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ACS chemical biology v.12 no.1, 2017년, pp.206 - 213   SCIE
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Catalytic Promiscuity of O-GlcNAc Transferase Enables Unexpected Metabolic Engineering of Cytoplasmic Proteins with 2-Azido-2-deoxy-glucose

Shen, David L. (Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ); Liu, Ta-Wei ( Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ); Zandberg, Wesley ( Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ); Clark, Tom ( Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ); Eskandari, Razieh ( Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ); Alteen, Matthew G. ( Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ); Tan, Hong Yee ( Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ); Zhu, Yanping ( Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ); Cecioni, Samy ( Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ); Vocadlo, David ( Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, );
  • 초록  

    O -GlcNAc transferase (OGT) catalyzes the installation of N -acetylglucosamine (GlcNAc) O -linked to nucleocytoplasmic proteins ( O -GlcNAc) within multicellular eukaryotes. OGT shows surprising tolerance for structural changes in the sugar component of its nucleotide sugar donor substrate, uridine diphosphate N -acetylglucosamine (UDP-GlcNAc). Here, we find that OGT uses UDP-glucose to install O -linked glucose ( O -Glc) onto proteins only 25-fold less efficiently than O -GlcNAc. Spurred by this observation, we show that OGT transfers 2-azido-2-deoxy- d -glucose (GlcAz) in vitro from UDP-GlcAz to proteins. Further, feeding cells with per- O -acetyl GlcAz (AcGlcAz), in combination with inhibition or inducible knockout of OGT, shows OGT-dependent modification of nuclear and cytoplasmic proteins with O -GlcAz as detected using microscopy, immunoblot, and proteomics. We find that O -GlcAz is reversible within cells, and an unidentified cellular enzyme exists to cleave O -Glc that can also process O -GlcAz. We anticipate that AcGlcAz will prove to be a useful tool to study the O -GlcNAc modification. We also speculate that, given the high concentration of UDP-Glc within certain mammalian tissues, O -Glc may exist within mammals and serve as a physiologically relevant modification. Graphic Abstract ACS Electronic Supporting Info


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