Novel mannosidase inhibitor blocking conversion of high mannose to complex oligosaccharides (original) (raw)

Nature volume 307, pages 755–758 (1984)Cite this article

Abstract

Many secretory and membrane proteins are glycoproteins carrying asparagine-linked (_N_-linked) oligosaccharides. There are two types of _N_-linked glycans, referred to as high-mannose and complex type, respectively. Biosynthesis of _N_-linked glycans of the complex type proceeds via a high-mannose intermediate. After the initial transfer of a high-mannose oligosaccharide with the composition (Glc)3(Man)9(GlcNAc)2 from a lipid carrier to the nascent polypeptide chain, trimming reactions take place. Trimming glucosidases remove the glucose residues quantitatively and mannosidases IA/B and II can remove all but three mannose residues. After trimming, terminal sugars such as _N_-acetylglucosamine, galactose, sialic acid and fucose may be added and result in the conversion to a glycan of the complex type1. Because suitable inhibitors were lacking, it was difficult to assess the importance of the trimming reactions for proper intracellular traffic, modification reactions other than the addition of terminal sugars, or as regulatory steps in glycoprotein processing. Here we describe the action of 1-deoxymannojirimycin (1,5-dideoxy-1,5-imino-D-mannitol, dMM; Fig. 1) on the biosynthesis of IgM and IgD. dMM is the mannose analogue of 1-deoxynojirimycin (dNM; Fig. 1), itself a glucosidase inhibitor2–4. We present evidence that dMM is a mannosidase inhibitor. In vivo dMM inhibits the equivalent of the mannosidase IA/B activities and blocks conversion of high-mannose to complex oligosaccharides. It is the first such inhibitor to be reported. Interference with the biosynthetic pathway of _N_-linked glycans could prove to be a powerful way to manipulate carbohydrate structure in vivo.

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Authors and Affiliations

  1. Institute for Genetics, University of Cologne, Weyertal 121, 5000, Cologne, 41, FRG
    Ulrike Fuhrmann & Hidde Ploegh
  2. Institute for Biochemistry, University of Cologne, Weyertal 121, 5000, Cologne, 41, FRG
    Ernst Bause & Günter Legler

Authors

  1. Ulrike Fuhrmann
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  2. Ernst Bause
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  3. Günter Legler
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  4. Hidde Ploegh
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Fuhrmann, U., Bause, E., Legler, G. et al. Novel mannosidase inhibitor blocking conversion of high mannose to complex oligosaccharides.Nature 307, 755–758 (1984). https://doi.org/10.1038/307755a0

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