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

Michael E. Pacold, Kyle R. Brimacombe, Sze Ham Chan, Jason M. Rohde, Caroline A. Lewis, Lotteke J Y M Swier, Richard Possemato, Walter W. Chen, Lucas B. Sullivan, Brian P. Fiske, Steve Cho, Elizaveta Freinkman, Klvanç Birsoy, Monther Abu-Remaileh, Yoav D. Shaul, Chieh Min Liu, Minerva Zhou, Min Jung Koh, Haeyoon Chung, Shawn M. DavidsonAlba Luengo, Amy Q. Wang, Xin Xu, Adam Yasgar, Li Liu, Ganesha Rai, Kenneth D. Westover, Matthew G. Vander Heiden, Min Shen, Nathanael S. Gray, Matthew B. Boxer, David M. Sabatini

Research output: Contribution to journalArticle

104 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)452-458
Number of pages7
JournalNature Chemical Biology
Volume12
Issue number6
DOIs
StatePublished - Jun 1 2016

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Phosphoglycerate Dehydrogenase
Serine
Carbon
Glucose
Nucleotides
Poisons
Heterografts
Thymidine
Neoplasms
Cell Culture Techniques
Breast Neoplasms
Amino Acids
Cell Line

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Pacold, M. E., Brimacombe, K. R., Chan, S. H., Rohde, J. M., Lewis, C. A., Swier, L. J. Y. M., ... Sabatini, D. M. (2016). A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nature Chemical Biology, 12(6), 452-458. https://doi.org/10.1038/nchembio.2070

A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. / Pacold, Michael E.; Brimacombe, Kyle R.; Chan, Sze Ham; Rohde, Jason M.; Lewis, Caroline A.; Swier, Lotteke J Y M; Possemato, Richard; Chen, Walter W.; Sullivan, Lucas B.; Fiske, Brian P.; Cho, Steve; Freinkman, Elizaveta; Birsoy, Klvanç; Abu-Remaileh, Monther; Shaul, Yoav D.; Liu, Chieh Min; Zhou, Minerva; Koh, Min Jung; Chung, Haeyoon; Davidson, Shawn M.; Luengo, Alba; Wang, Amy Q.; Xu, Xin; Yasgar, Adam; Liu, Li; Rai, Ganesha; Westover, Kenneth D.; Vander Heiden, Matthew G.; Shen, Min; Gray, Nathanael S.; Boxer, Matthew B.; Sabatini, David M.

In: Nature Chemical Biology, Vol. 12, No. 6, 01.06.2016, p. 452-458.

Research output: Contribution to journalArticle

Pacold, ME, Brimacombe, KR, Chan, SH, Rohde, JM, Lewis, CA, Swier, LJYM, Possemato, R, Chen, WW, Sullivan, LB, Fiske, BP, Cho, S, Freinkman, E, Birsoy, K, Abu-Remaileh, M, Shaul, YD, Liu, CM, Zhou, M, Koh, MJ, Chung, H, Davidson, SM, Luengo, A, Wang, AQ, Xu, X, Yasgar, A, Liu, L, Rai, G, Westover, KD, Vander Heiden, MG, Shen, M, Gray, NS, Boxer, MB & Sabatini, DM 2016, 'A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate', Nature Chemical Biology, vol. 12, no. 6, pp. 452-458. https://doi.org/10.1038/nchembio.2070
Pacold ME, Brimacombe KR, Chan SH, Rohde JM, Lewis CA, Swier LJYM et al. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nature Chemical Biology. 2016 Jun 1;12(6):452-458. https://doi.org/10.1038/nchembio.2070
Pacold, Michael E. ; Brimacombe, Kyle R. ; Chan, Sze Ham ; Rohde, Jason M. ; Lewis, Caroline A. ; Swier, Lotteke J Y M ; Possemato, Richard ; Chen, Walter W. ; Sullivan, Lucas B. ; Fiske, Brian P. ; Cho, Steve ; Freinkman, Elizaveta ; Birsoy, Klvanç ; Abu-Remaileh, Monther ; Shaul, Yoav D. ; Liu, Chieh Min ; Zhou, Minerva ; Koh, Min Jung ; Chung, Haeyoon ; Davidson, Shawn M. ; Luengo, Alba ; Wang, Amy Q. ; Xu, Xin ; Yasgar, Adam ; Liu, Li ; Rai, Ganesha ; Westover, Kenneth D. ; Vander Heiden, Matthew G. ; Shen, Min ; Gray, Nathanael S. ; Boxer, Matthew B. ; Sabatini, David M. / A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. In: Nature Chemical Biology. 2016 ; Vol. 12, No. 6. pp. 452-458.
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