A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate
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 lo...
| Үндсэн зохиолчид: | , , , , , , , , , , , , , , , , |
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| Бусад зохиолчид: | |
| Формат: | Өгүүллэг |
| Хэл сонгох: | en_US |
| Хэвлэсэн: |
Nature Publishing Group
2017
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| Онлайн хандалт: | http://hdl.handle.net/1721.1/107883 https://orcid.org/0000-0003-3688-2378 https://orcid.org/0000-0002-6883-3805 https://orcid.org/0000-0002-7043-5013 https://orcid.org/0000-0002-6745-8222 https://orcid.org/0000-0002-4236-0229 https://orcid.org/0000-0002-6702-4192 https://orcid.org/0000-0002-1446-7256 |
| Тойм: | 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. |
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