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ACS chemical biology v.12 no.1, 2017년, pp.214 - 224   SCIE
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A Chemical Biology Solution to Problems with Studying Biologically Important but Unstable 9-O-Acetyl Sialic Acids

Khedri, Zahra (Glycobiology Research and Training Center, University of California, San Diego, California 92093, ); Xiao, An ( Department of Chemistry, University of California, Davis, California 95616, ); Yu, Hai ( Department of Chemistry, University of California, Davis, California 95616, ); Landig, Corinna Susanne ( Glycobiology Research and Training Center, University of California, San Diego, California 92093, ); Li, Wanqing ( Department of Chemistry, University of California, Davis, California 95616, ); Diaz, Sandra ( Glycobiology Research and Training Center, University of California, San Diego, California 92093, ); Wasik, Brian R. ( Department of Microbiology and Immunology, Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, ); Parrish, Colin R. ( Department of Microbiology and Immunology, Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, ); Wang, Lee-Ping ( Department of Chemistry, University of California, Davis, California 95616, ); Varki, Ajit ( Glycobiology Research and Training Center, University of California, San Die ); Chen, Xi ( );
  • 초록  

    9-O-Acetylation is a common natural modification on sialic acids (Sias) that terminate many vertebrate glycan chains. This ester group has striking effects on many biological phenomena, including microbe-host interactions, complement action, regulation of immune responses, sialidase action, cellular apoptosis, and tumor immunology. Despite such findings, 9-O-acetyl sialoglycoconjugates have remained largely understudied, primarily because of marked lability of the 9-O-acetyl group to even small pH variations and/or the action of mammalian or microbial esterases. Our current studies involving 9-O-acetylated sialoglycans on glycan microarrays revealed that even the most careful precautions cannot ensure complete stability of the 9-O-acetyl group. We now demonstrate a simple chemical biology solution to many of these problems by substituting the oxygen atom in the ester with a nitrogen atom, resulting in sialic acids with a chemically and biologically stable 9-N-acetyl group. We present an efficient one-pot multienzyme method to synthesize a sialoglycan containing 9-acetamido-9-deoxy- N -acetylneuraminic acid (Neu5Ac9NAc) and compare it to the one with naturally occurring 9- O -acetyl- N -acetylneuraminic acid (Neu5,9Ac 2 ). Conformational resemblance of the two molecules was confirmed by computational molecular dynamics simulations. Microarray studies showed that the Neu5Ac9NAc-sialoglycan is a ligand for viruses naturally recognizing Neu5,9Ac 2 , with a similar affinity but with much improved stability in handling and study. Feeding of Neu5Ac9NAc or Neu5,9Ac 2 to mammalian cells resulted in comparable incorporation and surface expression as well as binding to 9-O-acetyl-Sia-specific viruses. However, cells fed with Neu5Ac9NAc remained resistant to viral esterases and showed a slower turnover. This simple approach opens numerous research opportunities that have heretofore proved intractable. Graphic Abstract ACS Electronic Supporting Info


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