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  3. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate

A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate

  • Nat Chem Biol. 2016 Jun;12(6):452-8. doi: 10.1038/nchembio.2070.
Michael E Pacold 1 2 3 4 5 6,  Kyle R Brimacombe 7,  Sze Ham Chan 1 2 3 4 6,  Jason M Rohde 7,  Caroline A Lewis 3,  Lotteke J Y M Swier 1 2 3 4,  Richard Possemato 8,  Walter W Chen 1 2 3 4,  Lucas B Sullivan 3,  Brian P Fiske 3,  Steve Cho 1 2 3 4,  Elizaveta Freinkman 1,  Kıvanç Birsoy 9,  Monther Abu-Remaileh 1 2 3 4,  Yoav D Shaul 10,  Chieh Min Liu 1 2 3 4,  Minerva Zhou 1 2 3 4,  Min Jung Koh 1 2 3 4,  Haeyoon Chung 1 2 3 4,  Shawn M Davidson 3,  Alba Luengo 3,  Amy Q Wang 7,  Xin Xu 7,  Adam Yasgar 7,  Li Liu 7,  Ganesha Rai 7,  Kenneth D Westover 11,  Matthew G Vander Heiden 3,  Min Shen 7,  Nathanael S Gray 5,  Matthew B Boxer 7,  David M Sabatini 1 2 3 4
Affiliations

Affiliations

  • 1 Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
  • 2 Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • 3 Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.
  • 4 Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • 5 Dana-Farber Cancer Institute, Longwood Center, Boston, Massachusetts, USA.
  • 6 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 7 National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
  • 8 New York University Langone Medical Center, New York, New York, USA.
  • 9 Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, New York, USA.
  • 10 Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • 11 University of Texas Southwestern Medical Center, Dallas, Texas, USA..
PMID: 27110680 DOI: 10.1038/nchembio.2070
Abstract

Serine is both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical pathway of glucose-derived serine synthesis, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic toward PHGDH-overexpressing breast Cancer cell lines even in the presence of exogenous serine. Here, we used a quantitative high-throughput screen to identify small-molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent Cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and we suggest that one-carbon unit wasting thus may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo.

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