Document Detail


Metabolism of vertebrate amino sugars with N-glycolyl groups: resistance of α2-8-linked N-glycolylneuraminic acid to enzymatic cleavage.
MedLine Citation:
PMID:  22692207     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The sialic acid (Sia) N-acetylneuraminic acid (Neu5Ac) and its hydroxylated derivative N-glycolylneuraminic acid (Neu5Gc) differ by one oxygen atom. CMP-Neu5Gc is synthesized from CMP-Neu5Ac, with Neu5Gc representing a highly variable fraction of total Sias in various tissues and among different species. The exception may be the brain, where Neu5Ac is abundant and Neu5Gc is reported to be rare. Here, we confirm this unusual pattern and its evolutionary conservation in additional samples from various species, concluding that brain Neu5Gc expression has been maintained at extremely low levels over hundreds of millions of years of vertebrate evolution. Most explanations for this pattern do not require maintaining neural Neu5Gc at such low levels. We hypothesized that resistance of α2-8-linked Neu5Gc to vertebrate sialidases is the detrimental effect requiring the relative absence of Neu5Gc from brain. This linkage is prominent in polysialic acid (polySia), a molecule with critical roles in vertebrate neural development. We show that Neu5Gc is incorporated into neural polySia and does not cause in vitro toxicity. Synthetic polymers of Neu5Ac and Neu5Gc showed that mammalian and bacterial sialidases are much less able to hydrolyze α2-8-linked Neu5Gc at the nonreducing terminus. Notably, this difference was not seen with acid-catalyzed hydrolysis of polySias. Molecular dynamics modeling indicates that differences in the three-dimensional conformation of terminal saccharides may partly explain reduced enzymatic activity. In keeping with this, polymers of N-propionylneuraminic acid are sensitive to sialidases. Resistance of Neu5Gc-containing polySia to sialidases provides a potential explanation for the rarity of Neu5Gc in the vertebrate brain.
Authors:
Leela R L Davies; Oliver M T Pearce; Matthew B Tessier; Siavash Assar; Victoria Smutova; Maria Pajunen; Mizuki Sumida; Chihiro Sato; Ken Kitajima; Jukka Finne; Pascal Gagneux; Alexey Pshezhetsky; Robert Woods; 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:  2014-01-10    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  28917-31     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Sugars / chemistry,  metabolism*
Animals
Bacteria / chemistry,  metabolism
Brain / metabolism*
Brain Chemistry / physiology*
Carbohydrate Conformation
Cattle
Dolphins
Elephants
Evolution, Molecular
Hydrolysis
Mice
N-Acetylneuraminic Acid
Nerve Tissue Proteins / chemistry,  metabolism
Neuraminic Acids / chemistry,  metabolism*
Neuraminidase / chemistry,  metabolism
Pan troglodytes
Rats
Species Specificity
Swine
Grant Support
ID/Acronym/Agency:
GM094919/GM/NIGMS NIH HHS; P41 GM103390/GM/NIGMS NIH HHS; R01 CA038701/CA/NCI NIH HHS; R01 GM032373/GM/NIGMS NIH HHS; R01 GM094919/GM/NIGMS NIH HHS; R01 GM095882/GM/NIGMS NIH HHS; R01CA38701/CA/NCI NIH HHS; R01GM32373/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Amino Sugars; 0/Nerve Tissue Proteins; 0/Neuraminic Acids; 1113-83-3/N-glycolylneuraminic acid; EC 3.2.1.18/Neuraminidase; GZP2782OP0/N-Acetylneuraminic Acid
Comments/Corrections

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