Serine synthesis through PHGDH coordinates nucleotide levels by maintaining central carbon metabolism

• DOI: 10.1038/s41467-018-07868-6
• Publication Date: 2018-12-17T16:32:41Z
• Authors: Michael A. Reid; Annamarie E. Allen; Shiyu Liu; Maria V. Liberti; Pei Liu; Xiaojing Liu; Ziwei Dai; Xia Gao; Qian Wang; Ying Liu; Luhua Lai; Jason W. Locasale
• Keywords: 0301 basic medicine; 0303 health sciences; Nucleotides; Science; Q; Citric Acid Cycle; HCT116 Cells; Article; Metabolic Flux Analysis; Pentose Phosphate Pathway; 03 medical and health sciences; MCF-7 Cells; Serine; Humans; Phosphoglycerate Dehydrogenase

AbstractPhosphoglycerate 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.