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
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Nat Chem Biol. 2016 Jun;12(6):452-8. doi: 10.1038/nchembio.2070. Epub 2016 Apr 25.
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.
丝氨酸既是一种蛋白质氨基酸，也是从头合成嘌呤和脱氧胸苷所必需的一碳单位的来源。在葡萄糖衍生的丝氨酸合成的经典途径中，人类磷酸甘油酸脱氢酶（PHGDH）催化第一步限速反应。即使存在外源性丝氨酸，PHGDH的基因缺失对过表达PHGDH的乳腺癌细胞系也具有毒性。在这里，我们使用定量高通量筛选来鉴定小分子PHGDH抑制剂。这些化合物减少了细胞中葡萄糖衍生的丝氨酸的产生，并抑制了培养物中和原位异种移植肿瘤中依赖PHGDH的癌细胞的生长。令人惊讶的是，PHGDH抑制减少了葡萄糖衍生的和外源性丝氨酸的一碳单位掺入核苷酸的量。我们得出结论，糖酵解丝氨酸合成协调了内源性和外源性丝氨酸的一碳单位在核苷酸合成中的使用，并且我们认为一碳单位的浪费可能因此有助于PHGDH抑制剂在体外和体内的疗效。
