Details

Autor(en) / Beteiligte

• 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, Kıvanç
• 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

Titel

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

Ist Teil von

• Nature chemical biology, 2016-06, Vol.12 (6), p.452-458

Ort / Verlag

United States

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.