A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate
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.; Koh, Min Jung; Chung, Haeyoon; Davidson, Shawn M; Luengo, Alba; Vander Heiden, Matthew G.; Sabatini, David; Pacold, Michael Edward; ... Show more Show less
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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.
Date issued
2016-04Department
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 MITJournal
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.
Version: Author's final manuscript
ISSN
1552-4450
1552-4469