Document Detail

Metabolism of vertebrate amino sugars with N-glycolyl groups: incorporation of N-glycolylhexosamines into mammalian glycans by feeding N-glycolylgalactosamine.
MedLine Citation:
PMID:  22692203     Owner:  NLM     Status:  MEDLINE    
The outermost positions of mammalian cell-surface glycans are predominantly occupied by the sialic acids N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). To date, hydroxylation of CMP-Neu5Ac resulting in the conversion into CMP-Neu5Gc is the only known enzymatic reaction in mammals to synthesize a monosaccharide carrying an N-glycolyl group. In our accompanying paper (Bergfeld, A. K., Pearce, O. M., Diaz, S. L., Pham, T., and Varki, A. (2012) J. Biol. Chem. 287, jbc.M112.363549), we report a metabolic pathway for degradation of Neu5Gc, demonstrating that N-acetylhexosamine pathways are tolerant toward the N-glycolyl substituent of Neu5Gc breakdown products. In this study, we show that exogenously added N-glycolylgalactosamine (GalNGc) serves as a precursor for Neu5Gc de novo biosynthesis, potentially involving seven distinct mammalian enzymes. Following the GalNAc salvage pathway, UDP-GalNGc is epimerized to UDP-GlcNGc, which might compete with the endogenous UDP-GlcNAc for the sialic acid biosynthetic pathway. Using UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase-deficient cells, we confirm that conversion of GalNGc into Neu5Gc depends on this key enzyme of sialic acid biosynthesis. Furthermore, we demonstrate by mass spectrometry that the metabolic intermediates UDP-GalNGc and UDP-GlcNGc serve as substrates for assembly of most major classes of cellular glycans. We show for the first time incorporation of GalNGc and GlcNGc into chondroitin/dermatan sulfates and heparan sulfates, respectively. As demonstrated by structural analysis, N-glycolylated hexosamines were found in cellular gangliosides and incorporated into Chinese hamster ovary cell O-glycans. Remarkably, GalNAc derivatives altered the overall O-glycosylation pattern as indicated by the occurrence of novel O-glycan structures. This study demonstrates that mammalian N-acetylhexosamine pathways and glycan assembly are surprisingly tolerant toward the N-glycolyl substituent.
Anne K Bergfeld; Oliver M T Pearce; Sandra L Diaz; Roger Lawrence; David J Vocadlo; Biswa Choudhury; Jeffrey D Esko; Ajit Varki
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-12
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-20     Completed Date:  2012-10-31     Revised Date:  2013-08-20    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  28898-916     Citation Subset:  IM    
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92093-0687, USA.
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MeSH Terms
CHO Cells
Carbohydrate Epimerases / genetics,  metabolism
Chondroitin Sulfates / genetics,  metabolism
Dermatan Sulfate / genetics,  metabolism
Heparitin Sulfate / genetics,  metabolism
Mice, Knockout
N-Acetylneuraminic Acid / genetics,  metabolism*,  pharmacology*
Phosphotransferases (Alcohol Group Acceptor) / genetics,  metabolism*
Uridine Diphosphate Sugars / genetics,  metabolism
Grant Support
Reg. No./Substance:
0/Uridine Diphosphate Sugars; 131-48-6/N-Acetylneuraminic Acid; 24967-94-0/Dermatan Sulfate; 9007-28-7/Chondroitin Sulfates; 9050-30-0/Heparitin Sulfate; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC kinase; EC 5.1.3.-/Carbohydrate Epimerases; EC acetylglucosamine-2-epimerase

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