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Genetic and biochemical determinants...
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Becker, Daniel James.
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Genetic and biochemical determinants of fucosylated glycan expression.
Record Type:
Electronic resources : Monograph/item
Title/Author:
Genetic and biochemical determinants of fucosylated glycan expression./
Author:
Becker, Daniel James.
Description:
135 p.
Notes:
Source: Dissertation Abstracts International, Volume: 65-02, Section: B, page: 0561.
Contained By:
Dissertation Abstracts International65-02B.
Subject:
Biology, Molecular. -
Online resource:
http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3121891
ISBN:
0496692429
Genetic and biochemical determinants of fucosylated glycan expression.
Becker, Daniel James.
Genetic and biochemical determinants of fucosylated glycan expression.
- 135 p.
Source: Dissertation Abstracts International, Volume: 65-02, Section: B, page: 0561.
Thesis (Ph.D.)--University of Michigan, 2004.
Fucose-containing glycoconjugates have diverse functions in mammals including roles in leukocyte trafficking, cell fate determination by the Notch family of signaling receptors, and host-microbe interactions. Fucosylated glycans are synthesized by fucosyltransferases that utilize a nucleotide-activated fucose donor, GDP-fucose. Multiple lines of evidence have suggested the existence of regulatory pathways that control biosynthesis of GDP-fucose, which may in turn serve as a determinant of the developmental and tissue specific expression of fucosylated glycans. GDP-fucose is synthesized in the cytosol of mammalian cells via two independent pathways. The de novo pathway converts GDP-mannose to GDP-fucose through the action of two enzymes, GDP-mannose 4,6-dehydratase (GMD) and the FX protein, whereas the salvage pathway synthesizes GDP-fucose from free fucose derived from the extracellular or lysosomal compartments. The studies that make up this thesis were aimed at understanding the mechanisms by which GDP-fucose biosynthesis, fucose availability, and fucosylated glycan expression are controlled, at both the cellular and organismal levels.
ISBN: 0496692429Subjects--Topical Terms:
1017719
Biology, Molecular.
Genetic and biochemical determinants of fucosylated glycan expression.
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Source: Dissertation Abstracts International, Volume: 65-02, Section: B, page: 0561.
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Chair: John B. Lowe.
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Thesis (Ph.D.)--University of Michigan, 2004.
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Fucose-containing glycoconjugates have diverse functions in mammals including roles in leukocyte trafficking, cell fate determination by the Notch family of signaling receptors, and host-microbe interactions. Fucosylated glycans are synthesized by fucosyltransferases that utilize a nucleotide-activated fucose donor, GDP-fucose. Multiple lines of evidence have suggested the existence of regulatory pathways that control biosynthesis of GDP-fucose, which may in turn serve as a determinant of the developmental and tissue specific expression of fucosylated glycans. GDP-fucose is synthesized in the cytosol of mammalian cells via two independent pathways. The de novo pathway converts GDP-mannose to GDP-fucose through the action of two enzymes, GDP-mannose 4,6-dehydratase (GMD) and the FX protein, whereas the salvage pathway synthesizes GDP-fucose from free fucose derived from the extracellular or lysosomal compartments. The studies that make up this thesis were aimed at understanding the mechanisms by which GDP-fucose biosynthesis, fucose availability, and fucosylated glycan expression are controlled, at both the cellular and organismal levels.
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In the first set of studies, we generated and characterized a panel of Chinese hamster ovary (CHO) mutant clones that lack expression of the FX protein. Cytosolic extracts from these clones, as well as FX-/- murine embryonic fibroblasts, exhibit impaired biochemical activity of GMD, despite normal sequence and expression of GMD protein. Culture of FX mutant cells in exogenous fucose to supply the salvage pathway not only restored fucosylated glycan expression, but also restored GMD activity, indicating a novel role for fucose-containing glycans in the regulation of GMD activity.
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The second set of studies focused on the partially penetrant lethal phenotype of mice with a deficiency in fucosylated glycan expression due to a targeted mutation at the FX locus. Genetic background was shown to exert profound effects on both intrauterine and postnatal survival of FX+/- and FX-/- mice, demonstrating that strain-specific modifier genes control lethality in FX mutant mice.
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These studies have shed light on regulatory processes related to GDP-fucose biosynthesis, laying the groundwork for elucidation of specific molecular mechanisms determining the expression and biological function of fucosylated glycoconjugates.
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http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3121891
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