Metabolism of vertebrate amino sugars with N-glycolyl groups: resistance of α2-8-linked N-glycolylneuraminic acid to enzymatic cleavage
| Autor: | 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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| Rok vydání: | 2012 |
| Předmět: |
Brain Chemistry
Bacteria Pan troglodytes Swine Dolphins Hydrolysis Elephants Brain Neuraminidase Glycobiology and Extracellular Matrices Amino Sugars Nerve Tissue Proteins N-Acetylneuraminic Acid Rats Evolution Molecular Mice Species Specificity Carbohydrate Conformation Animals Cattle Neuraminic Acids |
| Zdroj: | The Journal of biological chemistry. 287(34) |
| ISSN: | 1083-351X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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