A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate
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Sabatini_A phosphoglycerate.pdf
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Author(s)
Chan, Sze Ham
Lewis, Caroline
Swier, Lotteke J. Y. M.
Chen, Walter W.
Sullivan, Lucas Bryan
Fiske, Brian Prescott
Cho, Sung Won
Abu-Remaileh, Monther
Liu, Chieh Ming Jamin
Zhou, Minerva H.
Date Issued
April 2016
Journal
Nature Chemical Biology
Publisher
Nature Publishing Group
Citation
Pacold, Michael E, Kyle R Brimacombe, Sze Ham Chan, Jason M Rohde, Caroline A Lewis, Lotteke J Y M Swier, Richard Possemato, et al. “A PHGDH Inhibitor Reveals Coordination of Serine Synthesis and One-Carbon Unit Fate.” Nature Chemical Biology 12, no. 6 (April 25, 2016): 452–458. doi:10.1038/nchembio.2070.
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Author's final manuscript
Abstract
Serine is a both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical glucose-derived serine synthesis pathway, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, ratelimiting
step. Genetic loss of PHGDH is toxic towards PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we use 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 suggest that one-carbon unit wasting may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1038/nchembio.2070
