Ac4GlcNAcF3, an OGT-tolerated but OGA-resistant regulator for O-GlcNAcylation

  • Bioorg Med Chem Lett. 2019 Mar 15;29(6):802-805. doi: 10.1016/j.bmcl.2019.01.021.
Haifeng Wang  1 ,  Jianshuang Guo  1 ,  Nan Wang  1 ,  Jiajia Wang  2 ,  Qingqing Xue  1 ,  Jiyan Wang  1 ,  Wenjie Liu  1 ,  Kaihui Liu  1 ,  Xuefeng Cao  3 ,  Wei Zhao  1 ,  Rimo Xi  1 ,  Youhong Niu  4 ,  Peng Wang  1 ,  Jing Li  5
Affiliations
  • 1. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Reasearch, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China.
  • 2. School of Basic Medical Sciences, Henan University Joint National Laboratory for Antibody Drug Engineering, Kaifeng, Henan 475004, China.
  • 3. Department of Chemistry & Center for Diagnostics & Therapeutics Georgia State University, Atlanta, GA 30303, USA.
  • 4. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking Univeristy, Xue Yuan Road No.38, Beijing 100191, China.
  • 5. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Reasearch, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China; College of Chemistry and Molecular Engineering, Beijing National Laboratory for Molecular Sciences, Peking University, Beijing 100191, China. Electronic address: [email protected].
PMID: 30713024 DOI: 10.1016/j.bmcl.2019.01.021
Abstract

O-Linked N-acetylglucosamine (O-GlcNAc) is an abundant posttranslationalmonosaccaride-modification found on Ser or Thr residues of intracellular proteins in most eukaryotes. The dynamic nature of O-GlcNAc has enabled researchers to modulate the stoichiometry of O-GlcNAc on proteins in order to investigate its function. Cell permeable small moleculars have proven invaluable tools to increase O-GlcNAc levels. Herein, using in vitro substrate screening, we identified GlcNAcF3 as an OGT-accepted but OGA-resistant sugar mimic. Cellular experiments with cell-permeable peracetylated-GlcNAcF3 (Ac4GlcNAcF3) displayed that Ac4GlcNAcF3 was a potent tool to increase O-GlcNAc levels in several cell lines. Further, NIH3T3 cells interfered with OGT (siOGT) showed significant decreasing of O-GlcNAc levels with Ac4GlcNAcF3 treatment, indicating O-GlcNAcF3 was an OGT-dependent modification. In addition, cellular toxic assay confirmed O-GlcNAcF3 production has no significant effect on cell proliferation or viability. Thus, Ac4GlcNAcF3 represents a safe and dual regulator for both OGT and OGA, which will benefit the study of O-GlcNAc.

Keywords
Ac(4)GlcNAcF(3); Inhibitors; O-GlcNAc transferase; O-GlcNAcase; O-GlcNAcylation.
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