iScience (May 2022)
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
Affiliations
- Xiuxiu Jin
- 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
- Li Li
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Qinlu Peng
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Chunmei Gan
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Li Gao
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Siyu He
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Shuangyan Tan
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Wenchen Pu
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Yu Liu
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Yanqiu Gong
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Yuqin Yao
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
- Gang Wang
- School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563003, China
- Xiaohui Liu
- School of Life Sciences, Tsinghua University, Beijing 100084, China
- Meng Gong
- 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
- Peng Lei
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Huiyuan Zhang
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Shiqian Qi
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Heng Xu
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Hongbo Hu
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Biao Dong
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Yong Peng
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Corresponding author
- Dan Su
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Corresponding author
- Lunzhi Dai
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Corresponding author
- Journal volume & issue
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Vol. 25,
no. 5
p. 104349
Abstract
Summary: 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.
