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  • 1
    Electronic Resource
    Electronic Resource
    Synthetic substrate analogues for UDP-GlcNAc: Manα1-6R β(1-2)-N-acetylglucosaminyltransferase II. Substrate specificity and inhibitors for the enzyme (1994)
    Springer
    Glycoconjugate journal 11 (1994), S. 210-216 
    Details
    ISSN: 1573-4986
    Keywords: Synthetic oligosaccharides ; inhibitors ; N-glycans ; N-acetylglucosaminyltransferase ; biosynthesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract UDP-GlcNAc: Manα1-6R β(1-2)-N-acetylglucosaminyltransferase II (GlcNAc-T II; EC 2.4.1.143) is a key enzyme in the synthesis of complexN-glycans. We have tested a series of synthetic analogues of the substrate Man‴α1-6(GlcNAc″β1-2Man′α1-3)Manβ-O-octyl as substrates and inhibitors for rat liver GlcNAc-T II. The enzyme attachesN-acetylglucosamine in β1-2 linkage to the 2‴-OH of the Man‴α1-6 residue. The 2‴-deoxy analogue is a competitive inhibitor (K i=0.13mm). The 2‴-O-methyl compound does not bind to the enzyme presumably due to steric hindrance. The 3‴-, 4‴- and 6‴-OH groups are not essential for binding or catalysis since the 3‴-, 4‴- and 6‴-deoxy and -O-methyl derivatives are all good substrates. Increasing the size of the substituent at the 3‴-position to pentyl and substituted pentyl groups causes competitive inhibition (K i=1.0–2.5mm). We have taken advantage of this effect to synthesize two potentially irreversible GlcNAc-T II inhibitors containing a photolabile 3‴-O-(4,4-azo)pentyl group and a 3‴-O-(5-iodoacetamido)pentyl group respectively. The data indicate that none of the hydroxyls of the Man‴α1-6 residue are essential for binding although the 2‴- and 3‴-OH face the catalytic site of the enzyme. The 4-OH group of the Manβ-O-octyl residue is not essential for binding or catalysis since the 4-deoxy derivative is a good substrate; the 4-O-methyl derivative does not bind. This contrasts with GlcNAc-T I which cannot bind to the 4-deoxy-Manβ- substrate analogue. The data are compatible with our previous observations that a ‘bisecting’N-acetylglucosamine at the 4-OH position prevents both GlcNAc-T I and GlcNAc-T II catalysis. However, in the case of GlcNAc-T II, the bisectingN-acetylglucosamine prevents binding due to steric hindrance rather than to removal of an essential OH group. The 3′-OH of the Man′α1-3 is an essential group for GlcNAc-T II since the 3′-deoxy derivative does not bind to the enzyme. The trisaccharide GlcNAcβ1-2Manα1-3Manβ-O-octyl is a good inhibitor (K i=0.9mm). The above data together with previous studies indicate that binding of the GlcNAcβ1-2Manβ1-3Manβ- arm of the branched substrate to the enzyme is essential for catalysis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00731220
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  • 2
    Electronic Resource
    Electronic Resource
    Synthesis of Protected Hexp-(1 → 4)-β-D-GlcpNAc-(1 → 2)-α-D-Manp-(1 → O)(CH2)7CH3 sequences (hex = β-D-Glc, 4-deoxy-4-fluoro-β-D-Gal, or 4-deoxy-β-D-Gal) Using a Glc-GlcNPhth Donor, Eventually Fluorinated or Deoxygenated at the Oligosaccharide Level (1997)
    Weinheim : Wiley-Blackwell
    Liebigs Annalen 1997 (1997), S. 1227-1233 
    Details
    ISSN: 0947-3440
    Keywords: Carbohydrates ; Glycosylation ; Substrate analogs ; Fluorination ; Deoxygenation ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Three trisaccharide derivatives of the type β-D-Hexp-(1 → 4)-β-D-GlcpNAc(1 → 2)-α-D-Manp-(1 → O)(CH2)7CH3 have been synthesized, with Hex being either glucose (15), 4-deoxy-4-fluorogalactose (20), or 4-deoxygalactose (27). These trisaccharides have been designed for the study of the acceptor specificity of glycosyltransferases involved in termination of N-acetyllactosamine-type N-glycans. Allyl (2-O-acetyl-3,6-di-O-benzyl-β-D-glucopyranosyl)-(1 → 4)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-β-D-glucopyranoside (10) was synthesized by condensation of 2,4,6-tri-O-acetyl-3-O-benzyl-α-D-glucosypanosyl trichloroacetimidate with allyl 3,6-di-O-benzyl-2-deoxy-2-phthalimido-β-D-glucopyranoside, followed by 4′,6′-de-O-acetylation, 4′,6′-O-benzylidenation (8), and specific acetal ring opening. Acetylation or inverted fluorination of 10, followed by deallylation and imidation, gave suitable disaccharide donors which were each condensed with octyl 3,4,6-tri-O-benzyl-α-D-mannopyranoside (14) to afford the fully protected trisaccharides 15 and 20. Deallylation and imidation of 8, followed by coupling to 14 and subsequent specific acetal ring opening, triflation, halogenation, and reductive dehalogenation gave the protected 4″-deoxytrisaccharide.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jlac.199719970627
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  • 3
    Electronic Resource
    Electronic Resource
    Bausteine von Oligosacchariden, CI. Synthese von modifizierten Oligosacchariden der N-Glycoproteine zur Untersuchung der Substratspezifität der N-Acetylglucosaminyltransferase II des Trimming-Prozesses (1992)
    Weinheim : Wiley-Blackwell
    Liebigs Annalen 1992 (1992), S. 513-521 
    Details
    ISSN: 0170-2041
    Keywords: Carbohydrates ; Oligosaccharides ; N-Glycoproteins ; N-Acetylglucosaminyltransferases ; Enzymes ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Building Units of Oligosaccharides, CI.  -  Synthesis of Modified Oligosaccharides of the N-Glycoproteins Intended for Substrate Specificity Studies of N-Acetylglucosaminyltransferase II of the Trimming ProcessThe trichloroacetimidate method was very successful for the synthesis of the tetrasaccharide octyl O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-(1→2)-O-(α-D-mannopyranosyl)-(1→3)-O-[(α-D-mannopyranosyl)-(1→6)]-β-D-mannopyranoside (10). Further derivatives of the tetrasaccharide with a 4-O-methyl group 20 and with a 4-deoxy group 28 were synthesized. The tetrasaccharides are intended for substrate specificity studies of the N-acetylglucosaminyltransferase II of the trimming process in the biosynthesis of N-glycoproteins.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jlac.199219920189
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