| Autor: |
Ganesha Rai, Yoav D. Shaul, Kyle R. Brimacombe, Monther-Remaileh Abu, David M. Sabatini, Matthew B. Boxer, Li Liu, Haeyoon Chung, Adam Yasgar, Sze Ham Chan, Minerva Zhou, Jason M. Rohde, Brian P. Fiske, Matthew G. Vander Heiden, Kıvanç Birsoy, Lucas B. Sullivan, Steve Cho, Min Jung Koh, Caroline A. Lewis, Nathanael S. Gray, Xin Xu, Michael E. Pacold, Lotteke J Y M Swier, Chieh Min Liu, Walter W. Chen, Shawn M. Davidson, Alba Luengo, Richard Possemato, Kenneth D. Westover, Elizaveta Freinkman, Amy Wang, Min Shen |
| Rok vydání: |
2016 |
| Předmět: |
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| Zdroj: |
Nature chemical biology |
| ISSN: |
1552-4469 |
| Popis: |
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, rate-limiting 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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