Document Detail

Metabolism of vertebrate amino sugars with N-glycolyl groups: elucidating the intracellular fate of the non-human sialic acid N-glycolylneuraminic acid.
MedLine Citation:
PMID:  22692205     Owner:  NLM     Status:  MEDLINE    
The two major mammalian sialic acids are N-acetylneuraminic acid and N-glycolylneuraminic acid (Neu5Gc). The only known biosynthetic pathway generating Neu5Gc is the conversion of CMP-N-acetylneuraminic acid into CMP-Neu5Gc, which is catalyzed by the CMP-Neu5Ac hydroxylase enzyme. Given the irreversible nature of this reaction, there must be pathways for elimination or degradation of Neu5Gc, which would allow animal cells to adjust Neu5Gc levels to their needs. Although humans are incapable of synthesizing Neu5Gc due to an inactivated CMAH gene, exogenous Neu5Gc from dietary sources can be metabolically incorporated into tissues in the face of an anti-Neu5Gc antibody response. However, the metabolic turnover of Neu5Gc, which apparently prevents human cells from continued accumulation of this immunoreactive sialic acid, has not yet been elucidated. In this study, we show that pre-loaded Neu5Gc is eliminated from human cells over time, and we propose a conceivable Neu5Gc-degrading pathway based on the well studied metabolism of N-acetylhexosamines. We demonstrate that murine tissue cytosolic extracts harbor the enzymatic machinery to sequentially convert Neu5Gc into N-glycolylmannosamine, N-glycolylglucosamine, and N-glycolylglucosamine 6-phosphate, whereupon irreversible de-N-glycolylation of the latter results in the ubiquitous metabolites glycolate and glucosamine 6-phosphate. We substantiate this finding by demonstrating activity of recombinant human enzymes in vitro and by studying the fate of radiolabeled pathway intermediates in cultured human cells, suggesting that this pathway likely occurs in vivo. Finally, we demonstrate that the proposed degradative pathway is partially reversible, showing that N-glycolylmannosamine and N-glycolylglucosamine (but not glycolate) can serve as precursors for biosynthesis of endogenous Neu5Gc.
Anne K Bergfeld; Oliver M T Pearce; Sandra L Diaz; Tho Pham; 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:  28865-81     Citation Subset:  IM    
Department of Medicine, Glycobiology Research and Training Center, University of California San Diego, La Jolla, California 92093-0687, USA.
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MeSH Terms
Amino Sugars / genetics,  metabolism*
Cell Line, Tumor
Mice, Knockout
Mixed Function Oxygenases / genetics,  metabolism*
N-Acetylneuraminic Acid / genetics,  metabolism*
Neuraminic Acids / metabolism*
Species Specificity
Grant Support
Reg. No./Substance:
0/Amino Sugars; 0/Neuraminic Acids; 1113-83-3/N-glycolylneuraminic acid; 131-48-6/N-Acetylneuraminic Acid; EC 1.-/Mixed Function Oxygenases; EC monooxygenase

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