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 (US) |
|---|---|
| Pages (from-to) | 452-458 |
| Number of pages | 7 |
| Journal | Nature Chemical Biology |
| Volume | 12 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 1 2016 |
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ASJC Scopus subject areas
- Cell Biology
- Molecular Biology
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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 journal › Article
}
TY - JOUR
T1 - A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate
AU - Pacold, Michael E.
AU - Brimacombe, Kyle R.
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
AU - Zhou, Minerva
AU - Koh, Min Jung
AU - Chung, Haeyoon
AU - Davidson, Shawn M.
AU - Luengo, Alba
AU - Wang, Amy Q.
AU - Xu, Xin
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.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84964216448&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84964216448&partnerID=8YFLogxK
U2 - 10.1038/nchembio.2070
DO - 10.1038/nchembio.2070
M3 - Article
C2 - 27110680
AN - SCOPUS:84964216448
VL - 12
SP - 452
EP - 458
JO - Nature Chemical Biology
JF - Nature Chemical Biology
SN - 1552-4450
IS - 6
ER -