Acta Chimica Sinica ›› 2013, Vol. 71 ›› Issue (11): 1477-1487.DOI: 10.6023/A13050534 Previous Articles     Next Articles




  1. 中国科学院大学化学与化工学院 北京 100049
  • 投稿日期:2013-05-17 发布日期:2013-07-19
  • 通讯作者: 王玥
  • 作者简介:王玥博士1985 年出生于辽宁省, 2006 年在北京大学药学院获得学士学位, 2006 年到2012 年在北京大学天然药物及仿生药物国家重点实验室叶新山教授课题组攻读硕士和博士学位, 此后加入中国科学院大学化学与化工学院, 主要研究方向为糖化学生物学和糖类药物的发现.

O-GlcNAc Transferase and Its Inhibitors

Wang Yue   

  1. School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049
  • Received:2013-05-17 Published:2013-07-19

O-GlcNAc transferase (OGT), one of essential mammalian enzymes, catalyses the transfer of N-acetylglucos- amine from UDP-N-acetylglucosamine (UDP-GlcNAc) to hydroxyl groups of serines and threonines (Ser/Thr) in proteins. O-GlcNAcylation is widely located in cytoplasm and nucleus. This kind of protein post-translational modification is involved in the regulation of many cellular signaling pathways and closely associated with the occurrences and developments of numerous critical illnesses. In animals, OGT is encoded by a single highly conserved gene. However, human OGT includes three different isoforms at least: nucleocytoplasmic OGT (ncOGT), mitochondrial OGT (mOGT) and short OGT (sOGT). All of the isoforms comprise two distinct regions: a multidomain catalytic region and an N-terminal region with different numbers of tetratricopeptide repeats (TPRs), which is closely related to their subcellular localizations. The structures of the catalytic region and TPRs were reported and it was supported that OGT uses an ordered sequential "bi-bi" mechanism though the details of catalytic mechanism were not completely understood. To discover the inhibitors of OGT, several OGT activity assay methods were developed. The conventional method uses a radiolabeled glycosyl donor substrate such as UDP-[3H]-GlcNAc or UDP-[14C]-GlcNAc so that it is not suitable for in vivo test or rapid analysis. O-GlcNAc antibody-based western blot was performed to measure the activity of OGT in vivo, but it is infeasible to determine low abundance protein with single O-GlcNAc. Three high throughput activity assays were reported: ligand displacement OGT assay, protease-protection assay strategy and azido-enzyme-linked immunosorbent assay (azido-ELISA). The first two methods have especially been used to find new OGT inhibitors through screening compound libraries, but the results have to be verified by the conventional method. To date, OGT inhibitor activity of several candidates was evaluated and as found, two of them {2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-5-thio-α-D-glucopyranose and 4-methoxyphenyl 6-acetyl-2-oxobenzo[d]-oxazole-3(2H)-carboxylate} worked effectively in vivo and were valuable for understanding the functional roles of OGT. Nevertheless, there are still important questions to be answered in the research of OGT: (1) What is the general base that catalyzes O-GlcNAcylation reaction? (2) How can OGT recognize so many protein substances with the preservation of substance specificity? (3) How can we develop robust high-throughput OGT assays and isoform-specific OGT inhibitors? In conclusion, there is a long way to go for comprehensive understanding of OGT.

Key words: O-GlcNAcylation, O-GlcNAc transferase, enzyme inhibitors, protein post-translational modification, glycosyl transferase