Journal Article

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

Liu, Li, Shaul, Yoav D, Brimacombe, Kyle R, Gray, Nathanael S, Xu, Xin, Possemato, Richard, Yasgar, Adam, Shen, Min, Sabatini, David M, Chen, Walter W, Rai, Ganesha, Davidson, Shawn M, Fiske, Brian P, Birsoy, Kıvanç, Pacold, Michael E, Abu-Remaileh, Monther, Westover, Kenneth D, Lewis, Caroline A, Sullivan, Lucas B, Chan, Sze Ham, Wang, Amy Q, Cho, Steve, Boxer, Matthew B, Koh, Min Jung, Zhou, Minerva, Vander Heiden, Matthew G, Luengo, Alba, Rohde, Jason M, Swier, Lotteke J Y M, Liu, Chieh Min, Freinkman, Elizaveta, Chung, Haeyoon

2016

Overview

A quantitative high-throughput screen identified an inhibitor of phosphoglycerate dehydrogenase (PHGDH), a key enzyme for serine synthesis. This inhibitor limits one-carbon unit availability for nucleotide synthesis. 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 .

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/443/319 / 631/67/1059 / 631/92/507 / 631/92/613 / 64/60 / Amino acids / Animals / Biochemical Engineering / Biochemistry / Bioorganic Chemistry / Biosynthesis / Cancer therapies / Carbon / Carbon - chemistry / Carbon - metabolism / Cell Biology / Cell Proliferation - drug effects / Chemistry / Chemistry/Food Science / Dehydrogenase / Dose-Response Relationship, Drug / Enzyme Inhibitors - chemistry / Enzyme Inhibitors - pharmacology / Enzymes / Female / Glucose / Glycolysis - drug effects / Humans / Inhibitors / Mammary Neoplasms, Experimental - drug therapy / Mammary Neoplasms, Experimental - enzymology / Mammary Neoplasms, Experimental - metabolism / Mammary Neoplasms, Experimental - pathology / Metabolism / Mice / Molecular Structure / Phosphoglycerate Dehydrogenase - antagonists & inhibitors / Phosphoglycerate Dehydrogenase - metabolism / Purines - biosynthesis / Serine - biosynthesis / Serine - chemistry / Small Molecule Libraries - chemistry / Small Molecule Libraries - pharmacology / Structure-Activity Relationship / Thymidine - biosynthesis / Tumor Cells, Cultured / Xenograft Model Antitumor Assays