Department of Chemistry, Princeton University, Princeton NJ 08544.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton NJ 08544.
Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11404-11409. doi: 10.1073/pnas.1706617114. Epub 2017 Oct 9.
The enzyme serine hydroxymethyltransferse (SHMT) converts serine into glycine and a tetrahydrofolate-bound one-carbon unit. Folate one-carbon units support purine and thymidine synthesis, and thus cell growth. Mammals have both cytosolic SHMT1 and mitochondrial SHMT2, with the mitochondrial isozyme strongly up-regulated in cancer. Here we show genetically that dual SHMT1/2 knockout blocks HCT-116 colon cancer tumor xenograft formation. Building from a pyrazolopyran scaffold that inhibits plant SHMT, we identify small-molecule dual inhibitors of human SHMT1/2 (biochemical IC ∼ 10 nM). Metabolomics and isotope tracer studies demonstrate effective cellular target engagement. A cancer cell-line screen revealed that B-cell lines are particularly sensitive to SHMT inhibition. The one-carbon donor formate generally rescues cells from SHMT inhibition, but paradoxically increases the inhibitor's cytotoxicity in diffuse large B-cell lymphoma (DLBCL). We show that this effect is rooted in defective glycine uptake in DLBCL cell lines, rendering them uniquely dependent upon SHMT enzymatic activity to meet glycine demand. Thus, defective glycine import is a targetable metabolic deficiency of DLBCL.
酶丝氨酸羟甲基转移酶（SHMT）将丝氨酸转化为甘氨酸和四氢叶酸结合的一碳单位。叶酸一碳单位支持嘌呤和胸苷的合成，从而支持细胞生长。哺乳动物既有细胞质 SHMT1 又有线粒体 SHMT2，线粒体同工酶在癌症中强烈上调。在这里，我们通过遗传方法表明，双重 SHMT1/2 敲除会阻止 HCT-116 结肠癌细胞异种移植物的形成。我们以抑制植物 SHMT 的吡唑并吡喃骨架为基础，鉴定出对人 SHMT1/2 的小分子双重抑制剂（生化 IC∼10 nM）。代谢组学和同位素示踪研究表明有效靶向细胞。癌细胞系筛选显示 B 细胞系对 SHMT 抑制特别敏感。一碳供体甲酸盐通常可使细胞免受 SHMT 抑制，但矛盾的是，在弥漫性大 B 细胞淋巴瘤（DLBCL）中增加了抑制剂的细胞毒性。我们表明，这种效应源于 DLBCL 细胞系中甘氨酸摄取的缺陷，使它们独特地依赖 SHMT 酶活性来满足甘氨酸的需求。因此，甘氨酸摄取缺陷是 DLBCL 的一种可靶向代谢缺陷。
