title: Functional lysine modification by an intrinsically reactive primary glycolytic metabolite.
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.
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA. rmoeller@scripps.edu
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Moellering
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000378:metabolism; D002384:Catalysis; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D004163:Diphosphoglyceric Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000737:chemistry / Q000378:metabolism; D005994:Glycerophosphates / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010751:Phosphopyruvate Hydratase / Q000737:chemistry / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D004163:Diphosphoglyceric Acids; D005994:Glycerophosphates; D011506:Proteins; D025521:Tumor Suppressor Proteins; C015891:glycerate 1,3-biphosphate; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); C095157:ENO1 protein, human; D010751:Phosphopyruvate Hydratase; D005947:Glucose; D008239:Lysine
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