]}

De Brouwer, Arjan P. ^{[6
]}

Bluemel, Peter ^{[17
]}

Sykut-Cegielska, Jolanta ^{[15
]}

Houliston, Scott ^{[9
]}

Swistun, Dominika ^{[3
]}

Ali, Bassam R. ^{[1
]}

Dobyns, William B. ^{[18
]}

Babovic-Vuksanovic, Dusica ^{[19
,20
,21
,22
,23
]}

van Bokhoven, Hans ^{[6
,7
]}

Wevers, Ron A. ^{[4
]}

Raetz, Christian R. H. ^{[10
]}

Freeze, Hudson H. ^{[9
]}

Morava, Eva ^{[8
]}

Al-Gazali, Lihadh ^{[1
,2
]}

Gleeson, Joseph G. ^{[3
]}

机构：

[1] United Arab Emirates Univ, Sch Med & Hlth Sci, Dept Pathol, Al Ain 17666, U Arab Emirates

[2] United Arab Emirates Univ, Sch Med & Hlth Sci, Dept Pediat, Al Ain 17666, U Arab Emirates

[3] Univ Calif San Diego, Howard Hughes Med Inst, Dept Neurosci & Pediat, Inst Genom Med,Neurogenet Lab, La Jolla, CA 92093 USA

[4] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, Dept Lab Med, NL-6500 HB Nijmegen, Netherlands

[5] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, NL-6500 HB Nijmegen, Netherlands

[6] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands

[7] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Cognit Neurosci, NL-6500 HB Nijmegen, Netherlands

[8] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, Dept Paediat, NL-6500 HB Nijmegen, Netherlands

[9] Sanford Burnham Med Res Inst, Sanford Childrens Hlth Res Ctr, Genet Dis Program, La Jolla, CA 92037 USA

[10] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA

[11] Univ Regensburg, Lehrstuhl Zellbiol & Pflanzenbiochem, D-93053 Regensburg, Germany

[12] Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, Ludwig Inst Canc Res,Dept Med, La Jolla, CA 92093 USA

[13] Univ Calif San Diego, Sch Med, Ctr Canc, La Jolla, CA 92093 USA

[14] Childrens Mem Hlth Inst, Dept Biochem & Expt Med, PL-04730 Warsaw, Poland

[15] Childrens Mem Hlth Inst, Dept Metab Dis Endocrinol & Diabetol, PL-04730 Warsaw, Poland

[16] Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland

[17] Preyersches Kinderspital, A-1100 Vienna, Austria

[18] Univ Chicago, Dept Human Genet Neurol & Pediat, Chicago, IL 60637 USA

[19] Mayo Clin, Dept Med Genet, Rochester, MN 55905 USA

[20] Mayo Clin, Dept Pediat Neurol, Rochester, MN 55905 USA

[21] Mayo Clin, Dept Lab Genet, Rochester, MN 55905 USA

[22] Mayo Clin, Dept Pediat Endocrinol, Rochester, MN 55905 USA

[23] Mayo Clin, Dept Dermatol, Rochester, MN 55905 USA

来源：

CELL | 2010年 / 142卷 / 02期

基金：

美国国家卫生研究院;

关键词：

IONIZATION-MASS-SPECTROMETRY; AUTOSOMAL RECESSIVE SYNDROME; RATE-LIMITING STEP; STEROID; 5-ALPHA-REDUCTASE; SACCHAROMYCES-CEREVISIAE; N-GLYCOSYLATION; RAT-LIVER; BIOSYNTHESIS; PHOSPHATE; CDG;

D O I：

10.1016/j.cell.2010.06.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 5 alpha-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.

引用

页码：203 / 217

页数：15

共 60 条

[1] Defects in the N-linked oligosaccharide biosynthetic pathway in a Trypanosoma brucei glycosylation mutant [J].

Acosta-Serrano, A ;

O'Rear, J ;

Quellhorst, G ;

Lee, SH ;

Hwa, KY ;

Krag, SS ;

Englund, PT .

EUKARYOTIC CELL, 2004, 3 (02) :255-263

[2] Congenital disorders of glycosylation: genetic model systems lead the way [J].

Aebi, M ;

Hennet, T .

TRENDS IN CELL BIOLOGY, 2001, 11 (03) :136-141

[3] An overview on 5α-reductase inhibitors [J].

Aggarwal, Saurabh ;

Thareja, Suresh ;

Verma, Abhilasha ;

Bhardwaj, Tilak Raj ;

Kumar, Manoj .

STEROIDS, 2010, 75 (02) :109-153

[4] A new autosomal recessive syndrome of ocular colobomas, ichthyosis, brain malformations and endocrine abnormalities in an inbred Emirati family [J].

Al-Gazali, L. ;

Hertecant, J. ;

Algawi, K. ;

El Teraifi, H. ;

Dattani, M. .

AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2008, 146A (07) :813-819

[5]

ALBER T, 1982, Journal of Molecular and Applied Genetics, V1, P419

[6] CTP-DEPENDENT DOLICHOL PHOSPHORYLATION BY MAMMALIAN-CELL HOMOGENATES [J].

ALLEN, CM ;

KALIN, JR ;

SACK, J ;

VERIZZO, D .

BIOCHEMISTRY, 1978, 17 (23) :5020-5026

[7] DELETION OF STEROID 5-ALPHA-REDUCTASE 2-GENE IN MALE PSEUDOHERMAPHRODITISM [J].

ANDERSSON, S ;

BERMAN, DM ;

JENKINS, EP ;

RUSSELL, DW .

NATURE, 1991, 354 (6349) :159-161

[8] DOLICHOL MONOPHOSPHATE GLUCOSE - AN INTERMEDIATE IN GLUCOSE TRANSFER IN LIVER [J].

BEHRENS, NH ;

LELOIR, LF .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1970, 66 (01) :153-&

[9]

BLIGH EG, 1959, CAN J BIOCHEM PHYS, V37, P911

[10] The molecular basis of coupling of translocation and N-glycosylation [J].

Chavan, M ;

Lennarz, W .

TRENDS IN BIOCHEMICAL SCIENCES, 2006, 31 (01) :17-20

← 1 2 3 4 5 6 →