Glycyrrhetinic acid restricts mitochondrial energy metabolism by targeting SHMT2
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, Lei Peng, Huiyuan Zhang, Shiqian Qi, Heng Xu, Hongbo Hu, Biao Dong, Yong Peng, Dan Su, Lunzhi Dai
Abstract
. 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.