Natural product 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose is a reversible inhibitor of glyceraldehyde 3-phosphate dehydrogenase

doi:10.1038/s41401-021-00653-0

	Natural product 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose is a reversible inhibitor of glyceraldehyde 3-phosphate dehydrogenase
	Li, Wen 1; Liao, Li-ping 2,3; Song, Ning 3,4; Liu, Yan-jun 2,5; Ding, Yi-luan 6; Zhang, Yuan-yuan 2; Zhou, Xiao-ru 2,3,7; Sun, Zhong-ya 2,8; Xiao, Sen-hao 2,3,7; Wang, Hong-bo 1
刊名	ACTA PHARMACOLOGICA SINICA
	2021-04-13
页码	13
关键词	glyceraldehyde 3-phosphate dehydrogenase 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose hydrogen deuterium exchange mass spectrometry reversible inhibitor glycolysis
ISSN号	1671-4083
DOI	10.1038/s41401-021-00653-0
通讯作者	Zheng, Jie(jzheng@simm.ac.cn) ; Zhao, Ke-hao(kehaozhao@gmail.com) ; Luo, Cheng(cluo@simm.ac.cn)
英文摘要	Aerobic glycolysis, also known as the Warburg effect, is a hallmark of cancer cell glucose metabolism and plays a crucial role in the activation of various types of immune cells. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) catalyzes the conversion of D-glyceraldehyde 3-phosphate to D-glycerate 1,3-bisphosphate in the 6th critical step in glycolysis. GAPDH exerts metabolic flux control during aerobic glycolysis and therefore is an attractive therapeutic target for cancer and autoimmune diseases. Recently, GAPDH inhibitors were reported to function through common suicide inactivation by covalent binding to the cysteine catalytic residue of GAPDH. Herein, by developing a high-throughput enzymatic screening assay, we discovered that the natural product 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose (PGG) is an inhibitor of GAPDH with K-i = 0.5 mu M. PGG blocks GAPDH activity by a reversible and NAD(+) and Pi competitive mechanism, suggesting that it represents a novel class of GAPDH inhibitors. In-depth hydrogen deuterium exchange mass spectrometry (HDX-MS) analysis revealed that PGG binds to a region that disrupts NAD(+) and inorganic phosphate binding, resulting in a distal conformational change at the GAPDH tetramer interface. In addition, structural modeling analysis indicated that PGG probably reversibly binds to the center pocket of GAPDH. Moreover, PGG inhibits LPS-stimulated macrophage activation by specific downregulation of GAPDH-dependent glucose consumption and lactate production. In summary, PGG represents a novel class of GAPDH inhibitors that probably reversibly binds to the center pocket of GAPDH. Our study sheds new light on factors for designing a more potent and specific inhibitor of GAPDH for future therapeutic applications.
资助项目	National Natural Science Foundation of China[81728020] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[21820102008] ; K. C. Wong Education ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Chinese Academy of Sciences[CASIMM0120184015] ; Top Talents Program for One Case Discussion of Shandong Province
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000639768200002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/296656]
专题	中国科学院上海药物研究所
通讯作者	Zheng, Jie; Zhao, Ke-hao; Luo, Cheng
作者单位	1.Yantai Univ, Collaborat Innovat Ctr Adv Drug Delivery Syst & B, Key Lab Mol Pharmacol & Drug Evaluat, Sch Pharm,Minist Educ, Yantai 264005, Peoples R China 2.Chinese Acad Sci, State Key Lab Drug Res, Drug Discovery & Design Ctr, Ctr Chem Biol,Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Immunol Dis, Shanghai 201203, Peoples R China 5.Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Gastroenterol, Shanghai 201210, Peoples R China 6.Chinese Acad Sci, Dept Analyt Chem, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 7.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 8.Harbin Inst Technol, Sch Life Sci & Technol, Harbin 200092, Peoples R China 9.Fujian Med Univ, Coll Pharm, Dept Pharmacol, Fuzhou 350108, Peoples R China
推荐引用方式 GB/T 7714	Li, Wen,Liao, Li-ping,Song, Ning,et al. Natural product 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose is a reversible inhibitor of glyceraldehyde 3-phosphate dehydrogenase[J]. ACTA PHARMACOLOGICA SINICA,2021:13.
APA	Li, Wen.,Liao, Li-ping.,Song, Ning.,Liu, Yan-jun.,Ding, Yi-luan.,...&Luo, Cheng.(2021).Natural product 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose is a reversible inhibitor of glyceraldehyde 3-phosphate dehydrogenase.ACTA PHARMACOLOGICA SINICA,13.
MLA	Li, Wen,et al."Natural product 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose is a reversible inhibitor of glyceraldehyde 3-phosphate dehydrogenase".ACTA PHARMACOLOGICA SINICA (2021):13.