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. Davidson; Alba 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

doi:10.1038/nchembio.2070

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

Department of Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

366 Scopus citations

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 language	English
Pages (from-to)	452-458
Number of pages	7
Journal	Nature Chemical Biology
Volume	12
Issue number	6
DOIs	https://doi.org/10.1038/nchembio.2070
State	Published - 1 Jun 2016

Bibliographical note

Funding Information:
The Sally Gordon Fellowship of the Damon Runyon Cancer Research Foundation (DRG-112-12), a Department of Defense Breast Cancer Research Program Postdoctoral Fellowship (BC120208), and an ASTRO Resident Seed Grant (RA-2011-1) (all to M.E.P.)., by Susan G. Komen for the Cure (grant to R.L.P.), by an EMBO Long-Term Fellowship (to M.A.-R.), by the NIH (1 R03 DA034602-01A1 to D.M.S.) and by the Stewart Trust (to D.M.S.). D.M.S. is an investigator of the Howard Hughes Medical Institute.

Publisher Copyright:
© 2016 Nature America, Inc.

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Pacold, M. E., Brimacombe, K. R., Chan, S. H., Rohde, J. M., Lewis, C. A., Swier, L. J. Y. M., Possemato, R., Chen, W. W., Sullivan, L. B., Fiske, B. P., Cho, S., Freinkman, E., Birsoy, K., Abu-Remaileh, M., Shaul, Y. D., Liu, C. M., Zhou, M., Koh, M. J., Chung, H., ... 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

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title = "A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2016 Nature America, Inc.",

year = "2016",

month = jun,

day = "1",

doi = "10.1038/nchembio.2070",

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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

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AU - Pacold, Michael E.

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AU - Chan, Sze Ham

AU - Rohde, Jason M.

AU - Lewis, Caroline A.

AU - Swier, Lotteke J.Y.M.

AU - Possemato, Richard

AU - Chen, Walter W.

AU - Sullivan, Lucas B.

AU - Fiske, Brian P.

AU - Cho, Steve

AU - Freinkman, Elizaveta

AU - Birsoy, Klvanç

AU - Abu-Remaileh, Monther

AU - Shaul, Yoav D.

AU - Liu, Chieh Min

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AU - Koh, Min Jung

AU - Chung, Haeyoon

AU - Davidson, Shawn M.

AU - Luengo, Alba

AU - Wang, Amy Q.

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AU - Yasgar, Adam

AU - Liu, Li

AU - Rai, Ganesha

AU - Westover, Kenneth D.

AU - Vander Heiden, Matthew G.

AU - Shen, Min

AU - Gray, Nathanael S.

AU - Boxer, Matthew B.

AU - Sabatini, David M.

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

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