Functional lysine modification by an intrinsically reactive primary glycolytic metabolite

Science. 2013 Aug 2;341(6145):549-53. doi: 10.1126/science.1238327.

Abstract

The posttranslational modification of proteins and their regulation by metabolites represent conserved mechanisms in biology. At the confluence of these two processes, we report that the primary glycolytic intermediate 1,3-bisphosphoglycerate (1,3-BPG) reacts with select lysine residues in proteins to form 3-phosphoglyceryl-lysine (pgK). This reaction, which does not require enzyme catalysis, but rather exploits the electrophilicity of 1,3-BPG, was found by proteomic profiling to be enriched on diverse classes of proteins and prominently in or around the active sites of glycolytic enzymes. pgK modifications inhibit glycolytic enzymes and, in cells exposed to high glucose, accumulate on these enzymes to create a potential feedback mechanism that contributes to the buildup and redirection of glycolytic intermediates to alternate biosynthetic pathways.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Biomarkers, Tumor / chemistry
  • Biomarkers, Tumor / metabolism
  • Catalysis
  • Cell Line
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism
  • Diphosphoglyceric Acids / metabolism*
  • Glucose / metabolism
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / chemistry
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism
  • Glycerophosphates / metabolism*
  • Glycolysis*
  • Humans
  • Lysine / analogs & derivatives*
  • Lysine / metabolism*
  • Mice
  • Molecular Sequence Data
  • Phosphopyruvate Hydratase / chemistry
  • Phosphopyruvate Hydratase / metabolism
  • Protein Processing, Post-Translational*
  • Proteins / chemistry
  • Proteins / metabolism*
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / metabolism

Substances

  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Diphosphoglyceric Acids
  • Glycerophosphates
  • Proteins
  • Tumor Suppressor Proteins
  • glycerate 1,3-biphosphate
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
  • ENO1 protein, human
  • Phosphopyruvate Hydratase
  • Glucose
  • Lysine