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Bioorg Med Chem Lett. 2019 Mar 15;29(6):802-805. doi: 10.1016/j.bmcl.2019.01.021. Epub 2019 Jan 22.

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

Author information

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: jinglink@nankai.edu.cn.

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

PMID:
30713024
DOI:
10.1016/j.bmcl.2019.01.021

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