Jin Xiuxiu, Li Li, Peng Qinlu, Gan Chunmei, Gao Li, He Siyu, Tan Shuangyan, Pu Wenchen, Liu Yu, Gong Yanqiu, Yao Yuqin, Wang Gang, Liu Xiaohui, Gong Meng, Lei Peng, Zhang Huiyuan, Qi Shiqian, Xu Heng, Hu Hongbo, Dong Biao, Peng Yong, Su Dan, Dai Lunzhi
National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Henan Provincial People's Hospital, Henan Eye Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China.
iScience. 2022 May 4;25(5):104349. doi: 10.1016/j.isci.2022.104349. eCollection 2022 May 20.
Glycyrrhetinic acid (GA) is a natural product of licorice with mitochondria targeting properties and shows broad anticancer activities, but its targets and underlying mechanisms remain elusive. Here, we identified the mitochondrial enzyme serine hydroxymethyltransferase 2 (SHMT2) as a target of GA by using chemical proteomics. Binding to and inhibiting the activity of SHMT2 by GA were validated and . Knockout of SHMT2 or inhibiting SHMT2 with GA restricts mitochondrial energy supplies by downregulating mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid β-oxidation, and consequently suppresses cancer cell proliferation and tumor growth. Crystal structures of GA derivatives indicate that GA occupies SHMT2 folate-binding pocket and regulates SHMT2 activity. Modifications at GA carboxylic group with diamines significantly improved its anticancer potency, demonstrating GA as a decent structural template for SHMT2 inhibitor development.
甘草次酸（GA）是甘草的一种天然产物，具有靶向线粒体的特性，并显示出广泛的抗癌活性，但其靶点和潜在机制仍不清楚。在这里，我们通过化学蛋白质组学鉴定出线粒体酶丝氨酸羟甲基转移酶2（SHMT2）是GA的一个靶点。GA与SHMT2的结合及其对SHMT2活性的抑制作用均得到了验证。敲除SHMT2或用GA抑制SHMT2可通过下调线粒体氧化磷酸化（OXPHOS）和脂肪酸β氧化来限制线粒体能量供应，从而抑制癌细胞增殖和肿瘤生长。GA衍生物的晶体结构表明，GA占据SHMT2的叶酸结合口袋并调节SHMT2活性。用二胺对GA羧基进行修饰显著提高了其抗癌效力，证明GA是开发SHMT2抑制剂的一个合适的结构模板。
