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Nat Chem Biol. 2016 Jun;12(6):452-8. doi: 10.1038/nchembio.2070. Epub 2016 Apr 25.

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

Author information

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..

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.

Comment in

PMID:
27110680
PMCID:
PMC4871733
DOI:
10.1038/nchembio.2070
[Indexed for MEDLINE]
Free PMC Article

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