Tissue targeting of multivalent Le(x)-terminated N-linked oligosaccharides in mice

Ming H Chiu; V.  Hayden Thomas; Hilary J Stubbs; Kevin G Rice

doi:10.1074/jbc.270.41.24024

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Tissue targeting of multivalent Le(x)-terminated N-linked oligosaccharides in mice

Journal article

Open access

Peer reviewed

Tissue targeting of multivalent Le(x)-terminated N-linked oligosaccharides in mice

Ming H Chiu, V. Hayden Thomas, Hilary J Stubbs and Kevin G Rice

The Journal of biological chemistry, Vol.270(41), pp.24024-24031

10/13/1995

DOI: 10.1074/jbc.270.41.24024

PMID: 7592600

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Abstract

The target site for N-linked biantennary and triantennary oligosaccharides containing multiple terminal Le(x) determinants was analyzed in mice. N-linked oligosaccharides containing a single tert-butoxycarbonyl-tyrosine attached to the reducing end were used as synthons for human milk alpha-3/4-fucosyltransferase to prepare multivalent Le(x) (Gal beta 1-4[Fuc alpha 1-3]GlcNAc) terminated tyrosinamide oligosaccharides. The oligosaccharides were radioiodinated and examined for their pharmacokinetics and biodistribution in mice. The liver was the major target site in mice at 30 min, which accumulated 18% of the dose for Le(x) biantennary compared with 6% for a nonfucosylated Gal biantennary. By comparison, Le(x)- and Gal-terminated triantennary accumulated in the liver with a targeting efficiency of 66 and 59%, respectively. The liver targeting of Le(x)-biantennary was partially blocked by co-administration with either galactose or L-fucose whereas Le(x) triantennary targeting was only reduced by co-administration with galactose. In contrast to these results in mice, in vivo experiments performed in rats established that both Le(x) and Gal terminated biantennary target the liver with nearly identical efficiency (6-7%). It is concluded that the asialoglycoprotein receptor in mice preferentially recognize Le(x) biantennary over Gal biantennary, whereas little or no differentiation exists in rats. Thereby, the mouse asialoglycoprotein receptor apparently possesses additional binding pockets that accommodate a fucose residue when presented as Le(x).

Carbohydrate Sequence

Oligosaccharides - pharmacokinetics

Iodine Radioisotopes

Magnetic Resonance Spectroscopy

Species Specificity

Humans

Liver - metabolism

Molecular Sequence Data

Rats

Structure-Activity Relationship

Lewis X Antigen - metabolism

Tissue Distribution

Autoradiography

Fucosyltransferases - metabolism

Oligosaccharides - chemical synthesis

Kidney - metabolism

Animals

Oligosaccharides - chemistry

Mice

Intestine, Small - metabolism

Carbohydrate Conformation

Lewis X Antigen - chemistry

Details

Title: Subtitle: Tissue targeting of multivalent Le(x)-terminated N-linked oligosaccharides in mice
Creators: Ming H Chiu - College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA
V. Hayden Thomas
Hilary J Stubbs
Kevin G Rice
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.270(41), pp.24024-24031
DOI: 10.1074/jbc.270.41.24024
PMID: 7592600
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: DK45742 / NIDDK NIH HHS GM48048 / NIGMS NIH HHS
Language: English
Date published: 10/13/1995
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Medicinal and Natural Products Chemistry
Record Identifier: 9984065318302771

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