O-GlcNAcylation increases PYGL activity by promoting phosphorylation

Glycobiology. 2022 Mar 19;32(2):101-109. doi: 10.1093/glycob/cwab114.


O-GlcNAcylation is a post-translational modification that links metabolism with signal transduction. High O-GlcNAcylation appears to be a general characteristic of cancer cells. It promotes the invasion, metastasis, proliferation and survival of tumor cells, and alters many metabolic pathways. Glycogen metabolism increases in a wide variety of tumors, suggesting that it is an important aspect of cancer pathophysiology. Herein we focused on the O-GlcNAcylation of liver glycogen phosphorylase (PYGL)-an important catabolism enzyme in the glycogen metabolism pathway. PYGL expressed in both HEK 293T and HCT116 was modified by O-GlcNAc. And both PYGL O-GlcNAcylation and phosphorylation of Ser15 (pSer15) were decreased under glucose and insulin, whereas increased under glucagon and Na2S2O4 (hypoxia) conditions. Then, we identified the major O-GlcNAcylation site to be Ser430, and demonstrated that pSer15 and Ser430 O-GlcNAcylation were mutually reinforced. Lastly, we found that Ser430 O-GlcNAcylation was fundamental for PYGL activity. Thus, O-GlcNAcylation of PYGL positively regulated pSer15 and therefore its enzymatic activity. Our results provided another molecular insight into the intricate post-translational regulation network of PYGL.

Keywords: O-GlcNAcylation; enzyme activity; glycogen metabolism; liver glycogen phosphorylase (PYGL); phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / metabolism
  • Glucose / metabolism
  • Glycogen / metabolism
  • Humans
  • N-Acetylglucosaminyltransferases* / genetics
  • Neoplasms*
  • Phosphorylation
  • Protein Processing, Post-Translational


  • Glycogen
  • N-Acetylglucosaminyltransferases
  • Glucose
  • Acetylglucosamine