Glycosylation <i>in vitro</i> of Semliki‐Forest‐Virus and Influenza‐Virus Glycoproteins and Its Suppression by Nucleotide‐2‐deoxy‐hexose

Schwarz, Ralph Τ.; Schmidt, Michael F. G.; Lehle, Ludwig

doi:10.1111/j.1432-1033.1978.tb12224.x

Cited by 44 publications

(23 citation statements)

References 40 publications

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“…The GDP derivatives of 2dGlc, 2FMan and 4dMan have been previously shown to be inhibitors of Man-P-Dol formation in vitro [4,7,8]. In each case, the inhibition was due to the formation of the corresponding sugar analogue-P-Dol derivative.…”

Section: Inhibition Of Man-p-dol Synthesis By Gdp Derivatives Of Mannmentioning

confidence: 94%

“…Thus, analogues of glucose and mannose containing fluoro or deoxy substituents on carbons 2 and 4 were shown to interfere with the glycosylation of viral envelope glycoproteins by inhibiting the assembly of the oligosaccharide precursor, Glc3Man9(GlcNAc)z linked to dolichol pyrophosphate (DoI-PP) [1]. Analogues such as 2-deoxy-D-glucose (2dGlc), 2-deoxy-2-fluoro-D-glucose (2FGIc), 2-deoxy-2-fluoro-D-mannose (2FMan), 4-deoxy-D-mannose (4dMan) and 4-deoxy-4-fluoro-D-mannose (4FMan) are metabolised in vivo to their cotCorrespondence address: W. McDowell, MRC Collaborative Centre, 1-3 Burtonhole Lane, Mill Hill, London NW7 lAD, England responding GDP and/or UDP derivatives [1,3], and it is these metabolites that are the actual inhibitory agents [4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

“…Through the use of specific inhibitors it should be possible to gain insight into the mechanism of enzyme-substrate recognition for the glycosyltransferases involved in the assembly of dolichyl phosphate (DoI-P) monosaccharides and dolichol-linked oligosaccharides. With the exception of 2FGIc and 4FMan the GDP derivatives of the above sugar analogues are inhibitors of Man-P-Dol formation in vitro and are substrates for the synthesis of their respective DoI-P derivatives [4,7,8]. Thus, the function of the varioushydroxyl groups of the mannose moiety of GDP-Man in the recognition of GDP-Man by the mannosyltransferase (GDP-Man:Dol-P man-Volume 243, number 2 FEBS nosyltransferase, EC 2.4.1.83) catalysing the formation of Man-P-Dol can be investigated.…”

Section: Introductionmentioning

confidence: 99%

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Specificity of GDP‐Man:dolichyl‐phosphate mannosyltransferase for the guanosine diphosphate esters of mannose analogues containing deoxy and deoxyfluoro substituents

McDowell

Schwarz

1989

FEBS Letters

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Guanosine diphosphate (GDP) esters of 2-deoxy-D-glucose (2dG lc), 2-deoxy-2-fluoro-D-mannose (2FMan), 3-deoxy-Dmannose (3dMan), 4-deoxy-D-mannose (4dMan) and 6-deoxy-D-mannose (6dMan) have been synthesised and tested for their ability to act as inhibitors of dolichyl phosphate mannose synthesis (enzyme: GDP-mannose:dolichyl-phosphate mannosyltransferase, EC 2.4.1.83) in chick embryo cell microsomal membranes. The following order of efficiency was found with the apparent Ki in parentheses: GDP-6dMan (0.40/zM + 0.15) > GDP-3dMan (1.0 gM + 0.1) = GDP-2dGIc (1.3/zM+0.2) > GDP-4dMan (3.1/zM+0.1) GDP-2FMan (15 gM+0). For comparison the Km for GDP-Man was 0.52/zM + 0.02 and the Ki for GDP was 56/~M _+ 2. These results indicate that the 6-hydroxyl group of mannose is not crucial for emzyme-substrate recognition, whereas the 2-and 3-hydroxyls may have some involvement. The 4-hydroxyl appears to be an important determinant for enzyme-substrate recognition in this mannosyltransferase.

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Section: Inhibition Of Man-p-dol Synthesis By Gdp Derivatives Of Mannmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Specificity of GDP‐Man:dolichyl‐phosphate mannosyltransferase for the guanosine diphosphate esters of mannose analogues containing deoxy and deoxyfluoro substituents

McDowell

Schwarz

1989

FEBS Letters

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“…Its effect on glycoprotein formation seems to be the interfer- ence of the lipid-mediated mannosylation of proteins (6,7,26,27).…”

Section: Discussionmentioning

confidence: 99%

“…The analog can be transferred to Dol-P or to Dol-PPoligosaccharides. In the first case, GDP-dGlc competes with the physiological nucleotide-sugars for Dol-P, and this effect is overcome by the addition of the lipid (27). When dGlc is incorporated into lipid-oligosaccharides, no further elongation of the saccharide chain occurs, thus blocking the transfer of the completed oligosaccharide to the protein (6,7,23 DEAE-cellulose chromatography was carried out as described by Dankert et al (4) in 2-ml columns.…”

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confidence: 99%

Inhibition of β-1,4-Glucan Biosynthesis by Deoxyglucose

Datema¹,

Schwarz²,

Rivas³

et al. 1983

Plant Physiol.

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GDP-and UDP-deoxyglucose inhibit the incorporation of glucose from UDP-glucose into dolichyl phosphate glucose and dolichyl pyrophosphate oligosaccharides. GDP-deoxyglucose inhibits by competing with the physiological nucleotide sugars recently has it been shown in animal tissues that UDP-dGlc exhibits a different inhibition pattern: dGlc is not transferred to lipid-linked saccharides and thus inhibition cannot be reversed by Dol-P (5). It seems that UDP-dGlc inhibits the UDP-Glc:Dol-P glucosyltransferase.The chlorophytous alga Prototheca zopfii appears to be an interesting system to study the effect of dGlc as a glucose analog. The formation of lipid-linked sugars has been studied in this system. The lipid involved is indistinguishable from liver Dol-P (11), and Dol-P-Glc as well as Dol-PP-(Glc). are formed from UDP-Glc as sugar donor (13). The oligosaccharide moiety is then transferred from the lipid to a protein acceptor, and this step is inhibited by coumarin (15). The protein-oligosaccharide seems to be a primer for the formation ofcellulose using GDP-Glc as donor (13)(14)(15).In this paper, we present evidence of the inhibition produced by deoxyglucose derivatives, as glucose analog, on the formation of glucolipids, glucose-containing glycoproteins, and glucans. The effect of the analog is also compared with that produced by coumarin, a known inhibitor of cellulose formation (3, 9, 15). dGlc2 is an analog of glucose that inhibits the formation of glucan as well as an analog of mannose that blocks mannan synthesis in yeast (10,17). Protein glycosylation is also suppressed by dGlc (6,24,26). It is metabolized in different tissues to give rise to 2,23,25). It is likely that these nucleotide-deoxysugars, and not the free sugar, are the compounds responsible for the inhibition of those processes.In the case of glucan and mannan synthesis, the mechanism of inhibition of deoxyglucose is not clear. On the other hand, the inhibition of protein glycosylation by GDP-dGlc seems to be due to interference with the lipid-mediated mannosylation of glycoproteins. The analog can be transferred to Dol-P or to Dol-PPoligosaccharides. In the first case, GDP-dGlc competes with the physiological nucleotide-sugars for Dol-P, and this effect is overcome by the addition of the lipid (27). When dGlc is incorporated into lipid-oligosaccharides, no further elongation of the saccharide chain occurs, thus blocking the transfer of the completed oligosaccharide to the protein (6,7,23). In these examples, dGlc is an analog of mannose.

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The Unfolded Protein Response

Strudwick¹,

Schröder²

Cell Engineering

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Glycosylation in vitro of Semliki‐Forest‐Virus and Influenza‐Virus Glycoproteins and Its Suppression by Nucleotide‐2‐deoxy‐hexose

Cited by 44 publications

References 40 publications

Specificity of GDP‐Man:dolichyl‐phosphate mannosyltransferase for the guanosine diphosphate esters of mannose analogues containing deoxy and deoxyfluoro substituents

Specificity of GDP‐Man:dolichyl‐phosphate mannosyltransferase for the guanosine diphosphate esters of mannose analogues containing deoxy and deoxyfluoro substituents

Inhibition of β-1,4-Glucan Biosynthesis by Deoxyglucose

The Unfolded Protein Response

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