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

Autor: Yuanyuan Zhang, Yiluan Ding, Wen Li, C.Q. Liu, Hong-Bo Wang, Kaixian Chen, Jie Zheng, X. H. Zhou, Cheng Luo, Naixia Zhang, Hualiang Jiang, Liping Liao, Zhong-Ya Sun, Yanjun Liu, Jing Lu, Kehao Zhao, Ning Song, Senhao Xiao
Rok vydání: 2021
Předmět:
Male
0301 basic medicine
Magnetic Resonance Spectroscopy
Drug Evaluation
Preclinical
Hydrogen Deuterium Exchange-Mass Spectrometry
Dehydrogenase
Real-Time Polymerase Chain Reaction
Article
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
stomatognathic system
Glyceraldehyde
Organometallic Compounds
Animals
Humans
Pharmacology (medical)
Glycolysis
Lactic Acid
Glyceraldehyde 3-phosphate dehydrogenase
Pharmacology
chemistry.chemical_classification
biology
Glyceraldehyde-3-Phosphate Dehydrogenases
General Medicine
Hydrolyzable Tannins
Mice
Inbred C57BL
Glucose
030104 developmental biology
Enzyme
Biochemistry
chemistry
Anaerobic glycolysis
030220 oncology & carcinogenesis
biology.protein
NAD+ kinase
Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
Cysteine
Zdroj: Acta Pharmacol Sin
ISSN: 1745-7254
1671-4083
Popis: 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-β-D-glucopyranose (PGG) is an inhibitor of GAPDH with K(i) = 0.5 μM. 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.
Databáze: OpenAIRE
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