Science 341, 549–553 (2013)

The post-translational modification (PTM) of a protein—via the addition of chemical moieties such as acetate, phosphate or a carbohydrate—can dramatically alter the physiological behavior of that protein. The attachment and removal of most PTMs are catalyzed by enzymes; for example, kinases can phosphorylate a protein in a signaling cascade, and this PTM can be removed by a phosphatase. Moellering and Cravatt have identified a new PTM that seems to be added to target proteins in a nonenzymatic manner. The authors first showed that 1,3-bisphosphoglycerate, which is a product of GAPDH catalysis and contains an electrophilic acyl phosphate group, reacted with the amino groups of specific lysine side chains of GAPDH in vitro, forming 3-phosphoglyceryl-lysine (pgK) linkages. pgK modification of GAPDH increased the Km of the enzyme, suggesting that this PTM interfered with GAPDH's ability to interact with its substrate. The authors used proteomic profiling to show that pgK modifications were formed on diverse proteins in human cell lines and mouse tissues, frequently at catalytic or regulatory lysines in the active sites of metabolic enzymes. Exposing cells to high concentrations of glucose led to an increase in the amount of pgK-labeled proteins, suggesting that pgK modifications may help cells react to an increase in glycolytic flux. Additional work is needed to determine how the presence of this new PTM affects the physiological properties of other proteins in vivo.