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Analysis of glycoprotein processing in the endoplasmic reticulum using synthetic oligosaccharides.

Ito Y, Takeda Y - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2012)

Bottom Line: Recent studies have revealed that high-mannose-type glycans play a pivotal role in the QC process.To gain knowledge about the molecular basis of this process with well-defined homogeneous compounds, we achieved a convergent synthesis of high-mannose-type glycans and their functionalized derivatives.We focused on analyses of UDP-Glc: glycoprotein glucosyltransferase (UGGT) and ER Glucosidase II, which play crucial roles in glycoprotein QC; however, their specificities remain unclear.

View Article: PubMed Central - PubMed

Affiliation: RIKEN Advanced Science Institute, Saitama, Japan. yukito@riken.jp

ABSTRACT
Protein quality control (QC) in the endoplasmic reticulum (ER) comprises many steps, including folding and transport of nascent proteins as well as degradation of misfolded proteins. Recent studies have revealed that high-mannose-type glycans play a pivotal role in the QC process. To gain knowledge about the molecular basis of this process with well-defined homogeneous compounds, we achieved a convergent synthesis of high-mannose-type glycans and their functionalized derivatives. We focused on analyses of UDP-Glc: glycoprotein glucosyltransferase (UGGT) and ER Glucosidase II, which play crucial roles in glycoprotein QC; however, their specificities remain unclear. In addition, we established an in vitro assay system mimicking the in vivo condition which is highly crowded because of the presence of various biomacromolecules.

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Systematic synthesis of high-mannose-type oligosaccharide. (A) Stereoselective construction of β-mannoside linkage with intramolecular aglycon delivery (IAD). (B) Convergent synthesis of high-mannose-type oligosaccharide.
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Related In: Results  -  Collection


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fig02: Systematic synthesis of high-mannose-type oligosaccharide. (A) Stereoselective construction of β-mannoside linkage with intramolecular aglycon delivery (IAD). (B) Convergent synthesis of high-mannose-type oligosaccharide.

Mentions: However, fully chemical synthesis of biologically relevant glycans consisting of more than ten sugar residues is not a trivial task. Among several problems associated with stereochemical control, certain type of so-called 1,2-cis glycosides such as β-linked mannose (β-Man) are difficult to construct selectively.35) Our study established a strategy which realized completely selective and efficient synthesis of β-Man glycosides, by using a concept dubbed “intramolecular aglycon delivery” (IAD).36) (Fig. 2A) Our approach employed a p-methoxybenzyl (PMB) group introduced to 2-position of mannose. Under oxidative conditions, the PMB group was converted to mixed acetal-type tethered intermediate, from which exclusive formation of 1,2-cis glycoside was realized in high yield (>80%).37) More recent studies have shown that efficiency as well as generality of the IAD was further enhanced by using 2-naphthylmethyl (NAP) group in place of PMB.38)


Analysis of glycoprotein processing in the endoplasmic reticulum using synthetic oligosaccharides.

Ito Y, Takeda Y - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2012)

Systematic synthesis of high-mannose-type oligosaccharide. (A) Stereoselective construction of β-mannoside linkage with intramolecular aglycon delivery (IAD). (B) Convergent synthesis of high-mannose-type oligosaccharide.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3316936&req=5

fig02: Systematic synthesis of high-mannose-type oligosaccharide. (A) Stereoselective construction of β-mannoside linkage with intramolecular aglycon delivery (IAD). (B) Convergent synthesis of high-mannose-type oligosaccharide.
Mentions: However, fully chemical synthesis of biologically relevant glycans consisting of more than ten sugar residues is not a trivial task. Among several problems associated with stereochemical control, certain type of so-called 1,2-cis glycosides such as β-linked mannose (β-Man) are difficult to construct selectively.35) Our study established a strategy which realized completely selective and efficient synthesis of β-Man glycosides, by using a concept dubbed “intramolecular aglycon delivery” (IAD).36) (Fig. 2A) Our approach employed a p-methoxybenzyl (PMB) group introduced to 2-position of mannose. Under oxidative conditions, the PMB group was converted to mixed acetal-type tethered intermediate, from which exclusive formation of 1,2-cis glycoside was realized in high yield (>80%).37) More recent studies have shown that efficiency as well as generality of the IAD was further enhanced by using 2-naphthylmethyl (NAP) group in place of PMB.38)

Bottom Line: Recent studies have revealed that high-mannose-type glycans play a pivotal role in the QC process.To gain knowledge about the molecular basis of this process with well-defined homogeneous compounds, we achieved a convergent synthesis of high-mannose-type glycans and their functionalized derivatives.We focused on analyses of UDP-Glc: glycoprotein glucosyltransferase (UGGT) and ER Glucosidase II, which play crucial roles in glycoprotein QC; however, their specificities remain unclear.

View Article: PubMed Central - PubMed

Affiliation: RIKEN Advanced Science Institute, Saitama, Japan. yukito@riken.jp

ABSTRACT
Protein quality control (QC) in the endoplasmic reticulum (ER) comprises many steps, including folding and transport of nascent proteins as well as degradation of misfolded proteins. Recent studies have revealed that high-mannose-type glycans play a pivotal role in the QC process. To gain knowledge about the molecular basis of this process with well-defined homogeneous compounds, we achieved a convergent synthesis of high-mannose-type glycans and their functionalized derivatives. We focused on analyses of UDP-Glc: glycoprotein glucosyltransferase (UGGT) and ER Glucosidase II, which play crucial roles in glycoprotein QC; however, their specificities remain unclear. In addition, we established an in vitro assay system mimicking the in vivo condition which is highly crowded because of the presence of various biomacromolecules.

Show MeSH
Related in: MedlinePlus