| Metabolism of vertebrate amino sugars with N-glycolyl groups: resistance of α2-8-linked N-glycolylneuraminic acid to enzymatic cleavage. | |
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MedLine Citation:
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PMID: 22692207 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-06-12 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 287 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2012 Aug |
Date Detail:
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Created Date: 2012-08-20 Completed Date: 2012-10-31 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 28917-31 Citation Subset: IM |
Affiliation:
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Department of Medicine, Glycobiology Research and Training Center, University of California San Diego, La Jolla, California 92093-0687, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Sugars
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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:
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GM094919/GM/NIGMS NIH HHS; R01 CA038701/CA/NCI NIH HHS; R01 GM032373/GM/NIGMS NIH HHS; R01 GM095882/GM/NIGMS NIH HHS; R01CA38701/CA/NCI NIH HHS; R01GM32373/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amino Sugars; 0/Nerve Tissue Proteins; 0/Neuraminic Acids; 1113-83-3/N-glycolylneuraminic acid; 131-48-6/N-Acetylneuraminic Acid; EC 3.2.1.18/Neuraminidase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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