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J Biol Chem, Vol. 274, Issue 37, 25986-25989, September 10, 1999
,
From the Georg-August-Universität Göttingen, Abteilung
Biochemie II, Heinrich-Düker-Weg 12, D-37073 Göttingen,
Germany and the Klinik und Poliklinik für
Kinderheilkunde, 48149 Münster, Germany
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
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The fucosylation of glycoproteins was found to be
deficient in a patient with a clinical phenotype resembling that of
leukocyte adhesion deficiency type II (LAD II). While in LAD II
hypofucosylation of glycoconjugates is secondary to an impaired
synthesis of GDP-fucose due to a deficiency of the
GDP-D-mannose-4,6-dehydratase, synthesis of
GDP-fucose was normal in our patient (Körner, C., Linnebank, M.,
Koch, H., Harms, E., von Figura, K., and Marquardt, T. (1999) J. Leukoc. Biol., in press). Import of GDP-fucose into Golgi-enriched vesicles was composed of a saturable, high affinity and a nonsaturable component. In our patient the saturable high affinity import of GDP-fucose was deficient, while import of UDP-galactose and the activity of GDPase, which generates the nucleoside phosphate required for antiport of GDP-fucose, were normal. Addition of
L-fucose to the medium of fibroblasts restored the
fucosylation of glycoproteins. We propose that this new form of
carbohydrate-deficient glycoprotein syndrome is caused by impaired
import of GDP-fucose into the Golgi.
The glycosylation of proteins and lipids, which mainly takes place
in the luminal part of the endoplasmic reticulum and the Golgi
apparatus, requires the presence of specific nucleotide sugar
transporters. These proteins allow the import of cytoplasmically synthesized nucleotide sugars and function as antiporters by exchanging the nucleotide sugars with the corresponding nucleoside monophosphates. The latter is generated in the organelle lumen by the action of glycosyltransferases and nucleoside diphosphatases (1). Several of
these transporters have been identified by cDNA complementation studies using mutant cell lines with impaired nucleotide sugar transport. Examples are the cloning of the yeast and the mammalian transporter for UDP-N-acetylglucosamine (2, 3), the
transporter for GDP-mannose from Leishmania donovani (4),
the transporter for CMP-N-acetylneuraminic acid from Chinese
hamster (5) and the transporter for UDP-galactose from mouse
(6).
In the present study we describe for the first time the association of
a human disease with a defect in the translocation of a nucleotide
sugar. This disease belongs to the group of carbohydrate-deficient glycoprotein syndromes
(CDGS),1 a group of
hereditary disorders with impaired glycosylation of newly synthesized
glycoproteins. The clinical phenotype of CDGS is heterogenous. CDGS
present mostly with severe psychomotor and mental retardation as in
CDGS types Ia, II, III, IV, V and in leukocyte adhesion deficiency type
II (LAD II) (7-12). In addition there are forms presenting as a
hepatogastrointestinal disorder as in CDGS Ib (13) or as an anemia as
in congenital dyserythropoietic anemia II (14). All defects described
so far affect enzymes catalyzing the synthesis of GDP-mannose,
GDP-fucose, or
dolichyl-PP-GlcNAc2Man9Glc3 or
modifying N-linked oligosaccharides in newly synthesized glycoproteins.
We report here the decreased import of GDP-fucose into the Golgi
apparatus of skin fibroblasts from a patient who suffers from
dysmorphic signs, retarded growth, psychomotor retardation, and severe
infections. The biochemical hallmark is a general hypofucosylation of
N- and O-glycosylated proteins (for a detailed
description of the clinical and biochemical findings in this patient,
see Ref. 15). The clinical phenotype and the hypofucosylation of our
patient resemble a defect termed LAD II, which was described previously
in two other patients (12). In LAD II the conversion of GDP-mannose to
GDP-fucose is impaired due to the inactivity of
GDP-D-mannose-4,6-dehydratase (16). Since the activity of GDP-D-mannose-4,6-dehydratase was normal in fibroblasts
from our patient (17), the hypofucosylation must result from a
different defect. Here we report that the hypofucosylation results from a severely decreased import of GDP-fucose into the Golgi.
[2-3H]Mannose (636 GBq/mmol),
GDP-[14C]fucose (11.5 GBq/mmol),
UDP-[3H]galactose (359 GBq/mmol), and
[methoxy-14C]inulin (0.33 MBq/g) were
purchased from Amersham Pharmacia Biotech (Braunschweig, Germany).
Cell Culture--
Human primary fibroblast cultures from
controls, parents, and the patient were obtained from upper arm skin
biopsies. Cells were grown at 37 °C in the presence of 5%
CO2 on Dulbecco's modified Eagle's medium (Life
Technologies, Inc.) supplemented with 10% fetal calf serum
(Pansystems, Aidenbach, Germany).
Metabolic Labeling with
[2-3H]Mannose--
Labeling of fibroblasts with 125 µCi of [2-3H]mannose was carried out for 30 min or
6 h as described previously (18).
Analysis of GDP-[3H]mannose and
GDP-[3H]fucose--
GDP-[3H] mannose and
GDP-[3H]fucose were separated from other labeled
metabolites by descending paper chromatography.
[3H]Mannose and [3H]fucose were released
from nucleotide sugars by mild acid hydrolysis, separated by thin layer
chromatography (TLC), and quantified by TLC scanner (Berthold) as
described previously (18).
Preparation of Radiolabeled Glycopeptides and Analysis of
Glycopeptide-bound [3H]Mannose and
[3H]Fucose--
Glycoproteins of control and patient
fibroblasts labeled with [2-3H]mannose were sequentially
extracted as described previously (18) followed by a digestion with 100 µg/ml of Pronase (Roche Molecular Biochemicals) for 24 h at
50 °C in a buffer containing 0.1 M Tris/HCl, pH 7.5, and
0.5% SDS. [3H]Mannose and [3H]fucose were
released from the resulting glycopeptides by acid hydrolysis in 1 M trifluoroacetic acid at 100 °C for 4 h and
analyzed by TLC as described above.
Lens culinaris Affinity Chromatography--
Radiolabeled
glycopeptides were subjected to lectin affinity chromatography on a
column containing agarose bound L. culinaris lectin (Sigma)
as described previously (19).
Preparation of Golgi-enriched Membrane
Fractions--
Golgi-derived membrane fractions were prepared as
described previously (20) with some modifications. For each experiment two 150-cm2 cell culture dishes were seeded with 3 × 106 fibroblasts each. After culturing for 10 days, the
cells were washed three times with ice-cold PBS (0.15 M
NaCl in sodium phosphate, pH 7.4) and swollen for 30 s in 0.25 M sucrose, 3 mM imidazole, 1 mM
EDTA, pH 7.4. Cells were scraped into PBS and centrifuged for 5 min
with 500 × g at 4 °C. Pellets were redissolved in 2 ml of 0.25 M sucrose, 3 mM imidazole, pH 7.4, disrupted in a tight fitting Dounce homogenizer and centrifuged at
1000 × g for 10 min at 4 °C. Homogenization of the
pellet in sucrose/imidazole and centrifugation were repeated. The
supernatants were combined and overlaid onto a cushion of 1.3 M sucrose in 3 mM imidazole, pH 7.4, for
density gradient centrifugation in a SW 40-rotor (Beckman Instruments)
at 105 × g for 70 min at 4 °C.
Golgi-enriched membranes were collected at the 0.25-1.3 M
sucrose interphase and quantified by galactosyltransferase activity as
described (21). Protein determination followed the method of Lowry
et al. (22).
GDP-[14C]fucose and UDP-[3H]galactose
Import--
Import of nucleotide sugars into Golgi-enriched membranes
was determined as described previously (23) with the following modifications. The reaction was started by the addition of
Golgi-enriched membranes (60-100 µg) to buffer A (10 mM
Tris-HCl, pH 7.5, 150 mM KCl, 1 mM
MgCl2, 0.25 M sucrose) containing
GDP-[14C]fucose or UDP-[3H]galactose in a
final volume of 0.47 ml. Unless otherwise stated, the assays contained
3 µM GDP-[14C]fucose ( Determination of GDPase Activity in Golgi-enriched Membrane
Fractions--
For preparation of crude membranes cell monolayers were
washed with ice-cold 20 mM imidazole, pH 7.4, 2 mM CaCl2 (buffer B) and scraped into 1 ml of
the same buffer. The cells were passed 20 times through a 22-gauge
needle, and unbroken cells and nuclei were pelleted by centrifugation
at 1000 × g. Crude membranes were collected from the
supernatant by centrifugation at 105 × g for 30 min and redissolved in buffer B. GDPase activity was measured by a
modification of the method described by Abeijon et al. (24).
Incubations were carried out in buffer B containing 3 mM
GDP, 0.1% Triton X-100, and crude membranes (20 µg) in a final
volume of 100 µl. Following incubation at 37 °C for the indicated
times, reactions were stopped by adding 20 µl of 5% (w/v) SDS. The
samples were then diluted to 0.3 ml with buffer B containing 0.1%
Triton X-100, and inorganic phosphate was determined by the Ames method
(25).
A biochemical hallmark in leukocytes and fibroblasts of our
patient is the absence of We therefore analyzed the synthesis of GDP-fucose and the fucosylation
of glycoproteins in fibroblasts from our patient in more detail. When
fibroblasts were incubated for 30 min in the presence of
[2-3H]mannose the incorporation of radioactivity into
GDP-fucose was almost six times lower than in controls (Table
I). When the incubation period was
prolonged to 6 h, the incorporation of radioactivity into
GDP-fucose pool was close to normal, while the incorporation into
glycoproteins was about one-fourth of control (Table I). One
possibility to explain these observations is the assumption that the
import of cytosolic GDP-fucose into the Golgi is impaired, leading to
an accumulation of GDP-fucose in the cytosol, a deficiency of
GDP-fucose in the Golgi and a hypofucosylation of glycoproteins. The
increase of cytosolic GDP-fucose can explain the decreased rate of
GDP-mannose to GDP-fucose conversion by the known feed back inhibition
of GDP-D-mannose-4,6-dehydratase by GDP-fucose (26).
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
885,000 dpm) or
0.5 µM UDP-[3H]galactose (4.3 × 106 dpm). After an incubation for 10 min or the time
indicated at 30 °C the reaction was stopped by the addition of 0.8 ml of ice-cold buffer A, followed by centrifugation at 105 × g for 30 min at 4 °C in a TLA-45 rotor (Beckman
Instruments). The supernatant was removed and used for the calculation
of radioactivity in the incubation medium. The pellet was washed three
times with ice cold buffer A, redissolved in 0.5 ml of 50 mM Tris-HCl, pH 8.8, containing 5 mM EDTA and
2% SDS by sonification for 2 min (Branson), and incubated for 30 min
at 23 °C. The amount of radioactivity associated with the pellet
represents the nucleotide sugars imported into vesicles, including the
sugars transferred to glycoconjugates and the radioactivity trapped in
the extravesicular space of the pellet. To determine the latter,
membranes were incubated under identical conditions with
[methoxy-14C]inulin, which does not penetrate
into vesicles. The value for imported nucleotide sugar was obtained by
correcting the radioactivity associated with the pellet for the
radioactivity trapped in the extravesicular space (23). Under standard
conditions using membranes from control fibroblasts, the trapped
radioactivity represented 17 ± 5% of the
[14C]fucose or 12 ± 2% of the
[3H]galactose radioactivity associated with the pellet.
To differentiate in the vesicles between nucleotide sugar and
glycoprotein associated radioactivity, 0.05 ml of 0.5 N
HCl, containing 20% trichloroacetic acid and 1% phosphotungstic acid
were added to the solubilized pellet. After an overnight precipitation
and centrifugation the pellet was solubilized in 2.5 N
NaOH, and the radioactivity was determined. Under standard conditions
25% of the imported [14C]fucose and 14% of the imported
[3H]galactose were found to be transferred to
glycoproteins. For a precise description of the calculation, see Ref.
23.
RESULTS AND DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
1,2-, 1,3-, and 1,6-linked fucose residues in glycoconjugates (15). This suggests either a defect in the
cytoplasmic synthesis of GDP-fucose, of its import in the Golgi, or of
a common cofactor of fucosyltransferases. De novo synthesis
of GDP-mannose to GDP-fucose is catalyzed by
GDP-D-mannose-4,6-dehydratase together with the FX protein,
which has an epimerase and reductase activity. Extracts from
fibroblasts and leukocytes of our patient catalyzed the synthesis of
GDP-fucose from GDP-mannose at a normal rate (17).
Incorporation of radioactivity into fucose bound to nucleotide
sugars or glycoproteins
To verify the hypofucosylation of glycoproteins, fibroblasts were
metabolically labeled with [2-3H]mannose for 6 h.
When labeled glycopeptides prepared from these cells were subjected to
L. culinaris affinity chromatography, which retains
1,6-fucosylated glycopeptides, the bound fraction was less than 1%
of that in controls (Table II), thus
confirming the severe hypofucosylation of glycoproteins. Moreover, we
could demonstrate that incubation of the patients fibroblasts in the presence of 1 mM fucose, but not in the presence of 1 mM mannose overcomes by large the fucosylation defect
(Table I). One explanation for the correction of the defect by addition
of L-fucose to the medium would be a Km
defect in the GDP-fucose transport. The elevated amount of GDP-fucose
in the cytoplasm would increase the transport into the Golgi to an
extent that ensures nearly normal fucosylation of glycoproteins. The
corrective effect renders the possibility unlikely that the
hypofucosylation results from the deficiency of a cofactor common to
all fucosyltransferases.
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Next we assayed the import of GDP-[14C]fucose into
preparations enriched in Golgi vesicles. The import of
GDP-[14C]fucose under standard assay conditions was
linear with time for up to 10 min, leveled off after 20 min, and was
proportional to the amount of vesicles added for up to 110 µg of
protein per assay. Determination of import as a function of GDP-fucose
revealed that import of GDP-fucose is composed of a saturable and a
nonsaturable component (Fig.
1A). The Km
for the saturable component was 0.7 ± 0.3 µM
GDP-fucose. At standard assay conditions (3 µM GDP-fucose) import via the saturable mechanism accounted for about 85%
of total GDP-fucose import. GDP-fucose import by the patients' vesicles at standard assay conditions was 20% of controls (Fig. 1B). Following import for up to 60 min revealed that
GDP-fucose import into patients' vesicles reached its maximum within 5 min. When import was determined at 0.5-30 µM GDP-fucose,
it became apparent that the residual import was accounted largely if
not exclusively by the nonsaturable import mechanism (Fig.
1A).
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As a control we determined the activity of galactosyltransferase, a marker of trans Golgi membranes (Fig. 1C). The activity of galactosyltransferase was similar in membranes from controls (37 ± 11 pmol [3H]galactose/min × mg protein, n = 9) and the patient (25 ± 9 pmol [3H]galactose/min × mg protein, n = 7). Furthermore we determined the import of a second nucleotide sugar as a control for the integrity of the vesicles. The import rate for UDP-[3H]galactose in control and patients' membranes was comparable (Fig. 1D). This indicates that the patients' vesicles were import competent for nucleotide sugars and that the failure to import GDP-fucose represents a specific defect.
Nucleotide sugar transporters operate as antiporters with the
corresponding nucleoside monophosphate (1). Impaired GDP-fucose import
could therefore also result from a decreased transfer of fucose onto
glycoproteins or decreased GDPase, which converts the released GDP into
the GMP substrate of the transporter. A deficiency of
fucosyltransferase activity as a cause for the reduced import is
unlikely, due to the corrective effect of exogenous fucose (see above)
and the absence of 1,2-, 1,3-, and 1,6-linked fucose residues,
which are all transferred by different fucosyltransferases.
As shown previously, transport of GDP-mannose into the lumen of
Saccharomyces cerevisiae Golgi vesicles requires a guanosine diphosphatase. A null mutation (gda1) showed a five times reduced rate
of GDP-mannose import (27). Mammalian cells posses a Golgi UDPase
showing highest activity with UDP and GDP as substrates (28). The
UDP/GDPase is expressed in all human tissues. In order to exclude a
defect in the hydrolysis of GDP in our patient, we examined the GDPase
activity and found it to be comparable in control and patient's
membranes (Fig. 2). We conclude from
these data that in the Golgi vesicles of the patient, GDP-fucose is severely reduced due to a defect in the saturable, high affinity import
of GDP-fucose and that under cell culture conditions the deficiency of
GDP-fucose in the Golgi can largely be overcome by raising the fucose
concentration in the medium to 1 mM.
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The defect in our patient is assumed to be recessively transmitted. We
therefore examined the import of GDP-fucose and UDP-galactose into
vesicles prepared from the fibroblasts of the parents. GDP-fucose and
UDP-galactose were imported at a normal rate by vesicles from the
mother, while import into vesicles from the father was reduced by about
40% for both nucleotide sugars (Fig. 1, B and
D). It should be noted that the activity of
galactosyltransferase was comparable in the parents and about
1.5-2-fold higher than in control and patient's membranes (Fig.
1C). These data would be compatible with the view that the
impaired import of GDP-fucose in the patient's vesicles is secondary
to a defect in a gene unrelated to the GDP-fucose transporter and that
only homozygosity for a defect in this gene of unknown function affects
GDP-fucose import. Such a gene could encode for a cofactor of the
transporter. Alternatively the affected gene could encode for one of
the transporter subunits if the transporter for GDP-fucose is a
heterooligomer. It should be noted, however, that the only sugar
nucleotide transporter for which the quaternary structure has been
examined is likely to exist as a homodimer (29). The molecular nature
of the GDP-fucose transporter is unknown. Cloning of the gene
complementing the GDP-fucose import in our patient may help to identify
its molecular nature.
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FOOTNOTES |
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* This work was supported by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
§ To whom correspondence should be addressed. Tel.: 49-551-395948; Fax: 49-551-395902; E-mail: koerner@ukb2-00.uni-bc2.gwdw.de.
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ABBREVIATIONS |
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The abbreviations used are: CDGS, carbohydrate-deficient glycoprotein syndrome(s); LAD II, leukocyte adhesion deficiency type II.
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
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Y. Luo and R. S. Haltiwanger O-Fucosylation of Notch Occurs in the Endoplasmic Reticulum J. Biol. Chem., March 25, 2005; 280(12): 11289 - 11294. [Abstract] [Full Text] [PDF]
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L. Sturla, R. Rampal, R. S. Haltiwanger, F. Fruscione, A. Etzioni, and M. Tonetti Differential Terminal Fucosylation of N-Linked Glycans Versus Protein O-Fucosylation in Leukocyte Adhesion Deficiency Type II (CDG IIc) J. Biol. Chem., July 11, 2003; 278(29): 26727 - 26733. [Abstract] [Full Text] [PDF]
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 D. J. Becker and J. B. Lowe Fucose: biosynthesis and biological function in mammals Glycobiology, July 1, 2003; 13(7): 41R - 53R. [Abstract] [Full Text] [PDF]
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A. Hidalgo, S. Ma, A. J. Peired, L. A. Weiss, C. Cunningham-Rundles, and P. S. Frenette Insights into leukocyte adhesion deficiency type 2 from a novel mutation in the GDP-fucose transporter gene Blood, March 1, 2003; 101(5): 1705 - 1712. [Abstract] [Full Text] [PDF]
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R. G. Spiro Protein glycosylation: nature, distribution, enzymatic formation, and disease implications of glycopeptide bonds Glycobiology, April 1, 2002; 12(4): 43R - 56R. [Abstract] [Full Text] [PDF]
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H. H. Freeze Update and perspectives on congenital disorders of glycosylation Glycobiology, December 1, 2001; 11(12): 129R - 143R. [Abstract] [Full Text] [PDF]
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Y. Wang, L. Shao, S. Shi, R. J. Harris, M. W. Spellman, P. Stanley, and R. S. Haltiwanger Modification of Epidermal Growth Factor-like Repeats with O-Fucose. MOLECULAR CLONING AND EXPRESSION OF A NOVEL GDP-FUCOSE PROTEIN O-FUCOSYLTRANSFERASE J. Biol. Chem., October 19, 2001; 276(43): 40338 - 40345. [Abstract] [Full Text] [PDF]
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 P. Berninsone, H.-Y. Hwang, I. Zemtseva, H. R. Horvitz, and C. B. Hirschberg SQV-7, a protein involved in Caenorhabditis elegans epithelial invagination and early embryogenesis, transports UDP-glucuronic acid, UDP-N- acetylgalactosamine, and UDP-galactose PNAS, March 16, 2001; (2001) 61593098. [Abstract] [Full Text]
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K. Luhn, T. Marquardt, E. Harms, and D. Vestweber Discontinuation of fucose therapy in LADII causes rapid loss of selectin ligands and rise of leukocyte counts Blood, January 1, 2001; 97(1): 330 - 332. [Abstract] [Full Text] [PDF]
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P. Mattila, J. Rabina, S. Hortling, J. Helin, and R. Renkonen Functional expression of Escherichia coli enzymes synthesizing GDP-L-fucose from inherent GDP-D-mannose in Saccharomyces cerevisiae Glycobiology, October 1, 2000; 10(10): 1041 - 1047. [Abstract] [Full Text] [PDF]
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A. Etzioni, M. Tonetti;, D. Vestweber, and T. Marquardt Fucose supplementation in leukocyte adhesion deficiency type II Blood, June 1, 2000; 95(11): 3641 - 3643. [Full Text] [PDF]
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L. Puglielli and C. B. Hirschberg Reconstitution, Identification, and Purification of the Rat Liver Golgi Membrane GDP-fucose Transporter J. Biol. Chem., December 10, 1999; 274(50): 35596 - 35600. [Abstract] [Full Text] [PDF]
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S. Oelmann, P. Stanley, and R. Gerardy-Schahn Point Mutations Identified in Lec8 Chinese Hamster Ovary Glycosylation Mutants That Inactivate Both the UDP-galactose and CMP-sialic Acid Transporters J. Biol. Chem., July 6, 2001; 276(28): 26291 - 26300. [Abstract] [Full Text] [PDF]
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K. Aoki, N. Ishida, and M. Kawakita Substrate Recognition by UDP-galactose and CMP-sialic Acid Transporters. DIFFERENT SETS OF TRANSMEMBRANE HELICES ARE UTILIZED FOR THE SPECIFIC RECOGNITION OF UDP-GALACTOSE AND CMP-SIALIC ACID J. Biol. Chem., June 8, 2001; 276(24): 21555 - 21561. [Abstract] [Full Text] [PDF]
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P. Berninsone, H.-Y. Hwang, I. Zemtseva, H. R. Horvitz, and C. B. Hirschberg SQV-7, a protein involved in Caenorhabditis elegans epithelial invagination and early embryogenesis, transports UDP-glucuronic acid, UDP-N- acetylgalactosamine, and UDP-galactose PNAS, March 27, 2001; 98(7): 3738 - 3743. [Abstract] [Full Text] [PDF]
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