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The crystal structure of mammalian g...

Gibbons, Brian John.

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The crystal structure of mammalian glycogenin and its implications for the initiation phase of glycogen biosynthesis.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The crystal structure of mammalian glycogenin and its implications for the initiation phase of glycogen biosynthesis./
Author:	Gibbons, Brian John.
Description:	121 p.
Notes:	Source: Dissertation Abstracts International, Volume: 64-06, Section: B, page: 2650.
Contained By:	Dissertation Abstracts International64-06B.
Subject:	Chemistry, Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3094101

The crystal structure of mammalian glycogenin and its implications for the initiation phase of glycogen biosynthesis.
Gibbons, Brian John.

The crystal structure of mammalian glycogenin and its implications for the initiation phase of glycogen biosynthesis. - 121 p.

Source: Dissertation Abstracts International, Volume: 64-06, Section: B, page: 2650.

Thesis (Ph.D.)--Indiana University, 2003.

Glycogen is an important storage reserve of glucose present in many organisms, from bacteria to humans. Its biosynthesis is initiated by a specialized protein, glycogenin, which has the unusual property of transferring glucose from UDP-glucose to form an oligosaccharide covalently attached to itself at Tyr194. Glycogen synthase and the branching enzyme complete the synthesis of the polysaccharide. The structure of glycogenin was solved in two different crystal forms. Tetragonal crystals contained a pentamer of dimers in the asymmetric unit arranged in an improper non-crystallographic 10-fold relationship and orthorhombic crystals contained a monomer in the asymmetric unit that is arranged about a two-fold crystallographic axis to form a dimer. The structure was first solved to 3.4 Å using the tetragonal crystal form and a three-wavelength Se-Met MAD experiment. Subsequently, an apo-enzyme structure and a complex between glycogenin and UDP-glucose/Mn<super>2+</super> were solved by molecular replacement to 1.9 Å using the orthorhombic crystal form. Glycogenin contains a conserved DxD motif and an N-terminal β-α-β Rossmann-like fold that are common to the nucleotide-binding domains of most glycosyltransferases. Although sequence identity amongst glycosyltransferases is minimal, the overall folds are similar. In all of these enzymes, the DxD motif is essential for coordination of the catalytic divalent cation, most commonly Mn<super>2+</super>. Comparison of the known structures of retaining glycosyltransferases with glycogenin sheds some light on the poorly characterized retaining glycosyltransferase reaction. The structure of glycogenin suggests a mechanism in which the Mn<super> 2+</super> ion that associates with the UDP-glucose molecule functions as a Lewis acid to stabilize the leaving group UDP and facilitate the transfer of the glucose to an intermediate nucleophilic acceptor in the enzyme active site, most likely Asp162. Following transient transfer to Asp162, the glucose moiety is then delivered to the final acceptor, either directly to Tyr194 or to glucose residues already attached to Tyr194. The positioning of the bound UDP-glucose far from Tyr194 in the glycogenin structure raises questions as to the mechanism for the attachment of the first glucose residues. Possibly the initial glucosylation is via inter-dimeric catalysis with an intra-molecular mechanism employed later in oligosaccharide synthesis.Subjects--Topical Terms:

1017722
Chemistry, Biochemistry.

The crystal structure of mammalian glycogenin and its implications for the initiation phase of glycogen biosynthesis.
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100 1 $a Gibbons, Brian John. $3 1945299
245 1 0 $a The crystal structure of mammalian glycogenin and its implications for the initiation phase of glycogen biosynthesis.
300 $a 121 p.
500 $a Source: Dissertation Abstracts International, Volume: 64-06, Section: B, page: 2650.
500 $a Chair: Thomas D. Hurley.
502 $a Thesis (Ph.D.)--Indiana University, 2003.
520 $a Glycogen is an important storage reserve of glucose present in many organisms, from bacteria to humans. Its biosynthesis is initiated by a specialized protein, glycogenin, which has the unusual property of transferring glucose from UDP-glucose to form an oligosaccharide covalently attached to itself at Tyr194. Glycogen synthase and the branching enzyme complete the synthesis of the polysaccharide. The structure of glycogenin was solved in two different crystal forms. Tetragonal crystals contained a pentamer of dimers in the asymmetric unit arranged in an improper non-crystallographic 10-fold relationship and orthorhombic crystals contained a monomer in the asymmetric unit that is arranged about a two-fold crystallographic axis to form a dimer. The structure was first solved to 3.4 Å using the tetragonal crystal form and a three-wavelength Se-Met MAD experiment. Subsequently, an apo-enzyme structure and a complex between glycogenin and UDP-glucose/Mn<super>2+</super> were solved by molecular replacement to 1.9 Å using the orthorhombic crystal form. Glycogenin contains a conserved DxD motif and an N-terminal β-α-β Rossmann-like fold that are common to the nucleotide-binding domains of most glycosyltransferases. Although sequence identity amongst glycosyltransferases is minimal, the overall folds are similar. In all of these enzymes, the DxD motif is essential for coordination of the catalytic divalent cation, most commonly Mn<super>2+</super>. Comparison of the known structures of retaining glycosyltransferases with glycogenin sheds some light on the poorly characterized retaining glycosyltransferase reaction. The structure of glycogenin suggests a mechanism in which the Mn<super> 2+</super> ion that associates with the UDP-glucose molecule functions as a Lewis acid to stabilize the leaving group UDP and facilitate the transfer of the glucose to an intermediate nucleophilic acceptor in the enzyme active site, most likely Asp162. Following transient transfer to Asp162, the glucose moiety is then delivered to the final acceptor, either directly to Tyr194 or to glucose residues already attached to Tyr194. The positioning of the bound UDP-glucose far from Tyr194 in the glycogenin structure raises questions as to the mechanism for the attachment of the first glucose residues. Possibly the initial glucosylation is via inter-dimeric catalysis with an intra-molecular mechanism employed later in oligosaccharide synthesis.
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650 4 $a Chemistry, Biochemistry. $3 1017722
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Biophysics, Medical. $3 1017681
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710 2 0 $a Indiana University. $3 960096
773 0 $t Dissertation Abstracts International $g 64-06B.
790 1 0 $a Hurley, Thomas D., $e advisor
790 $a 0093
791 $a Ph.D.
792 $a 2003
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