A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate.
Authors | |
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. |
Year of Publication | 2016
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Journal | Nat Chem Biol
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Volume | 12
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Issue | 6
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Pages | 452-8
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Date Published | 2016 Jun
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ISSN | 1552-4469
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URL | |
DOI | 10.1038/nchembio.2070
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PubMed ID | 27110680
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PubMed Central ID | PMC4871733
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Links | |
Grant list | R01 CA103866 / CA / NCI NIH HHS / United States
K22 CA193660 / CA / NCI NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States
R21 CA198028 / CA / NCI NIH HHS / United States
R01 CA168653 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
R37 AI047389 / AI / NIAID NIH HHS / United States
Howard Hughes Medical Institute / United States
R03 DA034602 / DA / NIDA NIH HHS / United States
R01 CA129105 / CA / NCI NIH HHS / United States
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