Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation.

Publication Type:

Journal Article


Nat Commun, Volume 4, p.1790 (2013)


2,3-Diphosphoglycerate, Amino Acid Sequence, Animals, Cell Line, Tumor, Cell Proliferation, Enzyme Stability, Glyceric Acids, Glycolysis, Histidine, Humans, Mice, Models, Molecular, Molecular Sequence Data, Neoplasms, Phosphoglycerate Mutase, Phosphorylation, Phosphotyrosine


<p>How oncogenic signalling coordinates glycolysis and anabolic biosynthesis in cancer cells remains unclear. We recently reported that the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) regulates anabolic biosynthesis by controlling intracellular levels of its substrate 3-phosphoglycerate and product 2-phosphoglycerate. Here we report a novel mechanism in which Y26 phosphorylation enhances PGAM1 activation through release of inhibitory E19 that blocks the active site, stabilising cofactor 2,3-bisphosphoglycerate binding and H11 phosphorylation. We also report the crystal structure of H11-phosphorylated PGAM1 and find that phospho-H11 activates PGAM1 at least in part by promoting substrate 3-phosphoglycerate binding. Moreover, Y26 phosphorylation of PGAM1 is common in human cancer cells and contributes to regulation of 3-phosphoglycerate and 2-phosphoglycerate levels, promoting cancer cell proliferation and tumour growth. As PGAM1 is a negative transcriptional target of TP53, and is therefore commonly upregulated in human cancers, these findings suggest that Y26 phosphorylation represents an additional acute mechanism underlying phosphoglycerate mutase 1 upregulation.</p>