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

Haifeng Wang; Jianshuang Guo; Nan Wang; Jiajia Wang; Qingqing Xue; Jiyan Wang; Wenjie Liu; Kaihui Liu; Xuefeng Cao; Wei Zhao; Rimo Xi; Youhong Niu; Peng Wang; Jing Li

doi:10.1016/j.bmcl.2019.01.021

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. Epub 2019 Jan 22.

Authors

Haifeng Wang¹, Jianshuang Guo¹, Nan Wang¹, Jiajia Wang², Qingqing Xue¹, Jiyan Wang¹, Wenjie Liu¹, Kaihui Liu¹, Xuefeng Cao³, Wei Zhao¹, Rimo Xi¹, Youhong Niu⁴, Peng Wang¹, Jing Li⁵

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: jinglink@nankai.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylglucosamine / analogs & derivatives*
Acetylglucosamine / pharmacology*
Acetylglucosamine / toxicity
Animals
Cell Line, Tumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology*
Enzyme Inhibitors / toxicity
Glycosylation / drug effects
Humans
Mice
N-Acetylglucosaminyltransferases / metabolism*
NIH 3T3 Cells
beta-N-Acetylhexosaminidases / antagonists & inhibitors
beta-N-Acetylhexosaminidases / metabolism*

Substances

Enzyme Inhibitors
N-Acetylglucosaminyltransferases
O-GlcNAc transferase
hexosaminidase C
beta-N-Acetylhexosaminidases
Acetylglucosamine