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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-41220

Haeuptle, M A; Welti, M; Troxler, H; Huelsmeier, A J; Imbach, T; Hennet, T (2011). Improvement of dolichol-linked oligosaccharide biosynthesis by the squalene synthase inhibitor Zaragozic acid. Journal of Biological Chemistry, 286(8):6085-6091.

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The majority of Congenital Disorders of Glycosylation (CDG) are caused by defects of dolichol (Dol)-linked oligosaccharide assembly, which lead to under-occupancy of N-glycosylation sites. Most mutations encountered in CDG are hypomorphic, thus leaving residual activity to the affected biosynthetic enzymes. We hypothesized that increased cellular levels of Dol-linked substrates might compensate for the low biosynthetic activity and thereby improve the output of protein N-glycosylation in CDG. To this end, we have investigated the potential of the squalene synthase inhibitor zaragozic acid to redirect the flow of the poly-isoprene pathway towards Dol by lowering cholesterol biosynthesis. The addition of zaragozic acid to CDG fibroblasts with a Dol-P-Man synthase defect led to the formation of longer Dol-P species and to increased Dol-P-Man levels. This treatment was shown to decrease the pathologic accumulation of incomplete Dol-PP-GlcNAc2Man5 in Dol-P-Man synthase deficient fibroblasts. Zaragozic acid treatment also decreased the amount of truncated protein N-linked oligosaccharides in these CDG fibroblasts. The increased cellular levels of Dol-P-Man and possibly the decreased cholesterol levels in zaragozic acid-treated cells also led to increased availability of the glycosylphosphatidylinositol-anchor as shown by the elevated cell surface expression of the CD59 protein. The present study shows that manipulation of the cellular Dol pool, as achieved by zaragozic acid addition, may represent a valuable approach aimed at improving N-linked glycosylation in CDG cells.


8 citations in Web of Science®
9 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Date:25 February 2011
Deposited On:16 Jan 2011 19:54
Last Modified:05 Apr 2016 14:31
Publisher:American Society for Biochemistry and Molecular Biology
Additional Information:This research was originally published in Journal of Biological Chemistry, Haeuptle, M A; Welti, M; Troxler, H; Huelsmeier, A J; Imbach, T; Hennet, T, Improvement of dolichol-linked oligosaccharide biosynthesis by the squalene synthase inhibitor Zaragozic acid, Journal of Biological Chemistry 2011; 286(8):6085-6091 © the American Society for Biochemistry and Molecular Biology.
Publisher DOI:10.1074/jbc.M110.165795
PubMed ID:21183681

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