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

ME Pacold, KR Brimacombe, SH Chan… - Nature chemical …, 2016 - nature.com
ME Pacold, KR Brimacombe, SH Chan, JM Rohde, CA Lewis, LJYM Swier, R Possemato
Nature chemical biology, 2016nature.com
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 …
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.
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