Glycyrrhetinic acid restricts mitochondrial energy metabolism by targeting SHMT2

• DOI: 10.1016/j.isci.2022.104349
• Publication Date: 2022-05-04T12:42:48Z
• Authors: Xiuxiu Jin; Li Li; Qinlu Peng; Chunmei Gan; Li Gao; Siyu He; Shuangyan Tan; Wenchen Pu; Yu Liu; Yanqiu Gong; Yuqin Yao; Gang Wang; Xiaohui Liu; Meng Gong; Peng Lei; Huiyuan Zhang; Shiqian Qi; Heng Xu; Hongbo Hu; Biao Dong; Yong Peng; Dan Su; Lunzhi Dai
• Keywords: Serine hydroxymethyltransferase; Natural product

Glycyrrhetinic acid (GA) is a natural product of licorice with mitochondria targeting properties and shows broad anticancer activities, but its targets underlying mechanisms remain elusive. Here, we identified the mitochondrial enzyme serine hydroxymethyltransferase 2 (SHMT2) as target GA by using chemical proteomics. Binding to inhibiting activity SHMT2 were validated in vitro vivo. Knockout or restricts energy supplies downregulating oxidative phosphorylation (OXPHOS) fatty β-oxidation, consequently suppresses cancer cell proliferation tumor growth. Crystal structures derivatives indicate that occupies folate-binding pocket regulates activity. Modifications at carboxylic group diamines significantly improved potency, demonstrating decent structural template for inhibitor development.