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; Peng Lei; Huiyuan Zhang; Shiqian Qi; Heng Xu; Hongbo Hu; Biao Dong; Yong Peng; Dan Su; Lunzhi Dai

doi:10.1016/j.isci.2022.104349

Glycyrrhetinic acid restricts mitochondrial energy metabolism by targeting SHMT2

iScience. 2022 May 4;25(5):104349. doi: 10.1016/j.isci.2022.104349. eCollection 2022 May 20.

Authors

Xiuxiu Jin^{1

2}, Li Li¹, Qinlu Peng¹, Chunmei Gan¹, Li Gao¹, Siyu He¹, Shuangyan Tan¹, Wenchen Pu¹, Yu Liu¹, Yanqiu Gong¹, Yuqin Yao³, Gang Wang⁴, Xiaohui Liu⁵, Meng Gong⁶, Peng Lei¹, Huiyuan Zhang¹, Shiqian Qi¹, Heng Xu¹, Hongbo Hu¹, Biao Dong¹, Yong Peng¹, Dan Su¹, Lunzhi Dai¹

Affiliations

¹ National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
² Henan Provincial People's Hospital, Henan Eye Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China.
³ West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China.
⁴ School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563003, China.
⁵ School of Life Sciences, Tsinghua University, Beijing 100084, China.
⁶ Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 88 Keyuan South Road, Hi-Tech Zone, Chengdu 610041, China.

Abstract

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 in vitro and in vivo. 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.

Keywords: Biochemistry; Natural product biochemistry; Omics; Proteomics.