Functional Lysine Modification by an Intrinsically Reactive Primary Glycolytic Metabolite

Modification Without Enzymes Control of metabolic enzymes and regulation of many other biological processes is mediated in large part by binding of small molecules to proteins or through enzymatically medimediated covalent posttranslational modification of proteins. Moellering and Cravatt (p. 549 ) wondered whether another scenario might occur in which reactive intermediates in a metabolic pathway might specifically react with and modify particular amino acids in proteins to produce regulatory changes without the need for catalysis by another enzyme. A particularly reactive intermediate formed during glycolysis, 1,3-bisphosphoglycerate, could nonenzymatically modify specific lysines in proteins, providing a means by which accumulation of metabolic intermediates could provide regulatory feedback to balance or control flux through various pathways. Proteomic analysis showed that the 3-phosphoglyceryl-lysine formed when certain lysine residues interacted with 1,3-bisphosphoglycerate produced naturally in cells and was particularly common in proteins that function in glycolysis. Such modification decreased activity of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase.