A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate.
A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate.
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DOI：
10.1038/nchembio.2070
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发表时间：
2016-06
影响因子：
14.8
通讯作者：
Sabatini DM
中科院分区：
文献类型：
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作者：
Pacold ME;Brimacombe KR;Chan SH;Rohde JM;Lewis CA;Swier LJ;Possemato R;Chen WW;Sullivan LB;Fiske BP;Cho S;Freinkman E;Birsoy K;Abu-Remaileh M;Shaul YD;Liu CM;Zhou M;Koh MJ;Chung H;Davidson SM;Luengo A;Wang AQ;Xu X;Yasgar A;Liu L;Rai G;Westover KD;Vander Heiden MG;Shen M;Gray NS;Boxer MB;Sabatini DM
丝氨酸是一种蛋白质原氨基酸，也是从头合成嘌呤和脱氧胸腺嘧啶所必需的一碳单位的来源。在典型的葡萄糖衍生丝氨酸合成途径中，智人磷酸甘油脱氢酶（PHGDH）催化了第一个限速步骤。即使在外源性丝氨酸存在的情况下，PHGDH基因缺失对PHGDH过表达的乳腺癌细胞系也是有毒的。在这里，我们使用定量高通量筛选来鉴定小分子PHGDH抑制剂。这些化合物减少细胞中葡萄糖衍生丝氨酸的产生，并抑制培养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，抑制PHGDH减少了葡萄糖来源和外源丝氨酸的单碳单位核苷酸的掺入。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在核苷酸合成中的单碳单位的使用，并表明单碳单位的浪费可能有助于PHGDH抑制剂在体外和体内的疗效。
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.