PXD031021-1

PXD031021 is an original dataset announced via ProteomeXchange.

Title	Glycyrrhetinic acid restricts mitochondrial energy metabolism through targeting SHMT2
Description	Mitochondria are cell’s powerhouses to provide energy and essential metabolic intermediates to ensure cellular functions, and its dysregulation plays an important role during tumorigenesis. Targeting mitochondria is a promising approach for cancer therapy. Glycyrrhetinic acid (GA) is a natural product with mitochondria-targeting property and shows broad anti-cancer activities, but its targets and underlying mechanisms remain elusive. Here we identify the mitochondrial enzyme serine hydroxymethyltransferase 2 (SHMT2) as a target of GA by using chemical proteomics. Binding to and inhibiting the catalytic activity of SHMT2 by GA are systematically validated in vitro and in vivo. Knockout of SHMT2 or inhibiting SHMT2 with GA restricts mitochondrial energy supplies through down-regulating mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid β-oxidation, and consequently suppresses cancer cell proliferation and tumor growth in xenograft mice. Crystal structures of GA derivatives indicate that GA can sit into folate-binding pocket of SHMT2 and regulate SHMT2 activity. Besides, chemical modifications at the carboxylic group of GA with diamines allows to significantly improve its anti-cancer potency, demonstrating GA as a decent structural template for SHMT2 inhibitor development. Collectively, these findings reveal the precise mechanism of action of GA that could be a promising drug lead for targeted therapies of certain cancers.
HostingRepository	iProX
AnnounceDate	2022-01-16
AnnouncementXML	Submission_2022-01-17_00:52:04.967.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Xiuxiu Jin
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2022-01-17 00:51:51	ID requested
⏵ 1	2022-01-17 00:52:05	announced

Dataset with its publication pending

submitter keyword: glycyrrhetinic acid, serine hydroxymethyltransferase 2, anti-cancer, mitochondrial oxidative phosphorylation, fatty acid β-oxidation

Lunzhi Dai
contact affiliation	National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
contact email	lunzhi.dai@scu.edu.cn
lab head
Xiuxiu Jin
contact affiliation	National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
contact email	jindaxiu@163.com
dataset submitter

iProX dataset URI