Abstract
Phosphoglycerate dehydrogenase (PHGDH) catalyzes the committed step in de novo serine biosynthesis. Paradoxically, PHGDH and serine synthesis are required in the presence of abundant environmental serine even when serine uptake exceeds the requirements for nucleotide synthesis. Here, we establish a mechanism for how PHGDH maintains nucleotide metabolism. We show that inhibition of PHGDH induces alterations in nucleotide metabolism independent of serine utilization. These changes are not attributable to defects in serine-derived nucleotide synthesis and redox maintenance, another key aspect of serine metabolism, but result from disruption of mass balance within central carbon metabolism. Mechanistically, this leads to simultaneous alterations in both the pentose phosphate pathway and the tri-carboxylic acid cycle, as we demonstrate based on a quantitative model. These findings define a mechanism whereby disruption of one metabolic pathway induces toxicity by simultaneously affecting the activity of multiple related pathways.
Highlights
Phosphoglycerate dehydrogenase (PHGDH) catalyzes the committed step in de novo serine biosynthesis
A pathway analysis[9] revealed that the pathways most affected were related to serine-glycine-one carbon (SGOC) metabolism, central carbon metabolism, and nucleotide metabolism (Fig. 1e)
To study how PHGDH regulates nucleotide metabolism, we used stable isotope tracing by culturing cells in medium supplemented with uniformly labeled glucose ([U-13C] glucose), and measured glucose incorporation into numerous pathways that are involved in purine and pyrimidine synthesis with and without PHGDH inhibition via Liquid Chromatography coupled to High-Resolution Mass Spectrometry (LC-HRMS)
Summary
Phosphoglycerate dehydrogenase (PHGDH) catalyzes the committed step in de novo serine biosynthesis. To study how PHGDH regulates nucleotide metabolism, we used stable isotope tracing by culturing cells in medium supplemented with uniformly labeled glucose ([U-13C] glucose), and measured glucose incorporation into numerous pathways that are involved in purine and pyrimidine synthesis with and without PHGDH inhibition via LC-HRMS.
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