Phosphoglycerate dehydrogenase (PHGDH) is the first enzyme in de novo Ser biosynthesis. Numerous pathways rely on Ser as a precursor, most notably one-carbon metabolism and de novo nucleotide biosynthesis. Thus, glycolytic flux may be shunted to this pathway to serve the metabolic needs of the cell and facilitate cell proliferation and survival. Here we demonstrate the regulation of PHGDH by a recently reported PTM, lactoylLys. These modifications are derived through a non-enzymatic reaction with lysine and the glyoxalase cycle intermediate, lactoylglutathione (LGSH). Under basal conditions, LGSH is regulated through hydrolysis by glyoxalase 2 (GLO2); in GLO2 knockout cells, however, LGSH is elevated, resulting in increased lactoylLys modified proteins. Here, we show that GLO2 regulates lactoylLys status on PHGDH. Modification of PHGDH results in a significant reduction in activity in vitro and a decrease in intracellular Ser in cells. Stable isotope tracing reveals reduced flux through the de novo Ser biosynthetic pathway, resulting in reduced intracellular Ser. Collectively, these data identify PHGDH as a target for modification by lactoylLys, resulting in reduced enzymatic activity and a reduction in intracellular Ser, thus identifying GLO2 as a putative candidate for therapeutic intervention in diseases dependent on de novo Ser as a precursor.

Regulation of phosphoglycerate dehydrogenase by lactoylLysine

ACS Fall 2021

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