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

Author

Listed:
  • Michael A. Reid

    (Duke University School of Medicine)

  • Annamarie E. Allen

    (Duke University School of Medicine)

  • Shiyu Liu

    (Duke University School of Medicine)

  • Maria V. Liberti

    (Duke University School of Medicine)

  • Pei Liu

    (Peking University)

  • Xiaojing Liu

    (Duke University School of Medicine)

  • Ziwei Dai

    (Duke University School of Medicine)

  • Xia Gao

    (Duke University School of Medicine)

  • Qian Wang

    (Peking University)

  • Ying Liu

    (Peking University)

  • Luhua Lai

    (Peking University)

  • Jason W. Locasale

    (Duke University School of Medicine)

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.

Suggested Citation

  • 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, 2018. "Serine synthesis through PHGDH coordinates nucleotide levels by maintaining central carbon metabolism," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07868-6
    DOI: 10.1038/s41467-018-07868-6
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    Cited by:

    1. Kui Wang & Li Luo & Shuyue Fu & Mao Wang & Zihao Wang & Lixia Dong & Xingyun Wu & Lunzhi Dai & Yong Peng & Guobo Shen & Hai-Ning Chen & Edouard Collins Nice & Xiawei Wei & Canhua Huang, 2023. "PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Eirini Lionaki & Ilias Gkikas & Ioanna Daskalaki & Maria-Konstantina Ioannidi & Maria I. Klapa & Nektarios Tavernarakis, 2022. "Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Adrienne Tin & Pascal Schlosser & Pamela R. Matias-Garcia & Chris H. L. Thio & Roby Joehanes & Hongbo Liu & Zhi Yu & Antoine Weihs & Anselm Hoppmann & Franziska Grundner-Culemann & Josine L. Min & Vic, 2021. "Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus," Nature Communications, Nature, vol. 12(1), pages 1-18, December.

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